Clinical trial NCT03476239
Conditions: Acute Lymphoblastic Leukemia
Keywords: Relapsed Refractory B-precursor Acute Lymphoblastic Leukemia ALL Blinatumomab Chinese Adult Subjects
Sponsor: Amgen
Start date: 2017-10-18; Completion date: 2021-04-08
Enrollment: 121 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to evaluate the rate of hematological response (complete remission/complete remission with partial hematological recovery \[CR/CRh\*\]) induced by blinatumomab in Chinese adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

Detailed description:
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adults with relapsed/refractory B-precursor ALL. The study will consist of a screening period, a treatment period, and a follow-up period.

Treatment will consist of up to 5 cycles of blinatumomab. Participants who achieve a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh\*/CRi within 2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of blinatumomab. Thirty days after end of the last dose of protocol-specified therapy, participants will have a safety follow-up visit.

If subjects are suitable for allogeneic stem cell transplantation (alloHSCT) after treatment with blinatumomab, they may undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.

Participants will be followed via clinic visit or telephone contact every 3 months after their safety follow-up visit until death has been observed or a maximum of 2 years after start of treatment, whichever occurs first.

A planned interim analysis to assess efficacy and safety of blinatumomab was to be based on the interim analysis set (N = 90). The efficacious benefit assessment based on an O'Brien-Fleming alpha spending function (O'Brien and Fleming, 1979) with the critical boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh\* rate. If the interim analysis showed statistically efficacious and overall benefit-risk analysis to be promising per the data review team review, then the interim analysis could become the primary analysis of this study. In addition, the study would continue its enrollment until 120 participants had been enrolled and continued their participation in the study to complete protocol-specified procedures.

The data cutoff date of 12 April 2019 allowed for the 90th participant enrolled before 21 February 2019 to have had the opportunity to complete 2 cycles of treatment and the safety follow-up visit (if the participant had discontinued treatment after 2 cycles).

Arms: arm 1: Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders.

In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for Days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4). This is followed by two weeks without blinatumomab treatment.

In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
Interventions: intervention 1: Blinatumomab intervention 2: Dexamthasone
Intervention descriptions: intervention 1: Blinatumomab will be supplied as single-use glass injection vials as a sterile, preservative-free, white to off-white, lyophilized powder for reconstitution and administration by continuous intravenous infusion (CIVI).

A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab CIVI followed by a 2 week treatment-free interval. The treatment-free interval may be prolonged by up to 7 days, if deemed necessary by the investigator. intervention 2: Premedication with dexamethasone was intended to prevent cytokine release syndrome (CRS) events associated with blinatumomab treatment. Treatment could start pre-study. Dexamethasone 20 mg IV was administered within 3 hours before start of blinatumomab in each treatment cycle, and within 3 hours before dose step increase.

Protocol documents:
Prot_002.pdf: 
Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
Page 1 of 105 
CONFIDENTIAL 
 
 
Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety 
of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
Blinatumomab 
Amgen Protocol Number (Blinatumomab) 20130316 
 
Clinical Study Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
Key Sponsor Contact(s): 
, MD 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone:  
 
Email:  
 
NCT Number 
NCT03476239 
Date: 
29 July 2015 
Amendment 1 
07 December 2016 
Amendment 2 
20 February 2018 
Amendment 3 
22 August 2018 
Amendment 4 
30 November 2018 
Amendment 5 
27 August 2019 
Amendment 6 
09 March 2020 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; 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) 447-5000].  For all other study-related questions, continue to contact the Key 
Sponsor Contact.  
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
Page 2 of 105 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “An Open-label, Multicenter, Phase 3 Study to 
Evaluate Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult 
Subjects With Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL)”, 
dated 09 March 2020, 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 subinvestigators (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:  20130316 
Date:  09 March 2020 
Page 3 of 105 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  An open-label, multicenter, phase 3 study to evaluate efficacy and safety of the BiTE 
antibody blinatumomab in Chinese adult subjects with relapsed/refractory B-precursor acute 
lymphoblastic leukemia (ALL) 
Study Phase:  3 
Indication:  Relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia 
Primary Objective:  
 
To evaluate the rate of hematological response (complete remission/complete remission with 
partial hematological recovery [CR/CRh*]) induced by blinatumomab in Chinese adult 
subjects with relapsed/refractory B-precursor ALL. 
Secondary Objectives: 
 
To evaluate pharmacokinetics (PK) of blinatumomab 
 
To evaluate the effect of blinatumomab on overall survival (OS)  
 
To evaluate the relapse-free survival (RFS) induced by blinatumomab  
 
To evaluate minimal residual disease (MRD) response induced by blinatumomab 
 
To evaluate the incidence of allogeneic hematopoietic stem cell transplantation (alloHSCT) 
and 100-day mortality following HSCT in blinatumomab treated subjects 
 
To estimate the effect of blinatumomab on patient reported outcomes of global health 
status/quality of life (QoL) using the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). 
Safety Objective: 
 
To evaluate the safety of blinatumomab in Chinese subjects with relapsed/refractory 
B-precursor ALL 
Exploratory Objectives: 
 
To evaluate central nervous system (CNS) symptoms and explore potential predictive factors 
for CNS events associated with blinatumomab 
Hypotheses:  The clinical hypothesis is that blinatumomab will have clinically meaningful 
anti-tumor activity better than 30% as measured by CR/CRh* rate within 2 cycles in Chinese adult 
subjects with relapsed/refractory B-precursor ALL.  The anticipated CR/CRh* rate of 
blinatumomab within 2 cycles will be 45%. 
Primary Endpoint:   
 
CR/CRh* rate within 2 cycles of treatment with blinatumomab  
Secondary Endpoints:   
 
CR rate within 2 cycles of treatment with blinatumomab 
 
CR/CRh*/CRi (complete remission with incomplete hematological recovery) rate within 
2 cycles of treatment with blinatumomab 
 
PK parameters  
 
OS 
 
RFS 
 
MRD response rate within 2 cycles of treatment with blinatumomab  
 
Proportion of subjects undergoing alloHSCT among those who achieved CR/CRh* after 
treatment with blinatumomab 
Approved 
 
 


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Protocol Number:  20130316 
Date:  09 March 2020 
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 
100-day mortality after alloHSCT 
 
Time to a 10 point decrease from baseline in global health status/QoL using the 
EORTC QLQ-C30 
Safety Endpoints 
 
Overall incidence and severity of adverse events  
 
Incidence of anti-blinatumomab antibody formation 
Exploratory Endpoints 
 
Neurological adverse events 
 
Quantification and characterization of peripheral blood lymphocyte subsets 
 
Quantification and characterization of serum cytokines and chemokines 
Study Design: 
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the 
BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adult subjects with 
relapsed/refractory B-precursor ALL.  
The study will consist of a screening period, a treatment period, and a follow-up period.  
Treatment will consist of up to 5 cycles of blinatumomab (for details see Section 6.2.2).  Subjects 
who have achieved a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh*/CRi within 
2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of 
blinatumomab.  Thirty days (± 3 days) after end of the last dose of protocol-specified therapy, 
subjects will have a safety follow-up (SFU) visit. 
Following this, there will be long term (efficacy/survival) follow-up portion of the study for disease 
status and OS.  Subjects will be followed via clinic visit or telephone contact every 3 months 
(± 1 month) after their SFU visit until death has been observed or a maximum of 2 years after 
start of treatment, whichever occurs first.   
If subjects are suitable for alloHSCT after treatment with blinatumomab, they may undergo 
alloHSCT instead of receiving further consolidation cycles with blinatumomab.  It is recommended 
to administer at least 2 cycles of blinatumomab before alloHSCT.  The subjects should complete 
the SFU visit before undergoing a transplant, and these subjects will continue to be followed in 
the long-term follow-up phase of the study. 
In order to enroll representative and balanced adult ALL subjects in terms of the number of prior 
salvage treatments, the study requires that approximately 50% of subjects are receiving salvage 
treatment for the first time.   
Salvage treatment will be categorized in the Interactive Voice Response/Interactive Web 
Response system (IVRS/IWRS) in order to monitor the number of subjects enrolled in each 
category.  Subjects will be categorized to: (a) those expecting to receive blinatumomab as a first 
salvage treatment or (b) those expecting to receive blinatumomab as a second or greater salvage 
treatment.  
Sample Size:  Approximately 120 Chinese adult subjects with relapsed/refractory B-precursor 
ALL. 
Summary of Subject Eligibility Criteria:  This study will enroll Chinese adult subjects with R/R 
B-precursor ALL with any of the following: 
 
primary refractory after induction therapy or who had relapse within 12 months of first 
remission, or 
 
relapsed within 12 months of receiving alloHSCT, or 
 
relapsed or refractory after first salvage therapy or beyond 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
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Subjects with Philadelphia chromosome-positive (Ph-positive) ALL, subjects with Burkitt’s 
Leukemia according to World Health Organization (WHO) classification, subjects with history or 
presence of clinically relevant CNS pathology as epilepsy, seizure, paresis, aphasia, stroke, 
severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, 
psychosis, and subjects with active ALL in the CNS or testes are excluded. 
For a full list of eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Blinatumomab is administered as a 
continuous intravenous infusion (CIVI). 
A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of 
blinatumomab CIVI followed by a 2 week treatment-free interval.  The treatment-free interval may 
be prolonged by up to 7 days, if deemed necessary by the investigator. 
In the first induction cycle, the initial dose of blinatumomab will be 9 μg/day for the first 7 days of 
treatment (to mitigate for potential cytokine release syndrome (CRS) and CNS events associated 
with introduction to blinatumomab) which then will be escalated (dose step) to 28 μg/day starting 
on day 8 (week 2) through day 29 (week 4).  For all subsequent cycles (beginning with the 
second induction cycle and continuing through consolidation, for applicable subjects) 28 μg/day 
will be the dose for all 4 weeks of continuous treatment. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  Dexamethasone 
Procedures:  At specified time points as outlined in the Schedule of Assessments, subjects will 
undergo the following procedures:  collection of informed consent, medical history, demographics, 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), complete neurological 
examination, physical exam including height, weight, vital signs and temperature, lumbar 
puncture and a BM aspirate.  Subjects will provide samples for hematology with differential, blood 
chemistry profiles, urinalysis, and anti-blinatumomab antibodies.  Subjects will further provide 
samples for other specialty labs including lymphocyte subsets, quantitative immunoglobulins, PK 
samples, and a serum or urine pregnancy test for women of child-bearing potential.  Research 
staff will document the use of concomitant medications and all adverse events reported by the 
subject.  During the treatment phase of the study, subjects will also provide patient reported 
outcomes (EORTC QLQ-C30). 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 9).   
Statistical Considerations:  
General Approach 
Primary analysis will be performed when all the enrolled subjects have finished at least 2 cycles 
of blinatumomab and the SFU visit (if subjects discontinue treatment after 2 cycles), or have 
discontinued the treatment of blinatumomab and complete the SFU visit, whichever occurs first.  
The primary analysis of efficacy and safety will be performed on all enrolled subjects who 
received at least one infusion of blinatumomab (Primary Analysis Set [PAS]).  Final analysis will 
be performed at the end of the study when all the enrolled subjects have finished all the follow-up 
visits or have withdrawn from the study, whichever occurs first.  The analyses of RFS, OS, 
alloHSCT rate after achieving CR/CRh*, and safety will be updated. 
The binomial endpoints including CR/CRh* rate, CR rate, CR/CRh*/CRi rate, alloHSCT rate, and 
MRD response rate will be calculated and the exact binomial 95% confidence interval will be 
generated for the response rate. 
The time-to-event endpoints including RFS and OS will be summarized with hazard ratio, 
Kaplan-Meier (KM) curves, KM quartiles (when estimable), the number of subjects with events, 
the number of subjects censored, and the pattern of censoring. 
Sample Size Considerations 
The overall sample size of 120 subjects, calculated using the exact method for a single 
proportion,was estimated in order to ensure 90% power to detect a significant difference in terms 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
Page 6 of 105 
CONFIDENTIAL 
 
 
of CR/CRh* rate between historical control with 30% CR/CRh* rate and blinatumomab, assuming 
45% CR/CRh* rate in the alternative hypothesis, at the 2.5% one-sided significance level.  
Interim Analyses 
One interim analysis is planned when 75% of subjects (90 subjects) have had the opportunity to 
be treated with at least 2 cycles of blinatumomab and to finish the SFU visit.  The interim analysis 
will assess blinatumomab efficacy and safety.  The efficacious benefit assessment will be based 
on an O’Brien-Fleming alpha spending function with the critical boundary 42.2% at the interim 
analysis and 39.2% at the primary analysis in CR/CRh* rate.  If the interim analysis shows a 
statistically efficacious benefit assessment and an overall benefit-risk analysis that is promising, 
then the interim analysis will become the primary analysis of this study.  In addition, the study will 
still continue its enrollment until 120 subjects are enrolled and continue to complete the protocol 
specified procedures. 
Additional ad hoc Interim Analyses may be performed.  Pharmacokinetic samples collected at 
specific timepoints may be analyzed and reported.  The purpose of this additional interim data 
analyses is to provide descriptive analyses of PK, safety, and efficacy information (including 
95% confidence intervals) for regulatory submissions and interactions. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5 / 20 March 2015 
 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
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Figure 1.  Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/Pre-Phase          
(≤21 days) 
safety & Long-term b  
Follow-upb 
HSCT offered to patients in CR/CRh/CRi 
Blinatumomab 
28 μg/day a)  
CIVI  
4 weeks on, 
2 weeks off 
Up to 2 cycles 
Primary endpoint 
assessment 
Blinatumomab 
28 μg/day 
CIVI  
4 weeks on, 
2 weeks off 
Up to 3 cycles 
Consolidation 
CIVI = continuous intravenous infusion; CR = complete remission (≤ 5% bone marrow blasts, no evidence of disease, platelets > 100,000/μL, ANC > 1,000/μL);  
CRh* = complete remission with partial recovery of peripheral blood counts (≤ 5% bone marrow blasts, no evidence of disease platelets > 50,000/μl and ANC 
> 500/μl) 
a) 9 μg/day in cycle 1 (days 1 to 7) 
b) Safety follow-up:  30 days (± 3 days) after protocol specified therapy; long-term follow-up:  every 3 months (± 1 month) 
 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
Page 8 of 105 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ACR 
aclarubicin 
ALL 
acute lymphoblastic leukemia 
alloHSCT 
allogeneic hematopoietic stem cell transplantation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
Ara-C 
cytarabine 
AST 
aspartate aminotransferase 
BiTE 
bispecific T cell engagers 
BM 
bone marrow 
CAG 
aclarubicin, cytarabine, and granulocyte colony-stimulating factor 
CI 
confidence interval 
CIVI 
continuous intravenous infusion 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete remission 
CRh* 
complete remission with partial hematological recovery 
CRi 
complete remission with incomplete hematological recovery 
CRS 
cytokine release syndrome 
CSF 
cerebrospinal fluid 
Css 
steady state drug concentration 
CTCAE 
common terminology criteria for adverse events 
CTL 
cytotoxic T lymphocyte 
DFS 
disease free survival 
DILI 
drug-induced liver injury 
DRT 
data review team 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assays 
end of study for individual 
subject 
defined as the last day that protocol-specified assessments are 
conducted for an individual subject 
end of treatment phase 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
end of study (primary 
completion) 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint  
end of study (end of trial) 
defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; including  survival 
assessments 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20130316 
Date:  09 March 2020 
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Abbreviation or Term 
Definition/Explanation 
end of follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30 
FAS 
Full Analysis Set 
FDA 
(United States) Food and Drug Administration 
FLAG 
fludarabine, cytarabine and granulocyte colony-stimulating factor 
G-CSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GvHD 
Graft-versus-Host Disease 
Hb 
hemoglobin 
HRT 
hormonal replacement therapy 
Hyper-CVAD 
hyperfractionated cyclophosphamide, vincristine, doxorubicin and 
dexamethasone) regimen 
ICC 
immunocytochemistry 
ICF 
informed consent form  
ICH/GCP 
International Conference on Harmonization/Guideline for Good 
Clinical Practice 
IDA 
Idarubicin 
IFN-γ 
interferon-gamma 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
IL-6 
interleukin-6 
IMP 
investigational medicinal product  
INR 
international normalized ratio 
IPIM 
investigational product instructional manual 
IUS 
intrauterine hormonal-releasing system 
IUD 
intrauterine device 
IVRS/IWRS  
Interactive Voice Response / Interactive Web Response system 
IRB/IEC 
institutional review board/independent ethics committee 
IV 
intravenous 
KM 
Kaplan-Meier 
MRD 
minimal residual disease 
MRI 
Magnetic Resonance Imaging 
NASH 
nonalcoholic fatty liver disease including steatohepatitis 
NK 
natural killer 
NE 
not estimable 
NSAID 
nonsteroidal anti-inflammatory drug 
OS 
overall survival 
PAS 
Primary Analysis Set 
PETHEMA 
Programa Para El Tratamiento de Hemopatias Malignas 
Approved 
 
 


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Abbreviation or Term 
Definition/Explanation 
PCR 
polymerase chain reaction 
Ph-negative 
Philadelphia chromosome-negative 
Ph-positive 
Philadelphia chromosome-positive 
PK  
pharmacokinetic 
PKS 
pharmacokinetic analysis set 
PS 
performance status 
QoL 
quality of life 
RFS 
relapse-free survival 
R/R 
relapsed/refractory 
RUQ 
right upper quadrant 
SAS 
safety analysis set 
SC 
subcutaneous 
SD 
standard deviation 
SFU 
safety follow-up 
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. 
SOC 
System Organ Class 
study day 1 
defined as the first day that protocol-specified therapy is 
administered to the subject. 
sWFI 
sterile water for injection 
TBL 
total bilirubin 
TNF-α 
tumor necrosis factor-alpha 
ULN 
upper limit of normal 
VDLP 
vincristine, daunorubicin, L-asparaginase and prednisone 
WBC 
white blood cell 
WHO 
World Health Organization 
Approved 
 
 


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Date:  09 March 2020 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Glossary .................................................................................................................. 8 
1. 
OBJECTIVES ......................................................................................................... 16 
1.1 
Primary ....................................................................................................... 16 
1.2 
Secondary .................................................................................................. 16 
1.3 
Safety ......................................................................................................... 16 
1.4 
Exploratory ................................................................................................. 16 
2. 
BACKGROUND AND RATIONALE ........................................................................ 16 
2.1 
Disease ....................................................................................................... 16 
2.2 
Definition of Relapsed/ Refractory Disease ................................................ 17 
2.3 
Prognostic Factors ...................................................................................... 17 
2.4 
Blinatumomab Background ........................................................................ 22 
2.5 
Blinatumomab Clinical Studies ................................................................... 24 
2.5.1 
Study MT103-206 ....................................................................... 24 
2.5.2 
Study MT103-211 ....................................................................... 25 
2.5.3 
Blinatumomab Data in Asian Subjects ....................................... 28 
2.6 
Rationale .................................................................................................... 29 
2.7 
Clinical Hypotheses .................................................................................... 29 
3. 
EXPERIMENTAL PLAN ......................................................................................... 29 
3.1 
Study Design .............................................................................................. 29 
3.2 
Number of Sites .......................................................................................... 30 
3.3 
Number of Subjects .................................................................................... 31 
3.4 
Replacement of Subjects ............................................................................ 31 
3.5 
Estimated Study Duration ........................................................................... 31 
3.5.1 
Study Duration for Subjects ........................................................ 31 
3.5.2 
End of Study ............................................................................... 31 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 32 
4.1 
Inclusion and Exclusion Criteria ................................................................. 32 
4.1.1 
Inclusion Criteria ......................................................................... 32 
4.1.2 
Exclusion Criteria ........................................................................ 33 
5. 
SUBJECT ENROLLMENT ..................................................................................... 35 
5.1 
Randomization/Treatment Assignment ...................................................... 35 
6. 
TREATMENT PROCEDURES ............................................................................... 36 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 36 
6.2 
Investigational Product ............................................................................... 36 
6.2.1 
Amgen Investigational Product ................................................... 36 
6.2.2 
Dosage, Administration, and Schedule ...................................... 37 
6.2.2.1 
Blinatumomab Inpatient Dosing ............................... 38 
Approved 
 
 


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6.2.2.2 
Blinatumomab Outpatient Dosing ............................ 38 
6.3 
Dexamethasone Premedication ................................................................. 39 
6.3.1 
Pre-phase Therapy Before Blinatumomab Treatment ................ 40 
6.3.2 
Pre-dose Dexamethasone Before Each Blinatumomab 
Treatment ................................................................................... 41 
6.4 
CSF Prophylaxis Before Blinatumomab Treatment .................................... 41 
6.5 
Dose Modifications (Interruptions, Withholdings, and Criteria for 
Restarting Treatment) ................................................................................. 42 
6.6 
Criteria for Blinatumomab Discontinuation ................................................. 45 
6.7 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 46 
6.7.1 
Criteria for Permanent Discontinuation of 
Blinatumomab and Other Protocol-required Therapies 
due to Potential Hepatotoxicity ................................................... 46 
6.7.2 
Criteria for Conditional Withholding of Blinatumomab 
and Other Protocol-required Therapies due to 
Potential Hepatotoxicity .............................................................. 47 
6.7.3 
Criteria for Rechallenge of Blinatumomab and Other 
Protocol-required Therapies After Potential 
Hepatotoxicity ............................................................................. 47 
6.8 
Guidelines for Common Toxicities .............................................................. 47 
6.8.1 
Hydration During the Treatment Period ...................................... 47 
6.8.2 
Fever Management .................................................................... 47 
6.8.3 
Additional Treatment for Special Subject Populations ................ 48 
6.9 
Concomitant Therapy ................................................................................. 48 
6.10 
Excluded Treatments During Study Period ................................................ 48 
6.11 
Medical Devices ......................................................................................... 48 
6.12 
Product Complaints .................................................................................... 49 
6.13 
Contraceptive Requirements ...................................................................... 49 
6.13.1 
Female Subjects ......................................................................... 49 
6.13.2 
Unacceptable Methods of Birth Control for Women 
Subjects ..................................................................................... 50 
7. 
STUDY PROCEDURES ......................................................................................... 51 
7.1 
Schedule of Assessments .......................................................................... 51 
7.2 
General Study Procedures ......................................................................... 55 
7.2.1 
Informed Consent ....................................................................... 55 
7.2.2 
Demographics ............................................................................ 55 
7.2.3 
Medical History ........................................................................... 55 
7.2.4 
ECOG Performance Status ........................................................ 55 
7.2.5 
Physical Examination ................................................................. 55 
7.2.6 
Physical Measurements ............................................................. 56 
7.2.7 
Vital Signs ................................................................................... 56 
7.2.8 
Neurological Examination ........................................................... 56 
7.2.9 
Lumbar Puncture to Examine Cerebrospinal Fluid ..................... 56 
7.2.10 
Intrathecal Prophylaxis ............................................................... 57 
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7.2.11 
Bone Marrow Biopsy/Aspiration ................................................. 57 
7.2.12 
Concomitant Medications ........................................................... 58 
7.2.13 
Definitions of Treatment Response ............................................ 58 
7.2.14 
Patient Reported Outcomes:  EORTC Quality of Life 
Questionnaire ............................................................................. 61 
7.2.15 
Laboratory Assessments ............................................................ 61 
7.2.16 
Lymphocyte Subsets .................................................................. 63 
7.2.17 
Peripheral Blood Cytokines/Markers .......................................... 63 
7.2.18 
Immunoglobulins ........................................................................ 63 
7.2.19 
Pharmacokinetic Assessments ................................................... 63 
7.2.20 
Pregnancy Tests ......................................................................... 64 
7.3 
Screening/Pre-treatment ............................................................................ 64 
7.4 
Treatment ................................................................................................... 65 
7.4.1 
Days of Infusion (Day 1 to Day 29, Applies to Each 
Treatment Cycle) ........................................................................ 65 
7.4.1.1 
Prior to Infusion (D1) ................................................ 65 
7.4.1.2 
During Infusion (D1 to D28) ..................................... 65 
7.4.1.3 
End of Infusion (D29) ............................................... 66 
7.4.2 
Treatment Free Interval from Day 30 to Day 43 
(D43  =  D1 of sub-sequent cycle) .............................................. 66 
7.5 
Safety Follow-up Visit ................................................................................. 66 
7.6 
Long Term Follow-up .................................................................................. 66 
7.7 
End of Study ............................................................................................... 67 
7.8 
Antibody Testing Procedures ..................................................................... 67 
7.9 
Sample Storage and Destruction ................................................................ 67 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 68 
8.1 
Subjects’ Decision to Withdraw .................................................................. 68 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 69 
8.3 
Reasons for Removal From Treatment or Study ........................................ 69 
8.3.1 
Reasons for Removal From Treatment ...................................... 69 
8.3.2 
Reasons for Removal From Study ............................................. 70 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 70 
9.1 
Definition of Safety Events ......................................................................... 70 
9.1.1 
Disease Related Events ............................................................. 70 
9.1.2 
Adverse Events .......................................................................... 71 
9.1.3 
Serious Adverse Events ............................................................. 72 
9.2 
Safety Event Reporting Procedures ........................................................... 73 
9.2.1 
Reporting Procedures for Disease Related Events .................... 73 
9.2.2 
Adverse Events .......................................................................... 73 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do not Meet Serious Criteria ........................... 73 
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9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 74 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 76 
9.2.2.4 
Drug-induced Liver Injury Reporting and 
Additional Assessments Reporting .......................... 76 
9.2.2.5 
Serious Adverse Events That are NOT TO 
BE Reported in an Expedited Manner ..................... 77 
9.3 
Pregnancy and Lactation Reporting ........................................................... 77 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 78 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 78 
10.1.1 
Study Endpoints ......................................................................... 78 
10.1.1.1 
Primary Endpoint ..................................................... 78 
10.1.1.2 
Secondary Endpoints ............................................... 78 
10.1.1.3 
Safety Endpoints ...................................................... 78 
10.1.1.4 
Exploratory Endpoints .............................................. 78 
10.1.2 
Analysis Sets .............................................................................. 79 
10.1.3 
Covariates and Subgroups ......................................................... 79 
10.2 
Sample Size Considerations ...................................................................... 79 
10.3 
Planned Analyses ....................................................................................... 80 
10.3.1 
Interim Analyses ......................................................................... 80 
10.3.2 
Data Review Team (DRT) .......................................................... 80 
10.3.3 
Primary Analysis ......................................................................... 81 
10.3.4 
Final Analysis ............................................................................. 81 
10.4 
Planned Methods of Analysis ..................................................................... 81 
10.4.1 
General Considerations .............................................................. 81 
10.4.2 
Primary Efficacy Endpoint .......................................................... 81 
10.4.3 
Secondary Efficacy Endpoint ...................................................... 82 
10.4.4 
Pharmacokinetic Analysis ........................................................... 83 
10.4.5 
Safety Endpoints ........................................................................ 83 
10.4.6 
Exploratory Endpoints ................................................................ 84 
11. 
REGULATORY OBLIGATIONS ............................................................................. 84 
11.1 
Informed Consent ....................................................................................... 84 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 85 
11.3 
Subject Confidentiality ................................................................................ 85 
11.4 
Investigator Signatory Obligations .............................................................. 86 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 86 
12.1 
Protocol Amendments and Study Termination ........................................... 86 
12.2 
Study Documentation and Archive ............................................................. 87 
12.3 
Study Monitoring and Data Collection ........................................................ 87 
12.4 
Investigator Responsibilities for Data Collection ........................................ 88 
12.5 
Language.................................................................................................... 89 
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12.6 
Publication Policy ....................................................................................... 89 
12.7 
Compensation ............................................................................................ 90 
13. 
REFERENCES ....................................................................................................... 91 
14. 
APPENDICES ........................................................................................................ 93 
List of Tables 
Table 1.  Prognostic Factors For Risk Stratification of Adult ALL 
(Gökbuget and Hoelzer, 2009) ................................................................. 18 
Table 2.  Outcome After Salvage 1 Treatment (Adapted From Gökbuget and 
Hoelzer, 2011) ......................................................................................... 19 
Table 3.  Outcome After Salvage 2 or at Least 2 Prior Regimens  (Adapted 
From Gökbuget and Hoelzer, 2011) ........................................................ 20 
Table 4.  Outcome After Salvage Treatment ................................................................... 21 
Table 5.  Hematologic Remission Rates Within 2 Cycles of 
Treatment – Salvage Category by Prior HSCT ........................................ 25 
Table 6.  Best Response During the First 2 Cycles of Treatment in 
Study MT103-211 .................................................................................... 26 
Table 7.  Dexamethasone Premedication ....................................................................... 40 
Table 8.  Instructions for Treatment Interruption, Dose Modification and 
Restart ..................................................................................................... 42 
Table 9.  Schedule of Assessments ................................................................................ 52 
Table 10.  Cheson Criteria for Evaluation of Extramedullary Disease 
(From Cheson et al. 2007) ....................................................................... 60 
Table 11.  Laboratory Analyte Listing .............................................................................. 62 
Table 12.  95% Confidence Intervals of Various Observed CR/CRh* Rates in 
Blinatumomab Administered to 120 Subjects .......................................... 80 
List of Figures 
Figure 1.  Study Design and Treatment Schema .............................................................. 7 
Figure 2.  Mode of Action of Blinatumomab .................................................................... 23 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 94 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 95 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 100 
Appendix D.  Expected Disease-related Adverse Events by System Organ 
Class (SOC) ........................................................................................... 102 
Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale ........................................................................................... 103 
Appendix F.  EORTC Quality of Life Questionnaire ...................................................... 104 
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1. 
OBJECTIVES 
1.1 
Primary 
 
To evaluate the rate of hematological response (complete remission/complete 
remission with partial hematological recovery [CR/CRh*]) induced by blinatumomab 
in Chinese adult subjects with relapsed/refractory B-precursor acute lymphoblastic 
leukemia (ALL). 
1.2 
Secondary 
 
To evaluate pharmacokinetics (PK) of blinatumomab 
 
To evaluate the effect of blinatumomab on overall survival (OS)  
 
To evaluate the relapse-free survival (RFS) induced by blinatumomab  
 
To evaluate minimal residual disease (MRD) response induced by blinatumomab 
 
To evaluate the incidence of allogeneic hematopoietic stem cell transplantation 
(alloHSCT) and 100-day mortality following HSCT in blinatumomab treated subjects 
 
To estimate the effect of blinatumomab on patient reported outcomes of global health 
status/quality of life (QoL) using the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). 
1.3 
Safety 
 
To evaluate the safety of blinatumomab in Chinese subjects with relapsed/refractory 
B-precursor ALL 
1.4 
Exploratory 
 
To evaluate central nervous system (CNS) symptoms and explore potential 
predictive factors for CNS events associated with blinatumomab 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic disease 
characterized by the proliferation of immature lymphoid cells in the bone marrow (BM) 
and peripheral blood.  Normal blood cell development in the marrow is therefore arrested 
and replaced with immature and abnormal lymphoblasts.  The proliferation of these 
immature/abnormal lymphoid cells in the BM subsequently crowd out the production of 
normal BM elements ultimately resulting in decreased red blood cell, white blood cell 
and platelet counts (NCCN Practice Guidelines, 2014).  
ALL is a rare malignant disease with an overall incidence of 1.1/100,000 per year 
worldwide.  ALL has a bimodal distribution with an early peak at 4 to 5 years of age 
(incidence of 4.5/100,000 per year) followed by a second gradual increase at 50 years 
(incidence of 2/100,000 per year).  It represents 80% of acute childhood leukemia and 
20% of acute leukemia cases in adults (Pui and Evans 1998; Jabbour et al, 2005; 
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Larson, 2005).  In China, there are no national level epidemiology data for the incidence 
rate of ALL.  The average incidence rate of ALL in Shanghai from 2002 to 2006 was 
0.81/100,000 per year, the same as that in Nanjing from 2003 to 2007 (Ni Xiong, 2011; 
Baoan Chen, 2010).  
2.2 
Definition of Relapsed/ Refractory Disease 
The population that this study will recruit is adult subjects with relapsed/refractory (R/R) 
B-precursor ALL.  Primary refractory ALL is defined by absence of CR after standard 
induction therapy.  A patient has relapsed ALL if they achieved a CR during upfront 
therapy (CR1) and has then relapsed during, or after continuation of therapy.  
A similar classification is possible for salvage therapy.  Refractory relapse is defined by 
lack of CR after first salvage therapy.  Second relapse or later relapses are defined as 
relapse after achieving a second complete remission (CR2) in first salvage or later 
salvage therapies. 
These definitions are important for clinical trials of new therapeutic agents, which are in 
some cases tailored to recruit subjects in specific situations; for example, second or 
early first relapse (Gökbuget and Hoelzer, 2011). 
2.3 
Prognostic Factors 
The classic prognostic features at the time of newly diagnosed B-precursor ALL are age 
at diagnosis, white blood cell count (WBC), and time to complete remission following 
induction chemotherapy.  A younger age (depending on level of risk, below 25 and 
35 years of age) and WBC of < 30,000/µL at diagnosis are favorable factors in adult 
ALL.  Additionally, a short interval in the achievement of a CR (< 3 weeks) is also 
favorable (Gökbuget and Hoelzer, 2009). 
The detection of MRD (the presence of a low number of leukemic cells that are not 
detectable by light microscopy) after induction therapy and/or consolidation therapy is an 
independent prognostic factor for poor outcome of ALL.  Subjects highly responsive to 
chemotherapy with a MRD-level below 1 x 10-4 leukemic cells detectable induced by 
induction treatment, have a favorable prognosis.  Subjects whose MRD persists during 
induction and consolidation of front-line treatment or who become MRD-positive 
following treatment, have a poor leukemia free survival.   
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Key prognostic factors displayed in Table 1 outline risk stratification in adult ALL: 
Table 1.  Prognostic Factors For Risk Stratification of Adult ALL 
(Gökbuget and Hoelzer, 2009) 
Parameter 
Favorable 
Adverse (B-Lineage) 
Age at time of diagnosis 
< 25 years, < 35 years 
≥ 35 yrs > 55 yrs, > 70 yrs 
WBC at time of diagnosis 
< 30,000/µL 
> 30,000/µL 
Time to CR following 
1st line treatment  
Early 
Late (> 3-4 weeks) 
MRD following receipt of 
induction therapy 
Negative (< 10-4 leukemic cells 
detectable) 
Positive (> 10-4 leukemic cells 
detectable) 
Prognostic Factors After Relapse and Treatment 
For subjects at a lower age, refractory disease or early relapse during upfront treatment 
(compared with late relapse after upfront treatment or during maintenance therapy) are 
important factors for treatment selection.  In the former group of subjects, experimental 
drug combinations have to be applied, whereas in the latter group of subjects, repeated 
induction therapy is the treatment of choice.  
Subjects at a higher age have a significantly worse long-term prognosis than subjects at 
lower age.  This is mainly caused by poor tolerability of chemotherapy toxicities leading 
to higher mortality and morbidity, and the necessity of dose reduction.  Furthermore, 
elderly subjects rarely fulfill the requirements for alloHSCT in CR.  
In subjects who relapse after alloHSCT, less intensive treatments may be preferable.  In 
subjects who relapse during intensive chemotherapy, it is of no use to repeat 
administration of the same regimens (Gökbuget and Hoelzer, 2011). 
Treatment Results After Relapse 
Three study groups have published retrospective analyses of clinical trials in adult 
subjects with ALL in first relapse.  All results are summarized in Table 2.  
The French group published an overall CR rate of 44% in 421 adult subjects in first 
relapse after various regimens.  The median OS was 6 months with 8% OS at 5 years.  
In this analysis the only prognostic factor for OS was transplantation of any type 
(Tavernier et al, 2007).  
The Spanish Programa Para El Tratamiento de Hemopatias Malignas (PETHEMA) 
reported the outcome for 198 adult subjects in first relapse after chemotherapy or HSCT.  
The overall CR rate after various treatment approaches was 42%.  The CR rate in 
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subjects with a duration of first CR less than one year was 38%.  The median OS after 
relapse was 4.5 months.  Age and duration of first remission were significantly 
associated with disease-free survival and OS (Oriol et al, 2010). 
The MD Anderson group published an overall CR rate of 31% in 314 adult subjects in 
first relapse after a variety of salvage regimens.  The median OS was 6 months and the 
OS at 5 years was 6%.  In a multivariate regression model for survival, age and duration 
of first remission were identified as significant factors (Thomas et al, 1999).  In another 
study the complete remission rate was also 31% and the median survival was 5 months 
(Kantarjian et al, 2010).  
Table 2.  Outcome After Salvage 1 Treatment 
(Adapted From Gökbuget and Hoelzer, 2011) 
Reference 
Year 
Therapy 
Pts (N) 
CR rate 
Overall Survival 
(median)a 
Tavernier et al. 
2007 
Various 1st salvage 
421 
44% 
8% (6 months) 
Oriol et al. 
2010 
Various 1st salvage 
198 
42% 
5% 
Thomas et al. 
1999 
Various 1st salvage 
314 
31% 
6% (6 months) 
Kantarjian et al. 
2010 
Various 1st salvage 
245 
31% 
(5 months) 
a 5 year survival rate 
The MD Anderson group also specifically investigated the outcome in 288 adult subjects 
with relapsed ALL in second salvage treatment.  The CR rate reported for second 
salvage was 18% and thus lower than the CR rate reported for first salvage therapy.  
The median OS was only 3 months.  The type of regimen significantly influenced the 
outcome, being more favorable after salvage regimens based on hyper-CVAD 
(hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), 
high-dose cytarabine, or direct alloHSCT (O´Brien et al, 2008).  Various publications with 
single agents after at least 2 regimens in adult and pediatric subjects reported similar CR 
rates (Jeha et al, 2006; Berg et al, 2005; DeAngelo et al, 2007; O’Brien et al, 2010).  The 
results are summarized in Table 3. 
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Table 3.  Outcome After Salvage 2 or at Least 2 Prior Regimens  
(Adapted From Gökbuget and Hoelzer, 2011) 
Reference 
Year 
Therapy 
Pts (N) 
CR rate 
Overall Survival 
O´Brien et al. 
2008 
Various regimens 
(≥ 2nd salvage) 
288 
18% 
3 months 
Jeha et al. 
2006 
Clofarabine1 (≥ 2nd salvage) 
49 
20% 
 
Berg et al. 
2005 
Nelarabine1,2 (≥ 2nd salvage) 
39 
23% 
 
DeAngelo et al. 
2007 
Nelarabine2 (≥ 2nd salvage) 
28 
29% 
 
O´Brien et al. 
2010 
Marqibo (≥ 2nd salvage) 
101 
20% 
 
1 pediatric ALL  
2 T-ALL  
Pts subjects; N number  
In China, currently there is no standard recognized regimen for relapsed or refractory 
ALL subjects.  Hyper-CVAD  regimen, high dose cytarabine and anthracycline 
combination, FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), 
methotrexate combined with asparaginase and similar regimens are possibilities as 
salvage therapy for first or later relapse.  The best re-induction strategy remains to be 
determined. 
Five study groups in China have published the results of retrospective study in adult 
subjects with ALL.  The results are summarized in Table 4.  Most of the adult ALL 
subjects were treated as first salvage therapy. 
Dr.Liu’s retrospective study is the only multicenter study.  In total, 268 relapsed or 
refractory ALL subjects were enrolled.  The published CR for CAG [aclarubicin (ACR), 
cytarabine (Ara-C), and granulocyte colony-stimulating factor (G-CSF)] group, high dose 
CAG (HD-CAG) group and Hyper-CVAD are 45.45%, 51.85%, and 52.56%, respectively.  
Each group had nearly 20-30% subjects younger than 18 years old.  Among all the 
groups, there were no statistically significant differences with CR and OR rates except 
for CAG group in B-ALL (Liu et al, 2015). 
Liu’s group retrospectively compared the efficacy of FLAG (with VDLP (vincristine, 
daunorubicin, L-asparaginase and prednisone) or Idarubicin (IDA) combined regimens in 
first salvage ALL subjects.  The CR for FLAG group and VDLP/IDA group were 40% and 
35% respectively, median disease free survival (DFS) for CR subjects in each group 
were 6 months and 4 months; and median OS for CR subjects in each group were 
11 months and 9 months (Liu et al. 2013). 
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The only study including 2 or more salvage therapies study was from Yan’s group.  The 
CR rate of chemotherapy alone was only 12.5%.  The median OS was 2.5 months 
(95% CI: 1.31-3.69ms). (Yan et al. 2013) 
Table 4.  Outcome After Salvage Treatment 
Reference 
Year 
Therapy 
Pts (N) 
CR rate 
Liu et al. 
2015 
Various regimens 
268 
 
CAG  
90 (including 19 pts < 18 yrs) 
45.45% 
29.17% for B-ALL 
HD-CAG  
82 (including 24 pts < 18 yrs) 
51.85% 
42.86% for B-ALL 
Hyper-CVAD 
96 (including 20 pts < 18 yrs) 
52.08% 
55.56% for B-ALL 
Yan et al*. 
2013 
Various regimens 
32 
12.5% 
Various regimens 
+ modified DLI 
50 
64% 
Liu et al. 
2013 
FLAG regimens 
20 
40% 
VDLP/IDA 
combined  
20 
35% 
Zhang et al 
2010 
FLAG 
19 
42.1% 
Zhang et al. 
2008 
Various regimens 
25 
18.7% 
* includes some AML subjects 
AlloHSCT After Relapse 
For all salvage regimens, the duration of subsequent remissions, if achieved, is usually 
short (median 4 to 6 months) and therefore the only curative option for adult subjects 
with R/R ALL is alloHSCT.  The major goal of relapse treatment is the induction of a 
second CR with sufficient duration to prepare for alloHSCT.  Thus all attempts (including 
experimental drugs) should be made to obtain a second CR and then conduct alloHSCT 
(Gökbuget and Hoelzer, 2011).  
Subjects eligible for alloHSCT always represent a selected group, who have to survive at 
least as long as the donor search is conducted.  Salvage chemotherapy should be 
administered before alloHSCT, in order to reduce tumor load (Gökbuget and 
Hoelzer, 2011).  In the MRC UK study, 120 subjects (20%) were eligible to undergo an 
alloHSCT after relapse, either autologous (n = 13), matched unrelated (n = 65), or 
matched related (n = 42).  Survival rates after 2 years were 15% for auto graft, 16% for 
unrelated and 23% for sibling HSCT (Fielding et al, 2007).  
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The French group identified alloHSCT in second CR as favorable prognostic factor for 
OS.  Five-year survival after alloHSCT was 25% (Tavernier et al, 2007).  
In the Dr. Liu’s retrospective study, the subjects who underwent alloHSCT, the estimated 
3-years OS in CAG, HD-CAG, hyper-CVAD groups were 20.9% ± 7.5%, 18.4% ± 5.5%, 
and 29.0% ± 3.8%, respectively (Liu et al, 2015). 
Treatment and Prevention of Extramedullary Relapse 
A small fraction of relapses in adult subjects with ALL have an extramedullary location, 
for example in the CNS or testes.  In contrast to childhood ALL, the outcome for 
extramedullary relapse in adult subjects with ALL is not different from medullary relapse 
(Tavernier et al, 2007; Fielding et al, 2007).  If the relapse is treated only locally for 
example by intrathecal therapy, the extramedullary relapse is usually followed by 
medullary relapse.  Therefore extramedullary relapse of ALL should always be 
considered as systemic disease and local therapy such as intrathecal treatment of CNS 
relapse should be combined with systemic chemotherapy.  In subjects with medullary 
relapse CNS prophylaxis should be administered (Gökbuget and Hoelzer, 2011).  
2.4 
Blinatumomab Background 
Blinatumomab is a murine recombinant single-chain antibody construct combining both 
the binding specificity for the pan B-cell antigen CD19 and the epsilon chain of the T-cell 
receptor/CD3 complex on one polypeptide chain.  It is monomeric, not glycosylated and 
weighs approximately 55 kDa. 
It belongs to a new class of bispecific antibody constructs called bispecific T-cell 
engagers (BITE).  Bispecific T-cell engagers have been designed to direct T-effector 
memory cells towards target cells.  The proximity induced by the BITE® triggers target 
cell-specific cytotoxicity, which closely resembles standard cytotoxic T lymphocyte (CTL) 
activation.  This T-cell–mediated target-specific killing is the therapeutic mechanism of 
action of blinatumomab (Löffler et al, 2000; Wolf et al, 2005). 
Blinatumomab specifically targets cells that express CD19, a marker solely expressed by 
B cells, including B-precursor ALL cells, with an affinity of 1.49 x 10-9 M.  Blinatumomab 
recruits and activates T cells via a lower affinity interaction with CD3 (KD = 2.6 x 10-7 M).  
These activated T cells then induce a half-maximal target cell lysis ranging in vitro within 
a range of 1 to 1000 pg/mL (0.018 -18 pM), showing blinatumomab to be an extremely 
potent molecule (Dreier et al, 2002). 
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During the course of tumor cell elimination, activated T cells synthesize and secrete 
pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interferon-gamma 
(IFN-γ), interleukin (IL)-6, and IL-2, which might induce symptoms such as fever or 
decreases of blood pressure.  In vitro data demonstrate cytokine release as a result of 
blinatumomab-mediated activation, which can be attenuated by corticosteroids without 
impairing the cytotoxic activity.  In vivo data indicate cytokine release to be most 
prominent following the first dose of blinatumomab. 
Figure 2.  Mode of Action of Blinatumomab 
 
Due to its unique ability to redirect T cells via CD3 towards a CD19+ tumor cell lysis, 
blinatumomab can elicit repeated target cell elimination by cytotoxic T cells and a 
polyclonal response of previously primed CD4+ and C8+ T cells.  The antitumor activity is 
effective within a wide range of effector to target (E:T) ratios. 
In the absence of CD19+ target cells neither cytotoxicity nor release of cytokines will 
occur.  Blinatumomab acts strictly in a target cell specific and dependent manner, with 
regard to cytotoxic action.  The presence of both CD19+ target cells and T cells are 
required for its cytotoxic activity. 
In December 2014, blinatumomab was approved by U.S. Food and Drug Administration 
(FDA) for the treatment of subjects with Philadelphia chromosome-negative 
(Ph-negative) relapsed or refractory B-cell precursor ALL under accelerated approval.  
The blinatumomab approval is based on results of Study MT103-211, a phase 2, 
multicenter, single-arm open-label study (see Section 2.5.2).  
Refer to the Blinatumomab Investigator’s Brochure for additional information. 
Signal
Anti-CD19 Antibody
Anti-CD3 Antibody
BiTE®
MT103
VH
VH
VL
VL
B Cell
Cytotoxic T Cell
Redirected Cell Lysis
CD19
CD3
CD69
CD25
Activation
Proliferation
Apoptotic Cell
Death
(A)
(B)
Signal
Signal
Anti-CD19 Antibody
Anti-CD3 Antibody
BiTE®
MT103
VH
VH
VL
VL
B Cell
Cytotoxic T Cell
Redirected Cell Lysis
CD19
CD3
CD69
CD25
Activation
Proliferation
Apoptotic Cell
Death
(A)
(B)
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2.5 
Blinatumomab Clinical Studies 
2.5.1 
Study MT103-206 
Study MT103-206 was an open-label, multicenter, single arm, exploratory phase 2 study 
in adult subjects with R/R ALL.  Blinatumomab was administered by continuous 
intravenous (IV) infusion (CIVI) for 4 weeks followed by a 2 week treatment-free interval 
per cycle.  The primary endpoint was the hematologic CR rate within 2 cycles of 
treatment with blinatumomab.  A hematologic CR was defined as a CR or a CR with 
partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment.  
Complete remission was defined as:  less than or equal to 5% blasts in the BM, no 
evidence of disease, and full recovery of peripheral blood counts (platelets 
> 100.000/μL, hemoglobin [Hb] ≥ 11 g/dL, and absolute neutrophil count [ANC] 
> 1.500/μL).  Complete remission with only partial hematological recovery (CRh*) was 
defined as:  less than or equal to 5% blasts in the BM, no other evidence of disease, and 
partial recovery of peripheral blood counts (platelets > 50.000/μL, Hb ≥ 7 g/dL, and 
ANC > 500/μL).  
In Study MT103-206, 36 adult subjects with R/R B-precursor ALL were treated in this 
study, 7 subjects in Dose Cohort 1 (15 μg/m²/day), 5 subjects in Dose Cohort 2a 
(5-15 μg/m²/day), 6 subjects in Dose Cohort 2b (5-15-30 μg/m²/day), and 18 subjects in 
Dose Cohort 3 (5-15 μg/m²/day).  The overall median age was 32 years  
(range: 18 - 77 years); 14 were female, and 22 were male.  Thirty-three subjects (92.0%) 
in this study had relapsed ALL.  Three subjects had refractory disease.  Two subjects 
(6.0%) were Philadelphia chromosome-positive (Ph-positive), and 4 subjects (11.0%) 
had a t(4;11) translocation.  Fifteen subjects had undergone prior alloHSCT.   
Twenty-five subjects (69%) responded to treatment.  Fifteen subjects (42%) and 
10 subjects (28%) showed a CR and CRh*, respectively, within 2 cycles of 
blinatumomab treatment.  
Remission rates by number of salvage treatments, time to first relapse or refractory to 
treatment with or without a transplant are outlined in Table 5. 
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Table 5.  Hematologic Remission Rates Within 2 Cycles of Treatment – Salvage 
Category by Prior HSCT 
Hematologic 
Remission 
Relapse/Refractory Category 
No prior HSCT 
Prior HSCT 
Salvage 1 after 
CR 1 
≤ 18 Months 
(n = 8) 
Salvage 1 after 
CR 1 
> 18 Months  
(n = 8) 
≥ 2nd 
Salvage or 
Refractory 
(n = 5) 
Prior HSCT 
(n = 15) 
CR/CRh*, n (%) 
CR 
CRh* 
7 (88) 
3 (38) 
4 (50) 
8 (100) 
6 (75) 
2 (25) 
2 (40) 
2 (40) 
0 
8 (53) 
4 (27) 
4 (27) 
Blast Free 
Hypoplastic Bone 
marrow, n (%) 
0 
0 
0 
3 (20) 
No remission, n (%) 
1 (13) 
0 
1 (20) 
4 (27) 
Not evaluable, n (%) 
0 
0 
2 (40) 
0 
Eighty eight percent of subjects with hematologic CR also had complete MRD remission 
(defined as MRD polymerase chain reaction (PCR) < 1 x 10-4 leukemic cells detectable).  
The median RFS was 7.6 months with a median OS of 9.8 months.  
2.5.2 
Study MT103-211 
Study MT103-211 is an open-label, multicenter, global, single-arm, phase 2 study in 
high-risk adult subjects with Ph-negative B-precursor relapsed/refractory ALL, 
specifically that have 1) relapsed or refractory ALL with first remission duration less than 
or equal to 12 months in first salvage or 2) relapsed or refractory ALL after first salvage 
therapy or 3) relapsed or refractory ALL within 12 months of alloHSCT.  The primary 
endpoint of this study is the hematologic CR/CRh* rate within 2 cycles of treatment with 
blinatumomab.  This prespecified endpoint was met if > 30% of subjects achieved a 
CR/CRh* during this time interval.  Subjects who have achieved CR or CRh* within 
2 cycles of treatment can receive up to 3 additional cycles of maintenance treatment or 
proceed to BM transplantation.  Key efficacy endpoints include RFS, duration of 
complete remission, proportion of subjects eligible for alloHSCT who undergo the 
procedure after blinatumomab treatment, and rate of MRD response (defined as 
MRD < 1 x 10-4 leukemic cells detectable measured by PCR) within 2 cycles of 
blinatumomab treatment.  
A total of 189 subjects were enrolled and received ≥ 1 infusion of blinatumomab.  All 
189 subjects were included in the Primary Analysis Set (PAS) and Full Analysis Set 
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(FAS).  Overall, most subjects were men (63.0%) and white (85.8%), with a median age 
(range) of 39 years (range 18 to 79 years).  Approximately 41% of subjects received 
blinatumomab as third-line treatment, and 39% received it as fourth-line or greater; the 
remaining 20% of subjects were either primary refractory or had relapsed within 
12 months of first remission.  One-hundred thirty subjects (68.8%) had a BM blast count 
of 50% at baseline based on central laboratory assessments. 
In the PAS, the rate of CR/CRh* within the first 2 treatment cycles was 42.9% (81/189; 
95% CI: 35.7, 50.2).  Since the lower bound of the 95% CI was > 30%, the remission 
rate was significantly greater than 30%. 
The best response rates including the rates of CR/CRh* during the first 2 cycles are 
provided in Table 6.  Three subjects who had achieved a CRh* response at the end of 
2 cycles of treatment converted to CR by the end of the core study and one subject 
converted from a non-response to a CR, resulting in an overall CR rate of 35.4% for the 
core study. 
Table 6.  Best Response During the First 2 Cycles of Treatment in 
Study MT103-211 
 
ANC = absolute neutrophil count; BM = bone marrow; CI = confidence interval; CR = complete response; 
CRh* = complete response with partial recovery of peripheral blood counts; PAS = primary analysis set 
a Bone marrow blasts ≤• 5%, no evidence of disease, and full recovery of peripheral blood counts:  platelets 
> 100,000/μL and absolute neutrophil count (ANC) > 1,000/μL. 
b Bone marrow blasts ≤5%, no evidence of disease, and partial recovery of peripheral blood counts:  
platelets > 50,000/μL and ANC > 500/μL. 
c Less than or equal to 5% blasts in the BM, no evidence of disease, and insufficient recovery of peripheral 
blood counts:  platelets ≤ 50,000/μl and/or ANC ≤ 500/μl. 
d Bone marrow blasts 6% to 25% with at least a 50% reduction from baseline. 
e No response assessment is generally a result of subject withdrawal from treatment due to adverse events. 
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The median RFS for subjects who achieved CR/CRh* during the core study was 
5.9 months (95% CI:  4.8, 8.3).  When based on the best response within the first 
2 cycles, the median RFS for subjects who achieved a best response of CR was 
6.9 months (95% CI:  4.2 to 10.1 months) (N = 63) and 5.0 months (95% CI:  1.4 to 
6.2 months) (N = 18) for subjects who achieved a best response of CRh*. 
For subjects who achieved CR/CRh* and had a MRD assessment during the first 
2 cycles (N = 73), the MRD response rate was 82.2% (60/73; 95% CI:  71.5% to 90.2%), 
and the complete MRD response rate was 69.9% (51/73; 95% CI:  58% to 80.1%). 
The median OS for all subjects was 6.1 months (95% CI:  4.2, 7.5).  For subjects who 
achieved CR/CRh* and were alive and not censored by day 36 (n = 60), the median OS 
after day 36 was 11.2 months (95% CI:  7.8, not estimable [NE]).  For non-responders 
who were alive and not censored by day 36 (n = 101), the median OS after day 36 was 
3.0 months (95% CI:  2.4, 4).  For subjects who achieved CR/CRh* and were MRD 
negative, the median OS was 11.5 months (95% CI:  8.5, NE).  
Safety results from studies MT103-206 and MT103-211: 
As of the safety data cut-off date (10 October 2013), 225 subjects (189 in 
Study MT103-211 and 36 in Study MT103-206) were exposed to blinatumomab in the 
adult relapsed/refractory ALL population.  By study, the median exposure duration was 
42.2 days (range 1.2, 150.1) in Study MT103-211, and 55.6 days (range 24.15, 77.3) 
across dose groups in Study MT103-206.  The longest median duration of exposure was 
75.15 days (6 subjects) in the 5/15/30 μg/m2/d dose group in Study MT103-206. 
Of the 225 subjects in the adult relapsed/refractory ALL studies, 70.4% (133/189) of 
subjects in Study MT103-211 and 69.4% (25/36) of subjects in Study MT103-206 started 
and completed at least 1 cycle of treatment.  In Study MT103-211, the mean number of 
started treatment cycles was 2.0 (SD 1.2) and the mean number of completed treatment 
cycles was 1.4 (SD 1.4).  In Study MT103-206 the mean number of started treatment 
cycles was 2.5 (SD 1.7), and the mean number of completed cycles was 1.6 (SD 1.5).  
Almost all subjects (224/225 [99.6%]) experienced at least 1 treatment-emergent 
adverse event.  Across the 2 studies, the subject incidence of grade 
≥ 3 treatment-emergent adverse events  was 80.9% (182/225); by study the subject 
incidence of grade ≥ 3 treatment-emergent adverse events was 82% in 
Study MT103-211 and 75% in Study MT103-206.  The subject incidence of 
grade ≥ 4 treatment-emergent adverse events across the 2 studies was 44.9% 
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(101/225); by study the incidence was similar (44.4% in MT103-211 and 47.2% in 
MT103-206).  Across studies the subject incidence of serious adverse events  was 
64.9% (146/225), and fatal treatment-emergent adverse events were reported in 15.1% 
of subjects (34/225).  By study, the subject incidences of serious adverse events and 
fatal treatment-emergent adverse events were similar in Studies MT103-211 and 
MT103-206 (serious adverse events: 64% and 69.4%, respectively; fatal 
treatment-emergent adverse event s: 14.8% and 16.7%, respectively).  
The subject incidence of treatment-emergent adverse events leading to study drug 
discontinuation was lower in MT103-211 (18.0%) compared with MT103-206 (27.8%).  
The System Organ Classes (SOC) with the highest subject incidence of 
treatment-emergent adverse events across both studies was Infections and Infestations 
(5.3% [12/225]), and as anticipated, sepsis was the PT with the highest reported subject 
incidence.  Across both studies, events that led to treatment discontinuation that 
occurred in ≥ 2 subjects included disease progression, sepsis, aspartate 
aminotransferase (AST) increased, blood alkaline phosphatase (ALP) increased, 
muscular weakness, acute ALL, encephalopathy, headache, tremor, disorientation, and 
respiratory failure.  The subject incidence of treatment-emergent adverse events leading 
to study drug interruption was the same in each study (33.3%).  
Subjects receiving blinatumomab may experience a spectrum of neurologic and 
psychiatric events, such as seizure, encephalopathy, tremor, apraxia, speech disorders 
(aphasia, dysarthria), and disorientation.  The incidence of subjects experiencing 
neurologic and psychiatric events is greatest within the first few days of blinatumomab 
treatment. 
2.5.3 
Blinatumomab Data in Asian Subjects 
To date, the development of blinatumomab has been focused on Europe and the 
United States.  At the time of this protocol writing, a global phase 3 blinatumomab study 
(TOWER) and a phase 1b/2 study in Japanese subjects are currently ongoing in Asia; 
therefore, data are not yet available for Asian subjects from this study.   
In the pivotal phase 2 MT103-211 study, 7 Asian subjects were enrolled in the 
United States and Europe, of which 5 subjects had evaluable PK samples.  These 
subjects received blinatumomab at 9 µg/day during the first week and 28 µg/day for the 
remaining treatment time.  Data are currently limited, however the safety profile and PK 
profile in Asian subjects and non-Asian subjects appear to be comparable.  
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2.6 
Rationale 
Relapsed/refractory B-precursor ALL in adult subjects is an aggressive malignant 
disease with dismal prognosis.  Several studies have reported long term survival to be 
below 10%.  Major prognostic factors are duration of CR1 and age.  With current salvage 
chemotherapy, CR rate is low (20 to 30%) in subjects in first salvage with short duration 
(< 1 year) of first remission, subjects relapsed after first salvage, or subjects aged 
60 years and older.  Duration of CR is usually very short (median DFS: 2.0-7.5 months).  
AlloHSCT may provide a curative treatment option for subjects in CR with a satisfactory 
donor and appropriate clinical status including age, organ function, and remission status.  
AlloHSCT is not an option in most elderly subjects with relapsed ALL (for all data 
see Gökbuget and Hoelzer 2011).  Additional therapeutic approaches are urgently 
needed. 
Blinatumomab belongs to a new class of bispecific antibody derivatives called BITE.  
BITEs have been designed to direct T cells towards target cells.  Blinatumomab has 
demonstrated efficacy and safety in two phase 2 studies (MT 103-206 and MT 103-211) 
in adult subjects with Ph-negative B-precursor relapsed/refractory ALL.  Blinatumomab is 
the first FDA-approved bispecific CD19-directed CD3 T-cell engager (BiTE®) antibody 
construct product, and the first single-agent immunotherapy has been approved for the 
treatment of subjects with Ph-negative relapsed or refractory B-cell precursor ALL. 
Blinatumomab also has the potential to provide meaningful therapeutic benefits to 
Chinese subjects compared with existing treatments for this patient population. 
2.7 
Clinical Hypotheses 
The clinical hypothesis is that blinatumomab will have clinically meaningful anti-tumor 
activity better than 30% as measured by CR/CRh* rate within 2 cycles in Chinese adult 
subjects with relapsed/refractory B-precursor ALL.  The anticipated CR/CRh* rate within 
2 cycles will be 45%.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and 
safety of the BiTE antibody blinatumomab in Chinese adult subjects with 
relapsed/refractory B-precursor ALL.  
The study will consist of a screening period, a treatment period, and a follow-up period.  
Treatment will consist of up to 5 cycles of blinatumomab (for details see Section 6.2.2).  
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Subjects who have achieved a BM response (≤ 5% BM blasts) or CR/CRh*/CRi within 
2 induction cycles of treatment may continue to receive up to 3 additional consolidation 
cycles of blinatumomab.  Thirty days (± 3 days) after end of the last dose of 
protocol-specified therapy, subjects will have a safety follow-up (SFU) visit. 
Following this, there will be long term (efficacy/survival) follow-up portion of the study for 
disease status and OS.  Subjects will be followed via clinic visit or telephone contact 
every 3 months (± 1 month) after their SFU visit until death has been observed or a 
maximum of 2 years after start of treatment, whichever occurs first.   
If subjects are suitable for alloHSCT after treatment with blinatumomab, they may 
undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.  
It is recommended to administer at least 2 cycles of blinatumomab before alloHSCT.  
The subjects should complete the SFU visit before undergoing a transplant, and these 
subjects will continue to be followed in the long-term follow-up phase of the study. 
In order to enroll representative and balanced adult ALL subjects in terms of the number 
of prior salvage treatments, the study requires that approximately 50% of subjects are 
receiving salvage treatment for the first time.   
Salvage treatment will be categorized in the interactive voice response 
system/interactive web response system (IVRS/IWRS) in order to monitor the number of 
subjects enrolled in each category.  Subjects will be categorized to:  (a) those expecting 
to receive blinatumomab as a first salvage treatment or (b) those expecting to receive 
blinatumomab as a second or greater salvage treatment. 
The overall study design is described by a study schema (Figure 1) at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 25 centers located in China will participate in this study.  During the 
conduct of the study, additional sites may be added as necessary. 
Sites that do not enroll subjects within 6 months of site initiation may be considered for 
closure to further participation in the trial. 
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3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  It is 
anticipated that approximately 120 adult Chinese subjects will be enrolled into this study. 
Please refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects who withdraw or are withdrawn or removed from treatment or the study will not 
be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Each subject will participate for up to 37 weeks in the core study, which includes: 
 
A screening period of up to 3 weeks. 
 
A standard treatment period of up to 30 weeks. 
 
A SFU period of approximately 4 weeks 
The subjects will receive one to 5 consecutive cycles of blinatumomab treatment.  A 
cycle consists of a CIVI over 4 weeks followed by a treatment free interval of 2 weeks. 
Thirty days (± 3 days) after end of the last dose of protocol-specified therapy, subjects 
will have a SFU visit.  Following this, there will be long term (efficacy/survival) follow-up 
portion of the study for disease status and OS (24 months [± 2 weeks]) after treatment 
start or until death, whichever occurs first. 
For subjects who complete the protocol from the date of first dose through the long-term 
follow-up period, the entire duration of the study will take approximately 24 months to 
complete.  However, individual study duration will vary depending on the need for 
consolidation treatment with blinatumomab and survival of an individual subject.  The 
entire duration of this study including recruitment, screening, treatment, SFU, and 
long-term follow-up will take approximately 54 months. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
End of Study:  The end of study date is defined as the date when all the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
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subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific procedure, the appropriate written informed consent must be 
obtained (see Section 11.1).   
Salvage treatment will be categorized in IVRS/IWRS to enroll a representative and 
balanced adult ALL subjects in terms of the number of prior salvage treatments.  
Subjects will be categorized to:  (a) those expecting to receive blinatumomab as a first 
salvage treatment or (b) those expecting to receive blinatumomab as a second or 
greater salvage treatment.  
4.1 
Inclusion and Exclusion Criteria 
This study will enroll Chinese adult subjects that meet all of the inclusion and none of the 
exclusion criteria detailed below. 
4.1.1 
Inclusion Criteria 
101 
Subjects have provided informed consent/assent prior to initiation of any 
study-specific activities/procedures or subject’s legally acceptable representative 
has provided informed consent prior to any study-specific activities/procedures 
being initiated when the subject has any kind of condition that, in the opinion of 
the investigator, may compromise the ability of the subject to give written 
informed consent. 
102 
Subjects with Ph-negative B-precursor ALL, with any of the following: 
 
Primary refractory after induction therapy or who had relapsed within 
12 months of first remission or 
 
Relapsed within 12 months of receiving alloHSCT or 
 
Relapsed or refractory after first salvage therapy or beyond 
103 
> 5% blasts in BM (by morphology) 
104 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 
105 
Age ≥ 18 years at the time of  informed consent 
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4.1.2 
Exclusion Criteria 
Disease Related 
201 
Subjects with Ph-positive ALL 
202 
Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) 
classification 
203 
History or presence of clinically relevant CNS pathology as epilepsy, seizure, 
paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, 
cerebellar disease, organic brain syndrome, and psychosis 
204 
Active ALL in the CNS (confirmed by cerebrospinal fluid [CSF] analysis) or in 
testes  
205 
Isolated extramedullary disease 
206 
Current active autoimmune disease or history of autoimmune disease with 
potential CNS involvement  
Other Medical Conditions 
207 
History of malignancy other than ALL within 5 years prior to start of 
protocol-specified therapy with the exception of:  
 
Malignancy treated with curative intent and with no known active disease 
present for 5 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. 
208 
Known infection with human immunodeficiency virus (HIV) or chronic infection 
with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive) 
226 
Abnormal screening laboratory values as defined below: 
 
Aspartate aminotransferase (AST) and/or alanine aminotransferase ALT  
and/or ALP ≥ 5 x upper limit of normal (ULN) 
 
Total bilirubin (TBL) ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht 
disease) 
 
Creatinine ≥ 1.5 ULN and creatinine clearance < 60 ml/min (calculated) 
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Medications or Other Treatments 
210 
Autologous HSCT within 6 weeks prior to start of blinatumomab treatment 
211 
AlloHSCT within 3 months prior to start of blinatumomab treatment 
212 
Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the 
Glucksberg criteria or active chronic GvHD requiring systemic treatment 
213 
Any systemic therapy against active GvHD within 2 weeks prior to start of 
blinatumomab treatment 
214 
Cancer chemotherapy within 2 weeks prior to start of blinatumomab treatment 
(intrathecal chemotherapy and dexamethasone are allowed until start of 
blinatumomab treatment).  In addition, any subject whose organ toxicity 
(excluding hematologic) from prior ALL treatment has not resolved to common 
terminology criteria for adverse events (CTCAE) ≤ grade 1. 
215 
Radiotherapy within 2 weeks prior to start of blinatumomab treatment 
216 
Immunotherapy (eg, rituximab) within 4 weeks prior to start of blinatumomab 
treatment 
217 
Currently receiving treatment in another investigational device or drug study, or 
less than 4 weeks prior to start of blinatumomab treatment.  
218 
Previous treatment with anti-CD19 therapy 
General 
219 
Known hypersensitivity to immunoglobulins or to any other component of the IMP 
formulation 
220 
Pregnant women and women planning to become pregnant should not 
participate in this study.  Subjects who are breast feeding prior to start of 
blinatumomab treatment may be enrolled if they stop breast feeding with 
breast milk produced during blinatumomab treatment and for an additional 
48 hours after the last dose of blinatumomab 
222 
Male participants are not required to use birth control during treatment with 
blinatumomab.  However, you should let your female partner know you are in this 
study. 
223 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, including follow-up visits, and/or to comply with all required study 
procedures to the best of the subject and investigator’s knowledge.  
224 
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. 
225 
Previous treatment with blinatumomab 
227 
Woman of childbearing potential and is not willing to use an effective method of 
contraception during treatment and for an additional 48 hours after the last dose 
of blinatumomab.  Birth control is not required for postmenopausal women, or 
women with uterus/or both ovaries/ or both fallopian tubes removed. 
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5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  A 
written main study ICF must be signed and personally dated by the subject or by the 
subject’s legally acceptable representative and by the person who conducted the 
informed consent discussion before any protocol specified procedure is performed. 
Each subject who enters into the screening period for the study (defined as the point 
when the subject or the subject’s legally acceptable representative signs the IRB/IEC 
approved main study ICF) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned by the IVRS/IWRS.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria, and has entered enrollment into the IVRS/IWRS.  The investigator is 
to document this decision and date in the subject’s medical record and in/on the 
enrollment electronic case report form (eCRF).   
During the enrollment call, the subject will be categorized to:  (a) those expecting to 
receive blinatumomab as a first salvage treatment or (b) those expecting to receive 
blinatumomab as a second or greater salvage treatment.  
5.1 
Randomization/Treatment Assignment 
This is an open-label, non-randomized study.  The investigator, the subject, and the 
sponsor will know the treatment.  All subjects in this study will receive blinatumomab 
treatment. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment eCRF.  
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6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product (IP) used in this study is blinatumomab.  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, containing detailed information regarding the storage, preparation, and 
administration of blinatumomab will be provided to each investigational site.  
All other protocol-specified therapies including, pre-phase therapies, that are 
commercially available are not provided or reimbursed by Amgen (except if required by 
local regulation).  The Investigator will be responsible for obtaining supplies of these 
protocol-specified therapies. 
6.2 
Investigational Product  
6.2.1 
Amgen Investigational Product 
Blinatumomab will be manufactured by Boehringer Ingelheim Pharma Gmbh & Co KG 
and packaged by Amgen and distributed using Amgen clinical study drug distribution 
procedures. 
Blinatumomab will be supplied as single-use glass injection vials as a sterile, 
preservative-free, white to off-white, lyophilized powder for reconstitution and 
administration by IV infusion.  Each vial contains blinatumomab with additional 
excipients and buffers including citric acid monohydrate, trehalose dihydrate, lysine 
hydrochloride and polysorbate 80, pH 7. 
To prepare blinatumomab for IV infusion, the lyophilized powder is reconstituted with 
sterile water for injection.  The reconstituted solution is added to an infusion bag 
containing 0.9% NaCl and a product-specific stabilizer (IV Solution Stabilizer).  The IV 
solution stabilizer functions to prevent adsorption of blinatumomab to surfaces of the 
infusion components.  The IV Solution Stabilizer is supplied in a single-use glass 
injection vials as a sterile, preservative-free, clear, colorless-to-slightly-yellow liquid 
concentrate. 
Sterile water for injection and supplies required for reconstitution and injection of 
blinatumomab will not be provided to clinical sites. 
For information surrounding the use of a continuous infusion pump, refer to Section 6.11. 
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6.2.2 
Dosage, Administration, and Schedule 
Blinatumomab is administered as a CIVI. 
A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks 
of blinatumomab CIVI followed by a 2 week treatment-free interval.  The treatment-free 
interval may be prolonged by up to 7 days, if deemed necessary by the investigator. 
In the first induction cycle, the initial dose of blinatumomab will be 9 μg/day for the first 
7 days of treatment (to mitigate for potential cytokine release syndrome [CRS] and CNS 
events associated with introduction to blinatumomab) which then will be escalated (dose 
step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4).  For all 
subsequent cycles (beginning with the second induction cycle and continuing through 
consolidation, for applicable subjects) 28 μg/day will be the dose for all 4 weeks of 
continuous treatment.   
The drug administration should not be interrupted, if possible.  In case of infusion 
interruption, due to any technical or logistic reason, the interruption should be as short 
as possible and the infusion continued at the earliest time possible.  Every interruption 
longer than 1 hour should be documented.  If the interruption is longer than 4 hours, 
restart of the infusion should be performed in the hospital, under the supervision of the 
investigator.  The subject should be observed overnight for possible side effects after the 
restart, either in the hospital or in the outpatient setting as applicable.  Administration of 
dexamethasone premedication as described in Table 8.  It is recommended, if possible, 
that the infusion duration before and after an interruption should total 28 days per 
treatment cycle. 
The daily blinatumomab dose may be up to 10% lower or higher in order to account for 
possible pump inaccuracies.  For dose modifications in case of adverse events 
see Section 6.5. 
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.  
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. 
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The dose, start and stop date/time, and lot number of protocol-specified therapy is to be 
recorded on each subject’s eCRF. 
6.2.2.1 
Blinatumomab Inpatient Dosing 
It is strongly recommended that subjects are hospitalized at least during the first 9 days 
(1 week plus 2 days following dose step) of the first cycle and the first 2 days of the 
following cycle.   
The hospitalization time depends on investigator´s judgment, as well as safety and 
tolerability of blinatumomab.  However, the hospitalization must span at least the first 
2 days after treatment start in the first 2 cycles and after dose step.  For cycle 3 and 
beyond, subjects will at least come in for an 8 hours outpatient observation followed by 
daily outpatient follow-ups during the subsequent 2 days.  Additional hospitalization may 
be necessary, eg, in case of serious adverse events or restart of treatment after 
treatment interruptions due to adverse events. 
The infusion bags will be changed by site nursing personnel trained on the protocol and 
on the proper administration of blinatumomab.  Close monitoring during the first 48 hours 
of treatment in the first 2 cycles will be indicated because of the potential adverse events 
associated cytokine release triggered by the administration of blinatumomab.  
Nurses/physicians trained in emergency medicine should be available for immediate 
intervention in case of complications. 
6.2.2.2 
Blinatumomab Outpatient Dosing 
After a subject meets the minimum criteria for inpatient administration and monitoring as 
described in the above section, and if a subject is deemed stable by the investigator, 
continuation of blinatumomab infusion may continue as an outpatient.  
In the outpatient setting, either the subject will return to the study site for changes of the 
infusion bag or the subject will be visited by a well-trained ambulant/home care service 
provider at specific intervals to change the infusion bag.  The subject and the 
ambulant/home care service provider will be trained and will receive written instructions 
for storage of the IV bags.  
For the ambulant/home care service provider, study-specific requirements and recording 
of source documentation 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 separately provided in a home health care manual.  
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Following each visit, this information will be documented on the ambulant/home care 
services visit worksheet and forwarded to the investigator.  
In case of any adverse event in the outpatient setting, the ambulant/home care service 
provider should directly contact the investigator at the study center for further 
management.  Any unexpected or unusual events as well as any deviations will be 
communicated promptly to the investigator.  The ambulant/home care service 
professionals provide 24 hour emergency on-call service. 
In addition, the subject will visit the study center for the examinations according to the 
Schedule of Assessments (Table 9). 
In the event of drug interruptions of > 4 hours, the restart of the infusion should be 
performed in the clinic/hospital under the supervision of the investigator. 
6.3 
Dexamethasone Premedication 
Premedication with dexamethasone is intended to prevent CRS events associated with 
blinatumomab treatment. 
Table 7 below summarizes dexamethasone use before blinatumomab treatment during 
different phases of the study.  Please also refer to appropriate protocol sections for 
specific details as not all information is contained within Table 7.  The date and time of 
infusion bag changes, all infusion start and stop times, and any dose modifications 
should also be recorded accurately.  
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Table 7.  Dexamethasone Premedication  
Treatment Phase 
Target Subject: 
Dexamethasone Dose 
Comments 
Pre-phase 
Therapy Before 
Blinatumomab  
During screening and 
before the start of 
treatment: 
 
Mandatory for: 
 
Proportion of Blasts  
exceeds approximately 
50%, or 
 
Peripheral blast count 
≥ 15,000/µL 
Recommended for: 
 
LDH indicates rapidly 
progressing disease, or 
 
Extramedullary high 
tumor load 
Dexamethasone orally or IV 
up to 10 mg/m²/day can be 
administered during 
screening and pre-phase 
until cycle 1 day 1.  If 
indicated dexamethasone 
dose can be increased to 
an absolute maximum of  
24 mg/day 
See protocol 
Section 6.3.1 
Pre-dose 
Dexamethasone 
before each 
Blinatumomab 
Treatment 
All subjects  
(before each cycle and 
dose step/increase) 
Dexamethasone 20 mg IV:  
within 3 hours before start 
of treatment in each 
treatment cycle, and within 
3 hours before dose step 
(increase). 
See protocol 
Section 6.3.2 
Infusion 
Interruption/Dose 
Modification Due 
to Adverse Event 
Subjects who interrupt 
treatment  > 4 hours 
Dexamethasone 20 mg IV:  
within 3 hours before restart 
of treatment 
See protocol 
Section 6.5  
In case of signs of 
cytokine release 
(CRS) 
Subjects with signs of CRS 
Dexamethasone orally or IV 
at a maximum dose of 
8 mg, 3 times per day.  
Reduce step-wise over 
4 days or as otherwise 
appropriate per the 
investigator.  
See protocol 
Section 6.5 
Infusion 
Interruption/Dose 
Modification Due 
to CNS Events  
Subjects with CNS-related 
adverse event 
Dexamethasone up to 
24 mg/day for up to 3 days.  
Reduce step-wise over 
4 days or as otherwise 
appropriate per 
investigator.  
See protocol 
Section 6.5 
6.3.1 
Pre-phase Therapy Before Blinatumomab Treatment 
Premedication with dexamethasone is intended to prevent CRS events associated with 
blinatumomab treatment.  Please refer to Table 7 for pre-phase dosing instructions with 
dexamethasone. 
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For this study, mandatory pre-phase therapy with dexamethasone is required before 
blinatumomab treatment if one or more of the following criteria are met: 
 
Proportion of blasts (determined by cytomorphology) exceeds approximately 50%, or 
 
peripheral blood blast count ≥ 15,000/μL. 
Pre-phase therapy with dexamethasone is recommended before blinatumomab 
treatment if, in the opinion of the investigator: 
 
LDH indicates rapidly progressing disease, or 
 
signs of extramedullary disease show high tumor load. 
Pre-phase dexamethasone at a dose up to 10 mg/m2/day during screening.  If clinically 
indicated, the dexamethasone dose can be increased to an absolute maximum dose of 
24 mg/day. 
If the subject received dexamethasone (up to 24 mg/day) for other reasons than 
pre-phase within 14 days before the start of screening, further pre-phase treatment with 
dexamethasone is not required.  However, premedication with dexamethasone is 
required within 3 hours before the start of treatment in each treatment cycle and within 
3 hours before the dose step as described in Table 7. 
It should be noted that in cases of ALL that are refractory to dexamethasone treatment, 
a preventative effect on CRS can still be achieved.  If a subject is refractory to 
dexamethasone, a pre-phase is not mandatory, but dexamethasone up to a maximum 
dose of 24 mg/day should be administered at least for the first 2 days of treatment with 
step-wise reduction afterwards. 
Subjects who should receive dexamethasone treatments of at least 24 mg/day and who 
have already received the mandatory 20 mg IV premedication dose before  
blinatumomab infusion at day 1, may receive the remaining balance of dexamethasone 
up to a maximum of 24 mg/day. 
6.3.2 
Pre-dose Dexamethasone Before Each Blinatumomab Treatment 
Within 3 hours before the start of treatment in each treatment cycle and within 3 hours 
before dose step, mandatory premedication with dexamethasone at 20 mg IV is required 
for the prevention of CRS resulting from blinatumomab. 
6.4 
CSF Prophylaxis Before Blinatumomab Treatment  
Within 14 days before the start of blinatumomab and following each induction and 
consolidation treatment cycle (after BM aspiration on day 29) a mandatory CSF 
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prophylaxis consisting of an intrathecal regimen according to institutional or national 
guidelines will be administered (eg, methotrexate 12 to 15 mg, cytosine arabinoside 
40 mg, and dexamethasone 4 mg or equivalent steroid dose).  In case of anticipated 
safety risks caused by lumbar puncture, eg, in case of thrombocytopenia, CSF 
prophylaxis may be omitted.   
6.5 
Dose Modifications (Interruptions, Withholdings, and Criteria for 
Restarting Treatment) 
Table 8.  Instructions for Treatment Interruption, Dose Modification and Restart 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
Cytokine 
Release 
Syndrome 
(CRS) 
3 
 
Interrupt blinatumomab and administer corticosteroids (refer to 
Table 7)   
 
Restart blinatumomab at 9 µg/day once improved to grade ≤ 1 
or to baseline 
 
Dose step to 28 µg/day after 7 days if toxicity does not recur  
4 
 
Permanently discontinue blinatumomab 
Neurologic 
Events 
3 
 
Interrupt blinatumomab for at least 72 hours and administer 
corticosteroids (refer to Table 7) 
 
Restart blinatumomab at 9 µg/day once improved to grade ≤ 1 
or to baseline 
 
Dose step back to 28 µg/day after 7 days if toxicity does not 
recur 
 
Permanently discontinue if: 
 
Initial event occurred at 9 µg/day 
 
Initial grade 3 neurologic event does not improve to 
≤ grade 1 within 7 days OR 
 
Grade 3 neurologic event reoccurs at the lower dose level 
within 7 days of reinitiation 
4 
 
Permanently discontinue blinatumomab 
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Footnotes provided on last page of table 
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Table 8.  Instructions for Treatment Interruption, Dose Modification and Restart 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
 
Seizuresa  
 
Interrupt blinatumomab, administer corticosteroids (refer to 
Table 7) and anti-seizure medication per local practice 
 
For restart, refer to grade 3 neurologic events above for dose 
level rules for reinitiation 
 
Do not reinitiate 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 a second seizure 
occurs with reinitiation of blinatumomab at any dose 
Elevated 
liver 
enzymes 
Not 
applicable 
 
Interrupt blinatumomab (refer to Section 6.7.2) if any one of the 
following occurs: 
 
TBL > 3 x ULN at any time 
 
ALP > 8 x ULN at any time 
 
AST or ALT > 8 x ULN at any time 
 
AST or ALT > 5 x ULN but < 8 x ULN for ≥ 2 weeks 
 
AST or ALT > 3 x ULN with clinical signs or symptoms that 
are consistent with hepatitis (eg, RUQ abdominal 
pain/tenderness, fever, nausea, vomiting, jaundice) 
 
Permanently discontinue blinatumomab if: 
 
TBL > 2 x ULN OR INR > 1.5 (for subjects not on 
anticoagulant therapy) 
AND 
 
AST or ALT > 3 x ULN (when baseline was < ULN) 
AND 
 
No other cause for the combination of the above laboratory 
abnormalities is immediately apparent 
Refer to Section 6.7 for additional details 
Page 2 of 3 
Footnotes provided on the last page of table 
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Table 8.  Instructions for Treatment Interruption, Dose Modification and Restart 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
Other 
clinically 
relevant 
related 
adverse 
eventsb 
3 
 
Interrupt blinatumomab  
 
Restart blinatumomab at 9 µg/day once improved to grade ≤ 1 
or to baseline (refer to Table 7) 
 
Dose step to 28 µg/day after 7 days if toxicity does not recur 
 
Permanently discontinue if: 
 
Initial grade 3 event does not improve to grade ≤ 1 or 
baseline within 14 days, OR 
 
Grade 3 event reoccurs at the lower dose level within 
7 days or reinitiation, OR 
 
Grade 3 event reoccurs at a dose of 9 µg/day without prior 
step-dose escalation 
4 
 
Permanently discontinue blinatumomab 
Page 3 of 3 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
CRS = cytokine release syndrome; INR = international normalized ratio; RUQ = right upper quadrant;  
TBL = total bilirubin; ULN = upper limit of normal  
Grade scale is based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
a Obtain brain Magnetic Resonance Imaging (MRI) and perform cerebrospinal fluid (CSF) analysis, if there 
are no contraindications. 
b For grade 3 or 4 laboratory abnormalities, investigator assessment should be used to determine 
risk:benefit for each individual patient to continue, interrupt or discontinue blinatumomab treatment. 
If the interruption after an adverse event is no longer than 7 days, the same cycle will be 
continued.  The infusion duration before and after an interruption should total 28 days 
per treatment cycle.  If an interruption due to an adverse event is longer than 7 days, a 
new cycle will start.  In addition, an incomplete treatment cycle with a treatment duration 
of less than 2 weeks will have to be repeated (eg, if cycle 1 was interrupted on day 8 for 
more than 7 days, the next cycle will be denoted as cycle 1.1 and the same 
assessments will be performed as in cycle 1).  For cycle 1.1, subjects will be started at 
9 μg/day for the first 7 days of dosing followed by a dose step to 28 μg/day beginning at 
day 8 and continuing for the remainder of cycle 1. 
In the case of treatment interruptions which do not result in the initiation of a new cycle 
(ie, < 7 days), all assessments should be completed according to the number of active 
days on treatment. 
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6.6 
Criteria for Blinatumomab Discontinuation 
Treatment with blinatumomab should be discontinued in the event of any of the 
following: 
 
Hematological or extramedullary relapse subsequent to achieving ≤ 5% BM blasts on 
protocol treatment 
 
Exception:  subjects who develop isolated CNS leukemia, relapse during 
treatment and who have not met the criteria for an event as defined above, may 
continue on study and receive additional CNS directed therapy in addition to their 
systemic protocol-specified therapy.  Subjects should receive intrathecal 
chemotherapy until negative for CNS leukemia before starting blinatumomab. 
 
Failure to achieve BM response defined as ≤ 5% blasts within 2 treatment cycles 
 
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 
 
An infusion interruption of more than 2 weeks due to an adverse event related to 
blinatumomab (exception:  in case of logistical difficulties, restart of treatment can be 
postponed for up to 7 additional days without resulting in permanent treatment 
discontinuation) 
 
Investigator’s decision that a change of therapy (including immediate HSCT) is in the 
subject´s best interest 
 
Administration of relevant non-permitted concomitant medications (as outlined in 
Section 6.9) 
 
Investigator’s decision that a subject does not benefit from treatment anymore, 
eg, non-response or development of progressive disease 
 
Intercurrent medical condition, which in the opinion of the investigator or the subject  
precludes further treatment of the subject 
 
Withdrawal of subject’s consent to further study treatment 
All reasons for treatment discontinuation will be documented in the eCRFs.  If a subject 
fails to keep the appointments for study visits, the investigator will document the reason 
and circumstances as completely and accurately as possible. 
In case of premature treatment discontinuation, the assessments planned for end of 
treatment (end of infusion) should be performed immediately.  Exceptions:  The CSF 
examination/prophylaxis does not have to be done in case of premature treatment 
discontinuation.  Bone marrow aspiration/biopsy is not required in case of documented 
progressive disease.  In addition, the SFU visit should be performed 30 days (± 3 days) 
after the last dose of blinatumomab was administered or, if applicable, before the start of 
non-protocol-specified therapy or alloHSCT, whichever occurs first.  The subject should 
continue to come to all relevant long-term follow-up visits. 
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6.7 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, ALT, TBL), and/or 
international normalized ratio (INR), and/or signs/symptoms of hepatitis (as described 
below) may meet the criteria for withholding or permanent discontinuation of 
blinatumomab or other protocol-required therapies as specified in the guidance for 
industry Drug-Induced Liver Injury (DILI):  Premarketing Clinical Evaluation, July 2009. 
6.7.1 
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 A (Additional Safety Assessment Information) for possible DILI, if ALL of the 
criteria below are met: 
 
TBL > 2 x 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 
> 3x 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: 
o Hepatobiliary tract disease 
o Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus (CMV), Herpes Simplex Virus, Varicella, toxoplasmosis, 
and Parvovirus) 
o Right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia 
o Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal 
and dietary supplements, plants and mushrooms 
o Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
Syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir) 
o Alpha-one antitrypsin deficiency 
o Alcoholic hepatitis 
o Autoimmune hepatitis 
o Wilson’s disease and hemochromatosis 
o Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 
o Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
o Cytokine release syndrome 
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If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if blinatumomab and other protocol-required 
therapies should be withheld or permanently discontinued, as deemed appropriate for 
the safety of the subject. 
6.7.2 
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 concerning 
transaminases and TBL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules described above in Table 8 for 
withholding of blinatumomab and other protocol-required therapies. 
Blinatumomab and other protocol-required therapies, as appropriate should be withheld 
pending investigation into alternative causes of DILI.  If investigational product(s) is 
withheld, the subject is to be followed according to recommendations in Appendix A for 
possible DILI.  Rechallenge may be considered if an alternative cause for impaired liver 
tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the laboratory 
abnormalities resolve to normal or baseline (Section 6.7.3). 
6.7.3 
Criteria for Rechallenge of Blinatumomab and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
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 8) should never be rechallenged. 
6.8 
Guidelines for Common Toxicities 
6.8.1 
Hydration During the Treatment Period 
Because of the high tumor load the subjects should receive adequate hydration 
according to institutional guidelines. 
6.8.2 
Fever Management 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided if possible because 
they are a potential cause of endothelial stress and could potentially affect T-cells that 
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are required for blinatumomab action.  For symptomatic relief of fevers due to any cause 
(ie, infection, drug fever) the recommended first choice agents 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 
anti-emetic prophylaxis should be administered.  The treating physician should also use 
their clinical judgment to determine the underlying cause of the fever and treatment.  
6.8.3 
Additional Treatment for Special Subject Populations 
Subjects who enter the study who previously underwent alloHSCT and present with a 
medical history of GvHD must receive antifungal prophylaxis.   
For subjects with a high risk for CMV infection [prior CMV re-activation or risk 
constellation in prior alloHSCT (donor:  CMV negative, recipient:  CMV positive)], one of 
the following measures should be performed: 
 
Intensive (2x/week) CMV-PCR follow-up with early therapeutic intervention if positive 
or  
 
Prophylactic CMV treatment. 
6.9 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.10. 
6.10 
Excluded Treatments During Study Period 
The following medications are not permitted during a subject’s participation (including 
the induction, consolidation treatment) of this study: 
 
Any anti-tumor therapy other than the protocol specified therapy (ie, radiation 
therapy, immunotherapy, cytotoxic and/or cytostatic drugs); 
 
Chronic systemic (> 7 days) high-dose corticosteroid therapy 
(dexamethasone> 24 mg/day or equivalent); any other immunosuppressive therapies 
(except for transient use of corticosteroids); 
 
Any other investigational agent 
6.11 
Medical Devices 
Blinatumomab must be administered using infusion pumps approved for use by the 
appropriate regulatory authorities for the country in which the subject is undergoing 
treatment, in both the inpatient and outpatient setting. 
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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.  
Additional details for the use of the above mentioned medical devices and specific set of 
device specifications are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care.  Other medical devices (eg, syringes, sterile needles, alcohol prep 
pads), that are commercially available are not provided or reimbursed by Amgen 
(except, if required by local regulation).  The Investigator overseeing the conduct of the 
study at each respective institution will be responsible for obtaining these supplies.   
6.12 
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) or device(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. 
6.13 
Contraceptive Requirements 
6.13.1 
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 1 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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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 CIVI 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) 
 
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 CIVI 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.   
6.13.2 
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. 
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7. 
STUDY PROCEDURES 
Refer to the Schedule of Assessments (Table 9) for an outline of the procedures 
required at each visit.  Study procedures for days 1 through day 3 should occur as 
scheduled.  Beginning with Day 8, all study procedures have a window of  1 day, 
unless otherwise noted. 
Refer to the applicable supplement manuals (eg, IVRS/IWRS manual, laboratory manual 
and eCRF completion guidelines) for detailed data collection and procedural guidance. 
7.1 
Schedule of Assessments  
 
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Table 9.  Schedule of Assessments 
Examination 
Screening / 
Pre-Phase 
Treatment Period: 
Schedule for Each Cycle of Protocol-Specified 
Therapy 
SFU Visit 
Long-term FU 
Efficacy/Survival 
Day (D) 
Screening 
≤ 21 days 
D1a 
D2 
D3 
D8 
D15 
End of treatment 
cycle 
(D29 + 3days)n 
30 days 
(± 3 days) after 
protocol specified 
therapy 
Every 3 months  
(± 1 month) 
Informed Consent 
X  
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X  
 
 
 
 
 
 
 
 
Medical History/Demographics 
X  
 
 
 
 
 
 
 
 
ECOG Performance Status 
Assessment 
X  
 
 
 
 
 
 
X 
 
Neurological Examination 
X  
X 
 
 
 
 
 
X 
 
Physical Examination  
X  
X 
X 
 
X 
X 
X 
X 
 
Vital Signs & Temperatureb 
X  
X 
X 
 
X 
 
 
X 
 
Height & Weightc 
 
X 
 
 
 
 
 
X 
 
Lumbar Puncture/Intrathecal 
prophylaxism 
Xo 
 
 
 
 
 
X 
 
 
Bone Marrow Aspirate 
Xd,o 
 
 
 
 
 
X 
Xd 
X 
Chemistry 
X 
X 
X 
 
X 
X 
X 
X 
 
Coagulation 
 
X 
X 
 
 
 
 
X 
 
Hematology with Differential 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis  
 
X 
 
 
 
 
 
X 
 
Creatinine Clearancee 
X 
 
 
 
 
 
 
 
 
Lymphocyte Subsetsf 
 
X 
X 
 
 
 
X 
X 
(X) 
Page 1 of 2 
Footnotes provided on last page of table. 
 
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Table 9.  Schedule of Assessments 
Examination 
Screening / 
Pre-Phase 
Treatment Period: 
Schedule for Each Cycle of Protocol-Specified 
Therapy 
SFU Visit 
Long-term FU 
Efficacy/Survival 
Day (D) 
Screening 
≤ 21 days 
D1a 
D2 
D3 
D8 
D15 
End of treatment 
cycle 
(D29 + 3days)n 
30 days 
(± 3 days) after 
protocol specified 
therapy 
Every 3 months  
(± 1 month) 
Immunoglobulins (IgG)g 
 
X 
 
 
 
 
X 
X 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
 
 
X 
 
Anti-blinatumomab antibodiesh 
 
X 
 
 
 
 
X 
X 
 
Intensive Pharmacokinetic Samplei 
 
X 
X 
 
 
X 
X 
 
 
Non-intensive Pharmacokinetic 
Samplei 
 
 
X 
 
 
X 
 
 
 
Cytokinel 
 
X 
X 
X 
 
 
 
 
 
EORTC QLQ-C30k 
 
X 
 
 
X 
X 
X 
X 
 
Protocol-Required Therapy  
 
Blinatumomab 
 
 
Concomitant Medication 
Continuously throughout the whole core study 
X 
Disease Related Events/Adverse 
Events/Serious Adverse Events 
Continuously throughout the whole core study 
 
Disease/Survival Statusj 
 
X 
Page 2 of 2 
ALL = acute lymphoblastic leukemia; BM = bone marrow; CSF = cerebrospinal fluid; ECOG = Eastern Cooperative Oncology Group;  
EORTC QLC-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; FU = follow-up; PK = pharmacokinetics; 
SFU = safety follow-up; ULN = upper limit of normal 
a All procedures completed on Day 1, must be completed before the initiation of protocol-specified therapy. 
b Vital signs (ie, systolic/diastolic blood pressure, heart rate, and respiratory rate) and temperature collected every 12 hours during cycle 1, day 1 (D1) and day 2 (D2), 
once daily on D1 and D2 for each subsequent cycle.  Vital signs collected at cycle 1, day 8 (D8) only if dose step is performed and the SFU visit (± 3 days).  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 as possible. 
c Height and weight performed pre-dose at baseline (Cycle 1 D1) only.  Weight performed at SFU visit (± 3 days) only. 
 
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d ALL BM assessments have + 3 days window during treatment phase.  BM assessments at Screening:  sample has to be taken prior to treatment start.  Bone marrow 
aspirate/biopsy will be performed at the SFU visit (± 3 days), if the subject ended treatment for any other reason than relapse and has not had a bone marrow 
aspirate/biopsy performed within 6 weeks (± 3 days) of this visit.  If a subject has not relapsed by day 29 (D29) of their last treatment cycle, BM aspirate should be 
performed every 3 months (± 1 month) until relapse. 
e Calculation of creatinine clearance only required if screening creatinine is ≥ 1.5 ULN. 
f Lymphocyte subsets will be collected at baseline (before first dose on Cycle 1 D1), at cycle 1 (24 hours after the beginning of the infusion [D2] and at the end of the 
infusion), and at the SFU visit.  If B cells have not recovered (number of CD19-positive cells is 90 to 570 per μL) at the SFU visit lymphocyte subsets will also be 
collected 6 months (+3 months) after the SFU visit.  
g Immunoglobulin (IgG) samples will be collected pre-dose at baseline (Cycle 1 D1), at D29 (+3) days of each treatment cycle, and the SFU visit (± 3 days). 
h Anti-blinatumomab antibody samples are collected at baseline (before first dose on Cycle 1 D1), on D29 after the completion of cycle 2, and at the SFU visit  
(± 3 days).  See Section 7.8 for details regarding additional samples needed if Anti-blinatumomab antibody sample is positive at SFU.  
i Intensive PK (20 subjects):  only within the first 2 treatment cycles.  In cycle 1, samples will be taken prior to treatment start (prefer day 1, acceptable on day -1), and 
during infusion on day 1 (2 hours, 6 hours, 10 hours, ± 30 minutes), any time during day 2 and day 15 as well as on day 29 within 2 hours prior to the end of infusion 
and after the end of infusion at 3 hours (± 30 minutes) and 6 hours (± 30 minutes).  In cycle 2, samples are collected at any time on day 2, day 15 and within 2 hours 
prior to end of infusion on day 29.  
   Non-intensive PK (rest of study population):  PK samples will be collected on D2 and D15 in both cycle 1 and cycle 2 at the same time as other blood samples 
scheduled. 
j Subjects who did not respond to or relapsed after protocol-specified therapy and are being followed in long-term follow-up will only undergo a telephone contact to 
determine survival status by either the research investigational site or treating physician and collection of anti-leukemic treatment concomitant medications.  Bone 
marrow and hematology assessments are required only for subjects who remain in remission.  
k EORTC QLQ C30 should be completed on D1, D8, D15, and D29 during Cycle 1; D1, D15, and D29 during cycle 2 and each consolidation cycle, and at the 
SFU visit (± 3 days). 
l Cytokine samples will be taken prior to treatment start (baseline), day 1 at 6 hours after infusion start and at any time on day 2 and day 3 in cycle 1. 
m Intrathecal prophylaxis within 14 days before the start of protocol-specified therapy AND following each treatment cycle (after BM aspirate on D29). 
n In case of premature treatment discontinuation, the end of treatment assessments should be performed immediately except CSF examination/prophylaxis 
(see Section 6.6 for details).  
o Standard of care procedures such as bone marrow aspiration/biopsy and lumbar puncture are not considered study specific.  Standard of care procedures may be 
performed prior to informed consent and used to determine eligibility, but must occur within 21 days prior to starting treatment with blinatumomab, unless specified 
otherwise.  The intrathecal chemotherapy needs to be administered within 14 days prior to starting treatment with blinatumomab. 
 
 
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7.2 
General Study Procedures  
An overview of study assessments/procedures is provided below.  A description for each 
phase of the study is provided in Section 7.3 through Section 7.6.  Refer to the eCRF 
completion guidelines for data collection requirements and documentation of study 
assessments/procedures. 
7.2.1 
Informed Consent 
All subjects or their legally acceptable representative (ie, legal guardian) must sign and 
date the most current IRB/EC approved ICF.  Confirmation that the ICF has been signed 
should occur before any study specific procedures are performed.  
All subjects who are enrolled and 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.  
7.2.2 
Demographics 
Demographic data that will be collected include sex, age, race, and ethnicity to study 
their possible association with subject safety and treatment effectiveness.  Additionally 
demographic data will be used to study the impact on PK of blinatumomab.  
7.2.3 
Medical History 
The Investigator or designee will collect relevant medical history before the start of 
adverse event reporting. 
In addition to the medical history noted above, all history related to the subjects 
diagnosis of ALL (eg, risk stratification, immunophenotype, information on prior 
anti-tumor therapies and HSCT data) must date back to the original diagnosis.   
7.2.4 
ECOG Performance Status 
The subject’s PS will be assessed using the ECOG performance scale (see Appendix E) 
at intervals identified in the Schedule of Assessments (Table 9).  
7.2.5 
Physical Examination 
The baseline physical examination will be a complete physical examination.  The 
physical examination at subsequent study visits will consist of an interim examination to 
monitor for any changes from the baseline physical examination.  Abnormal findings 
should be documented in the appropriate eCRF. 
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7.2.6 
Physical Measurements 
Height should be measured without shoes.  Weight should be measured without shoes.  
The baseline assessment includes height and weight.  The SFU physical measurements 
will include weight only.  
7.2.7 
Vital Signs 
Systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature are 
measured as per Schedule of Assessments (Table 9).  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 as possible.  The position selected for a 
subject should be the same that is used throughout the study and documented on the 
vital sign eCRF. 
Record all measurements on the vital signs eCRF. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the eCRF. 
7.2.8 
Neurological Examination 
A neurological examination will be performed as outlined in the Schedule of 
Assessments (Table 9).  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, and neuropsychological 
findings (eg, speech, cognition and emotion).  If neurologic abnormalities are present at 
screening, then they will be considered as medical history.  Any new findings on 
neurological examination during the study will be considered adverse events and graded 
per CTCAE Version 4.03.  
7.2.9 
Lumbar Puncture to Examine Cerebrospinal Fluid  
A lumbar puncture will be performed as outlined in the Schedule of Assessments 
(Table 9) to assess for possible leukemic involvement.  Cerebrospinal fluid (CSF), 
including 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.  
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If an Ommaya reservoir is in place and there is no evidence of blockage of CSF flow in 
the spinal canal, withdrawal of a sample through the Ommaya reservoir is permitted. 
7.2.10 
Intrathecal Prophylaxis 
Within 14 days before the start of protocol-specified therapy AND following each 
treatment cycle (after BM aspiration on Day 29) a mandatory CSF prophylaxis consisting 
of an intrathecal regimen will be administered (eg, methotrexate 12 to 15 mg, cytosine 
arabinoside 40 mg, and dexamethasone 4 mg or equivalent steroid dose).  
In case of anticipated safety risks caused by lumbar puncture during the treatment 
period of the study (eg, in case of thrombocytopenia) CSF prophylaxis may be omitted. 
7.2.11 
Bone Marrow Biopsy/Aspiration 
Bone marrow (BM) will be used for hematological assessment and for evaluation of 
MRD.  The following samples will be obtained for cytomorphological assessment and 
MRD measurement: 
 
Cytomorphology:  BM smears (slides) at screening and at the end of each 
treatment cycle.  In case of insufficient quality of the aspiration material at the 
end of each treatment cycle, a core biopsy should be performed before treatment 
start in the next cycle or at the SFU visit, if the subject has not progressed and no 
further treatment cycles are to be administered. 
 
A fresh BM sample will be collected and analyzed at a central lab for MRD 
assessment by multi-color flow cytometry at screening and at the end of the first 
and second treatment cycles. 
If a marrow aspiration is not possible, or the aspirate does not contain any BM, a core 
biopsy will be done.  In case of core biopsies, no central MRD assessment will be 
possible due to the need to preserve the biopsy with formalin before shipment. 
If a subject has not relapsed by their last induction and consolidation treatment cycle, a 
BM biopsy or aspirate should be performed every 3 months (± 1 month) until relapse. 
The degree of BM infiltration defined by the percentage of leukemic blasts in BM will be 
evaluated by local laboratories as per cytological assessment.  In addition, the BM slides 
will be provided to the designated central laboratories for hematological assessment.  If 
immunocytochemistry (ICC) is not possible, then immunohistochemistry (IHC) will be 
done instead on the back-up core biopsy to confirm cytomorphology.  The following 
markers will be analyzed as needed:  CD3, CD5, CD10, CD13, CD19, CD22, CD23, 
CD33, CD34, CD79A, POX, TDT.  
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The results of the local laboratory are applicable for inclusion into the study and for the 
decision if pre-treatment and/or blinatumomab treatment should be administered if the 
results of the central laboratory are not yet available at the time these decisions are 
made.  For evaluation of baseline and response, the result of the central laboratory will 
prevail.  
Known cytogenetic and molecular aberrations will be documented in the eCRF. 
Results of additional tests routinely conducted by the investigators, but not required by 
the protocol such as immunophenotypic, cytogenetic or molecular analyses conducted 
during the study, will be collected and documented in the eCRF. 
Note:  the time window for all BM assessments as per Schedule of Assessments in  
Table 9.  
7.2.12 
Concomitant Medications 
Concomitant therapies are to be collected from signing of the consent form through the 
SFU period.  Following the SFU visit, only medications taken for the treatment of ALL will 
be collected. 
For concomitant therapies, the therapy name, indication, dose, unit, frequency, start date 
and stop date will be collected.   
Concomitant medication collection requirements and instructions are included in the 
eCRF completion guidelines. 
7.2.13 
Definitions of Treatment Response 
The treatment is defined to be efficacious, when the subject is stated to be in CR or in 
CRh* or CRi.  
Hematological remissions are defined by the following criteria:  
Complete Remission (CR): 
 
Less than or equal to 5% blasts in the BM  
 
No evidence of disease 
 
Full recovery of peripheral blood counts: 
 
Platelets > 100,000/µl 
 
ANC > 1,000/µl 
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Complete Remission with only Partial Hematological Recovery (CRh*):  
 
Less than or equal to 5% blasts in the BM 
 
No evidence of disease 
 
Partial recovery of peripheral blood counts: 
 
Platelets > 50,000/µl and 
 
ANC > 500/µl 
Complete Remission with only incomplete blood count recovery (CRi):  
 
Less than or equal to 5% blasts in the BM 
 
No evidence of disease 
 
Partial recovery of peripheral blood counts: 
 
Platelets >100,000/µl;  or  
 
ANC > 1000/µl 
Subjects who will have achieved CR or CRh* or CRi within 2 cycles of treatment will 
receive up to 3 additional cycles of treatment for consolidation. 
Blast free hypoplastic or aplastic BM: 
 
Less than or equal to 5% blasts in the BM 
 
No evidence of disease 
 
Insufficient recovery of peripheral counts:  platelets ≤ 50,000/µl and/or ANC ≤ 500/µl 
The onset of remission is defined by the date of the first aspiration/biopsy on which the 
remission was documented. 
When criteria are met for both CRh* and CRi, CRh* should be reported.  When criteria 
are met for both CRi and blast-free marrow, CRi should be reported. 
Progressive Disease:  
 
An increase of at least 25%, or an absolute increase of at least 5,000 cells/µL 
(whichever is greater), in the number of circulating leukemia cells, development of 
extramedullary disease, or other laboratory or clinical evidence of progressive 
disease 
Non-response: 
 
None of the above 
Hematological Relapse: 
 
Proportion of blasts in BM > 5% or 
 
Blasts in peripheral blood after documented CR/CRh*  
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An extramedullary relapse will be assessed as hematological relapse. 
The relapse will be analyzed by immuno-phenotyping whether it still fulfills the criteria for 
B-precursor ALL.  The onset of relapse is defined by the date of the first sample on 
which relapse was documented.  
All hematological assessments of BM will be reviewed in a central reference laboratory.  
In the event of disease progression or hematological relapse within the treatment period, 
treatment will be terminated. 
Extramedullary disease: 
If clinical signs of extramedullary lesions are present, assessments will be performed 
according to Cheson criteria (Table 10).  If computed tomography (CT) scans are 
conducted, this should be done according to standard clinical practice.  If a CT scan has 
been performed within one month before start of blinatumomab treatment and if no 
clinical signs of a change of disease state have been observed, this assessment can be 
regarded as screening assessment. 
Table 10.  Cheson Criteria for Evaluation of Extramedullary Disease 
(From Cheson et al. 2007) 
 
MRD response: 
MRD < 10-4  leukemic cells detectable measured by flow cytometry.  
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. 
 
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MRD complete response: 
No detectable leukemic cells by flow cytometry 
MRD relapse: 
Re-appearance of leukemic cells detectable by flow cytometry. 
MRD progression: 
Increase in the MRD level by one log as compared to the baseline level which is equal to 
a 10-fold increase in the number of MRD cells. 
7.2.14 
Patient Reported Outcomes:  EORTC Quality of Life Questionnaire 
The PRO questionnaire (EORTC QLQ C30) should be completed by the subject before 
any other clinical assessments and before receiving any study medications.  Subjects 
who are blind or illiterate may have the PRO questionnaires read to them by the study 
staff.  The study staff, however, cannot interpret any of the questions for the subject.  
Patient reported questionnaires will be completed as outlined in Schedule of 
Assessments (Table 9). 
The EORTC quality of life questionnaire (QLQ) is a generic patient reported outcomes 
instrument for assessing the health related quality of life (HRQoL) of cancer subjects 
participating in clinical trials. 
The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures.  
These include 5 functional scales, 3 symptom scales, a global health status/QoL scale, 
and 6 single items.  Each of the multi-item scales includes a different set of items.  No 
item occurs in more than one scale.  All of the scales and single-item measures range in 
score from 0 to 100.  A high scale score represents a higher response level. 
Thus a high score for a functional scale represents a high/healthy level of functioning; a 
high score for the global health status/QoL represents a high QoL, but a high score for a 
symptom scale/item represents a high level of symptomatology/problems. 
7.2.15 
Laboratory Assessments 
All screening and on-study laboratory samples will be collected and processed at the 
investigators local laboratory and analyzed locally or centrally.  Chemistry (with the 
exception of amylase and lipase), creatinine clearance, coagulation tests, hematology, 
urinalysis, IgG, leukemic blasts, and pregnancy confirmation will be performed locally.  
Chemistry (amylase and lipase), anti-blinatumomab antibody samples, PK samples, 
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cytokine samples, lymphocyte subsets, as well as BM samples for hematological and 
MRD assessments may 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.  
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 11 below outlines the specific analytes that will be assessed during the study at 
time points outlined in the Schedule of Assessments (Table 9). 
Table 11.  Laboratory Analyte Listing 
Chemistry 
Coagulation 
Urinalysisa 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinineb 
Uric acid 
Alk phos 
LDH 
AST  
ALT  
C-reactive protein 
Bilirubin (total) 
GGT 
aPTT and INR 
Blood 
Protein  
Glucose 
 
 
Hemoglobin 
Hematocrit 
Reticulocytes 
Platelets 
RBC 
WBC 
Differential 
 Neutrophils 
 Lymphocytes 
 Monocytes 
 
Optional: 
 Bands or stabs 
 Eosinophils 
 Basophils 
 Blasts 
 Lymphoblasts 
 Myeloblasts 
 Promyelocytes 
 Myelocytes 
 Metamyelocytes 
 Atypical 
lymphocytes 
Local: 
Serum or urine 
pregnancy 
IgG 
CSF analytes 
Percentage of 
leukemia blasts in 
bone marrow 
(cytological 
assessment during 
screening) 
 
Central: 
Bone marrow 
Aspirate/Biopsyc 
(cytomorphology, 
markers, MRD) 
Anti-blinatumomab 
Antibodies 
Lymphocyte 
subsets 
PK 
Cytokines 
MRD 
Central Chemistry: 
Amylase 
Lipase 
 
 
 
 
Footnotes defined on next page 
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ALT = alanine aminotransferase; aPTT = active partial thromboplastin time; AST =  spartate 
aminotransferase; BUN  =  blood urea nitrogen; CSF = cerebrospinal fluid; D1 = day 1;  
GGT = gamma glutamyl transferase; IgG = Immunoglobulin G; INR = international normalized ratio;  
LDH = lactate dehydrogenase; MRD = minimal residual disease; PK = pharmacokinetics; RBC = red blood 
cell; SFU = safety follow-up; ULN = upper limit of normal; WBC = white blood cell 
a The presence of glucose, protein and blood in urine will be assessed during baseline at D1 before the start 
of infusion at each cycle, and at the SFU visit 
b Calculation of creatinine clearance will only be required during the screening period if creatinine 
determined by serum chemistry is ≥ 1.5 ULN 
c The following markers will be analyzed as needed:  CD3, CD5, CD10, CD13, CD19, CD22, CD23, CD33, 
CD34, CD79A, POX, TDT 
7.2.16 
Lymphocyte Subsets 
Immunophenotyping by flow cytometry to monitor peripheral blood changes in 
lymphocytes (B, T and natural killer [NK] cells), leukocyte populations (leucocytes, 
lymphocytes, monocytes, and granulocytes), T cells subsets, T cells activation markers 
as well as potential drug resistance mechanisms (T cells exhaustion markers, Tregs and 
immune checkpoint ligands) will be completed.  Lymphocyte subsets will be collected at 
time points outlined in the Schedule of Assessments (Table 9). 
If B-cell counts have not recovered at the SFU visit (recovered is defined as number of 
CD19-positive cells per µL is 90 to 570), another sample will also be taken 6 months 
(+3 months) after SFU visit for determination of lymphocyte subsets. 
7.2.17 
Peripheral Blood Cytokines/Markers 
To monitor activation of immune effector cells and better understand T cell activation, 
blood samples will be taken at various time points as indicated in the Schedule of 
Assessments (Table 9).  Serum cytokines and chemokines will be measured. 
7.2.18 
Immunoglobulins 
Immunoglobulins (IgG only) will be collected at time points outlined in the Schedule of 
Assessments (Table 9) to detect hypogammaglobulinemia or immunological changes. 
7.2.19 
Pharmacokinetic Assessments 
If the subject consents to the intensive pharmacokinetics portion of this study, additional 
PK samples will be obtained.  For intensive PK sample collection, serum samples will be 
collected for approximately 20 subjects at baseline and at scheduled time points during 
the treatment period within the first 2 treatment cycles.  In cycle 1, samples will be taken 
prior to treatment start (prefer day 1, acceptable on day -1), and during infusion on day 1 
(2 hours, 6 hours, 10 hours, ± 30 minutes), any time during day 2 and day 15 as well as 
on day 29 within 2 hours prior to the end of infusion and after the end of infusion at 
3 hours (± 30 minutes) and 6 hours (± 30 minutes).  In cycle 2, samples are collected at 
any time on day 2, day 15, and within 2 hours prior to end of infusion on day 29.  
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For non-intensive PK sample collection, 4 serum samples will be collected to measure 
blinatumomab serum concentration during the blinatumomab treatment period in all 
subjects who received the drug.  PK samples will be collected on D2 and D15 in both 
cycle 1 and cycle 2 for determination of serum steady state drug concentrations (Css).  
Pharmacokinetic samples may be collected during the infusion at the same time that the 
other blood samples are collected.  The samples will be measured with a validated 
assay. 
PK samples must be drawn from a site that is distal from the site where the 
investigational product has been administered to avoid contamination of the PK samples 
and to better estimate PK parameters.  On PK assessment days, the date and time of 
infusion bag changes and any dosing interruptions will be recorded in the eCRF. 
7.2.20 
Pregnancy Tests 
Urine or serum pregnancy tests will be performed locally at each site on all females 
except for female subjects who are surgically sterile or  2 years post-menopausal.  If 
the pregnancy test is positive at screening the subject should not be enrolled.  If a 
standard of care pregnancy test is collected during the course of the study, and the 
result is positive, the investigator should contact the Amgen medical monitor for 
instructions. 
If a female subject, or the partner of a male subject, becomes pregnant during the 
conduct of the study it must be reported on the Pregnancy and Lactation Notification 
Worksheet, (Appendix C). 
7.3 
Screening/Pre-treatment 
Screening procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 9).  In addition, the obligatory 
premedication (Section 6.3) will be administered during screening. 
The screening process begins on the date the subject signs the IRB/IEC approved ICF 
and continues until enrollment.  Informed consent must be obtained before completing 
any study specific procedures.  Standard of care procedures such as bone marrow 
aspiration/biopsy and lumbar puncture are not considered study specific.  Standard of 
care procedures may be performed prior to informed consent and used to determine 
eligibility, but must occur within 21 days prior to starting treatment with blinatumomab, 
unless specified otherwise. 
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Rescreening: 
Subjects who are unable to complete or meet eligibility at the initial screening will be 
permitted to rescreen once, provided study recruitment has not closed.  Upon signing a 
new ICF, a new 21-day screening window will begin.  Subjects will retain the same 
subject identification number assigned at the original screening.   
After reconsenting, all screening procedures, including the lumbar puncture and 
BM biopsy, must be repeated unless the procedure was performed within 14 days prior 
to treatment start. 
7.4 
Treatment  
It is strongly recommended that subjects are hospitalized at least during the first 9 days 
(1 week plus 2 days following dose step) of the first cycle and the first 2 days of the 
following cycle.  The hospitalization time depends on investigator´s judgment, as well as 
safety and tolerability of blinatumomab.  However, the hospitalization must span at least 
the first 2 days after treatment start in the first 2 cycles and after dose step.  For cycle 
3 and beyond, subjects will at least come in for an 8 hours outpatient observation 
followed by daily outpatient follow-ups during the subsequent 2 days.  Additional 
hospitalization may be necessary, eg, in case of serious adverse events or restart of 
treatment after treatment interruptions due to adverse events (see Section 6.5).  
7.4.1 
Days of Infusion (Day 1 to Day 29, Applies to Each Treatment Cycle)   
7.4.1.1 
Prior to Infusion (D1) 
Prior to infusion (D1), subjects have to complete all protocol–required procedures as per 
Table 9.  In addition, the obligatory premedication (Section 6.3) will be administered.  
Screening BM assessment sample has to be taken prior to treatment start or during the 
screening period.  For subjects who interrupted treatment because of a CNS event 
grade 3, an MRI of the head must be performed (read locally) before a new treatment 
cycle will be started. 
The results of the D1 laboratory tests taken prior to infusion start will not have to be 
available before starting treatment with blinatumomab.  Assessments that were done 
within 24 hours prior to treatment start do not need to be repeated at D1 prior to infusion.  
7.4.1.2 
During Infusion (D1 to D28) 
The infusion continues for 28 days, all protocol-required procedures and tests as per 
Table 9 will be performed on D1 to D15 of each treatment cycle.  In addition, the 
obligatory medication (Section 6.3) will be given.  Replacement of infusion bags will be 
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performed as described in the IPIM.  For the visits on D8, D15 there is a visit window of 
 1 day.  Time window for all BM assessments is + 3 days during treatment phase. 
7.4.1.3 
End of Infusion (D29) 
Protocol-required procedures and tests as per Table 9 will be performed on D29 (end of 
infusion).  For the visit on D29 there is a visit window of + 3 days. 
7.4.2 
Treatment Free Interval from Day 30 to Day 43 (D43  =  D1 of 
sub-sequent cycle) 
After each treatment cycle there will be a treatment free interval of 2 weeks before the 
next treatment cycle will be started.  In exceptional cases, the treatment free interval 
may be extended by up to one week to accommodate hospital scheduling or patient 
travel.  If the treatment will be continued with a further cycle, D43 corresponds to D1 of 
the following cycle, and the procedures and tests as per Table 9 will be performed.  In 
the final cycle to be administered if therapy is completed or discontinued, D43/D1 
assessments will not be performed and the next visit will be the SFU visit. 
7.5 
Safety Follow-up Visit 
All subjects, including subjects who withdraw early, should complete a SFU visit 30 days 
(± 3 days) after the last dose of protocol-specified therapy, or before 
HSCT/chemotherapy if applicable, or have discontinued the treatment of blinatumomab, 
whichever occurs first.  The procedures per Table 9 will be performed. 
7.6 
Long Term Follow-up  
Following the SFU visit, there will be long-term follow-up portion of the study for disease 
status and OS.  Subjects will be followed via clinical visit or telephone contact every 3 
months (± 1 month) after their SFU visit until death has been observed or a maximum of 
2 years after start of treatment, whichever occurs first.  Subjects will allow Amgen 
continued access to medical records, so that information related to subjects’ health 
condition including disease status and OS may be obtained.   
The following procedures will be completed for subjects who remain in remission 
(including subjects who have undergone alloHSCT) at each visit: 
 
Bone marrow aspirate/biopsy (morphological assessment only)  
○ every effort should be made to perform BM aspirate/biopsy until relapse is 
confirmed 
 
Hematology with differential  
 
Documentation of concomitant medications limited to only anti-leukemic treatments 
 
Disease/Survival status  
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The following procedures will be completed for subjects who did not respond to or 
relapsed after protocol-specified therapy and are being followed in long-term follow-up: 
 
Telephone contact to determine survival status by either the research investigational 
site or treating physician.  
 
Documentation of concomitant medications limited to only anti-leukemic treatments 
If B-cell counts have not recovered at the SFU visit (recovered is defined as number of 
CD19-positive cells per µL is 90 to 570), another sample will also be taken 6 months 
(+3 months) after SFU visit for determination of lymphocyte subsets (Section 7.2.17). 
Should a subject fail to return to the clinic for a scheduled protocol visit, sites will need to 
make 3 attempts to contact subjects by a combination of telephone and mail.  Sites must 
document all 3 attempts to contact the subject.  If a subject does not respond within 
1 month after the third contact, the subject will be considered lost to follow-up and no 
additional contact will be required. 
7.7 
End of Study 
The end of study visit is defined as the date of the final study visit (eg, long-term follow-
up) when assessments and/or procedures are performed. 
7.8 
Antibody Testing Procedures 
Blood samples will be collected at timepoints as outlined in the Schedule of 
Assessments (Table 9) for the measurement of anti-blinatumomab binding antibodies.  
Samples testing positive for binding antibodies may be further characterized for 
quantity/titer, isotype, affinity, in vitro neutralizing activity,  and presence of immune 
complexes.  Additional blood samples may be obtained to rule out anti-drug antibodies 
during the study.   
Subjects who test positive for binding antibodies and have clinical sequelae that are 
considered potentially related to an anti-blinatumomab antibody response may also be 
asked to return for additional follow-up testing. 
7.9 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 9) 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.  
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All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 9), 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints and adverse 
events.  Subjects who have discontinued investigational product and/or protocol-required 
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therapies or procedures should not be automatically removed from the study.  Whenever 
safe and feasible it is imperative that subjects remain on-study to ensure safety 
surveillance and/or collection of outcome data.  The investigator must document the 
level of follow-up that is agreed to by the subject.   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Protocol-specified criteria: 
 
Hematological or extramedullary relapse subsequent to CR/CRh*/CRi on 
protocol treatment 
 
Failure to achieve  a BM response defined as ≤ 5% blasts within 2 complete 
treatment cycles 
 
Investigator decision that a change of therapy (eg, immediate HSCT) is in the 
subject’s best interest 
 
subject request  
 
safety concern (eg, due to toxicity of protocol-specified therapy or other adverse 
event) 
 
decision by sponsor (other than subject request or safety concern) 
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 
death 
 
lost to follow-up 
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 
At the time of the primary analysis and/or at the end of the long-term follow-up portion 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.  Please refer to Appendix D for disease 
related events by system organ class.  Such events do not meet the definition of an 
Adverse Event unless assessed to be more severe than expected for the subject’s 
condition.  All serious disease-related events will be recorded and reported to the 
sponsor or designee within 24 hours. 
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. 
Disease Related Events and/or Disease Related Outcomes that do not qualify as 
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 eCRF. 
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9.1.2 
Adverse Events 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of 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 eCRF. 
For situations when an adverse event or serious adverse event is due to ALL, 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 
B-precursor ALL).  
Note:  The term “disease progression” should not be used to describe the disease 
related event or adverse event.   
“Lack of efficacy” or “failure of expected pharmacological action” will not be reported as 
an adverse event or serious adverse event.  Such instances will be captured in the 
efficacy assessment.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as adverse event or serious adverse event if they 
fulfill the definition of an adverse event or serious adverse event. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8 for additional instructions on the 
procedures recommended for safe withdrawal from protocol-required therapies or the 
study.   
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9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1): 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
A disease related event as listed in Appendix D is to be reported as a serious adverse 
event if  
 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
 
 if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay), and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs a hospitalization or fulfills any other serious criteria, the event is serious.  When 
in doubt as to whether “hospitalization” occurred or was necessary, the adverse event is 
to be considered serious.  Hospitalization for elective treatment of a pre-existing 
condition that did not worsen from baseline is not considered an adverse event.   
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  The definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
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 invasive or malignant cancers, intensive treatment in the emergency room or at 
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home for allergic bronchospasm, convulsions, or blood dyscrasias that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
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 
protocol-required therapies through the SFU visit are recorded using the Event eCRF as 
a disease-related event.   
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious disease-
related event data to the sponsor within 24 hours of it being available. 
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event CRF as serious adverse events, and reported per Section 9.2.2.2.  
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 protocol-required therapies 
through the SFU visit are reported using the Event eCRF.  Adverse events related to 
obligatory pre-medication as well as adverse events related to study procedures during 
the screening period will be reported on the Event eCRF.  If any other anti-leukemic 
therapy is started within 30 days after last administration of blinatumomab, subsequently 
only adverse events assessed as being related to blinatumomab will be reported.  
During the long-term follow-up period, only adverse events assessed as related to 
blinatumomab or study procedures will be recorded. 
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], 
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 
Assessment of relatedness to blinatumomab, and 
 
Action taken. 
The adverse event grading scale used will be the CTCAE version 4.03.  The grading 
scale used in this study is described in Appendix A.  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 investigational product (blinatumomab) or other 
protocol-required therapies?   
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 clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur during the entire study period 
including the screening period (from the signing of the informed consent) through the 
SFU visit 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.   
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If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet/electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the electronic Serious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  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/procedure”?  
The investigator is expected to follow reported serious adverse events until resolution, 
stabilization of the condition, or until the subject is lost to follow-up.  
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.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event eCRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities  
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 procedures and statutes. 
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9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries, investigators are required 
to report serious adverse events that they become aware of after end of study.  If serious 
adverse events are reported, the investigator is to report them to Amgen within 24 hours 
following the investigator’s knowledge of the event.   
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.2.2.4 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.7 require 
the following: 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations have 
been concluded).  
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed and 
sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
See Appendix B for a sample of the Serious Adverse Event Worksheet/eSAE 
Contingency Report Form.  For EDC studies where the first notification of a serious 
adverse event is reported to Amgen via the eSAE Contingency Report Form, the data 
must be entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  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/procedure”? 
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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
9.2.2.5 
Serious Adverse Events That are NOT TO BE Reported in an 
Expedited Manner  
Serious disease related events are not subjected to report individually in an expedited 
manner by Amgen unless it meets the criteria listed in Section 9.1.3.  A Data Review 
Team (DRT) will be used to monitoring the benefit/risk of such events.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking blinatumomab, report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur within 48 hours after the last dose of blinatumomab.   
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.  If 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.  
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If a lactation case occurs while the female subject is 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 after the last dose of protocol-required therapies through 
48 hours.   
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested.  
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
 
CR/CRh* rate within 2 cycles of treatment with blinatumomab 
10.1.1.2 
Secondary Endpoints 
 
CR rate within 2 cycles of treatment with blinatumomab 
 
CR/CRh*/CRi (complete remission with incomplete hematological recovery) rate 
within 2 cycles of treatment with blinatumomab 
 
PK parameters  
 
OS  
 
RFS 
 
MRD response rate within 2 cycles of treatment with blinatumomab 
 
Proportion of subjects undergoing alloHSCT among those who achieved CR/CRh* 
after treatment with blinatumomab 
 
100 day mortality after alloHSCT 
 
Time to a 10 point decrease from baseline in global health status/Quality of Life 
(QoL) using the EORTC QLQ-C30. 
10.1.1.3 
Safety Endpoints 
 
Overall incidence and severity of adverse events 
 
Incidence of anti-blinatumomab antibody formation 
10.1.1.4 
Exploratory Endpoints 
 
Neurological adverse events 
 
Quantification and characterization of peripheral blood lymphocyte subsets 
 
Quantification and characterization of serum cytokines and chemokines 
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10.1.2 
Analysis Sets 
The statistical analysis will be based on the following study populations: 
 
Primary Analysis Set (PAS):  All enrolled subjects who received at least one infusion 
of blinatumomab. 
 
Safety Analysis Set (SAS):  All enrolled subjects who received at least 1 infusion of 
blinatumomab.  The definition is the same as primary analysis set. 
 
Pharmacokinetic Analysis Set (PKS):  All subjects who received any infusion of 
blinatumomab and had at least 1 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, dose interruption, or sampling 
information is missing. 
The primary analysis of efficacy and safety will be performed on PAS and SAS 
separately.   
10.1.3 
Covariates and Subgroups 
The following covariates may be used to examine efficacy and/or safety in subgroups or 
covariates analyses: 
 
Sex (female vs male) 
 
Age (< 35 vs ≥ 35 to 55 vs ≥ 55)  
 
Prior salvage therapy (yes vs no) 
 
Prior alloHSCT (yes vs no) 
 
Bone marrow blast at baseline (< 50% vs ≥ 50%) 
 
Disease status (primary refractory vs first relapse vs second or later relapse)  
 
Refractory to last previous therapy (yes vs no) 
10.2 
Sample Size Considerations 
The overall sample size of 120 subjects, calculated using the exact method for a single 
proportion, was estimated in order to ensure 90% power to detect a  significant 
difference in terms of CR/CRh* rate between historical control with 30% CR/CRh* rate 
and blinatumomab assuming  45% CR/CRh* rate in the alternative hypothesis, at the 
2.5% one-sided significance level.   
Table 12  lists the exact 95% confidence intervals of various observed clinically 
meaningful CR/CRh* rates by using single-agent blinatumomab given to 120 subjects.  
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Table 12.  95% Confidence Intervals of Various Observed CR/CRh* Rates in 
Blinatumomab Administered to 120 Subjects 
Observed CR/CRh* rate 
Exact 95% CI for CR/CRh* rate 
40% 
[31.1%, 49.3%] 
45% 
[35.9%, 54.3%] 
50% 
[40.7%, 59.2%] 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
The Interim Analysis Set is defined as the first 90 subjects (75% of the expected total) 
who have had the opportunity to be treated with at least 2 cycles of blinatumomab and to 
finish the SFU visit (if subjects discontinue treatment after 2 cycles), or have 
discontinued the treatment of blinatumomab and complete the SFU visit, whichever 
occurs first.  The interim analysis will assess blinatumomab efficacy and safety and will 
be based on this Interim Analysis Set.  The efficacious benefit assessment will be based 
on an O’Brien-Fleming alpha spending function with the critical boundary 42.2% at the 
interim analysis and 39.2% at the primary analysis in CR/CRh* rate.  If the interim 
analysis shows a statistically efficacious benefit assessment and an overall benefit-risk 
analysis is promising, then the interim analysis will become the primary analysis of this 
study.  In addition, the study will still continue its enrollment until 120 subjects are 
enrolled and continue to complete the protocol specified procedures. 
Additional ad hoc Interim Analyses may be performed.  Pharmacokinetic samples 
collected at specific timepoints may be analyzed and reported.  The purpose of this 
additional interim data analyses is to provide descriptive analyses of PK, safety, and 
efficacy information (including 95% confidence intervals) for regulatory submissions and 
interactions. 
10.3.2 
Data Review Team (DRT) 
The interim analysis will be reviewed by an Amgen internal DRT including medical 
scientist, biostatistician, safety scientist, pharmacologist without jeopardizing the study 
integrity as the study is a single-arm trial.  The interim analysis will be performed by the 
independent biostatistician and the programmers supporting the DRT without 
jeopardizing the study integrity as the study is a single-arm trial. 
The DRT will also review safety data at the time of interim analysis. 
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10.3.3 
Primary Analysis 
Primary analysis will be performed when all the enrolled subjects have finished at least 
2 cycles of blinatumomab and the SFU visit (if subjects discontinue treatment after 
2 cycles), or have discontinued the treatment of blinatumomab and complete the SFU 
visit, whichever occurs first.    
10.3.4 
Final Analysis  
Final analysis will be performed at the end of the study when all the enrolled subjects 
have finished all the follow-up visits or have withdrawn from the study, whichever occurs 
first.  The analyses of RFS, OS, alloHSCT rate after achieving CR/CRh*, and safety will 
be updated. 
10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
The binomial endpoints including CR/CRh* rate, CR rate, CR/CRh*/CRi rate, alloHSCT 
rate and  MRD response rate will be calculated and the exact binomial 95% confidence 
interval will be generated for the response rate. 
The time-to-event endpoints including RFS and OS will be summarized with hazard 
ratio, Kaplan-Meier (KM) curves, KM quartiles (when estimable), the number of subjects 
with events, the number of subjects censored, and the pattern of censoring. 
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, first and third quartiles, minimum, and maximum.  
Categorical variables will be summarized by the percentage in each category.  
The analyses of the exploratory endpoints will be documented in the statistical analysis 
plan.  The analyses of biomarker will be separately documented. 
10.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the CR/CRh* rate within 2 cycles of treatment with 
blinatumomab.  CR/CRh* rate is the proportion of subjects who achieve CR/CRh* within 
2 cycles of treatment with blinatumomab.  Subjects without response assessment will be 
accounted for in the denominator when calculating the response rate, ie, these subjects 
will be counted as non-responders.  
The response rate will be calculated and the exact binomial 95% confidence interval will 
be generated for the response rate. 
The primary analysis will be based on the Primary Analysis Set.   
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10.4.3 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints include RFS, CR rate, CR/CRh*/CRi rate, alloHSCT 
rate, OS, MRD response rate, and time to a 10 point decrease from baseline in global 
health status/Quality of Life (QoL) using the EORTC QLQ-C30.  
 
RFS:  RFS time will be calculated from the first onset of CR/CRh* within the 2 cycles 
until the documented hematological relapse, extra-medullary disease, or death due 
to any cause, whichever occurs first.  The analysis is restricted to subjects who 
achieve CR/CRh* within 2 cycles of treatment.  The subjects still alive and 
relapse-free will be censored at the date of last disease assessment.  If the last 
disease assessment date is after the date that triggers the analysis, the subject will 
be censored at the analysis trigger date.  Sensitivity analyses of RFS will be 
calculated similarly for those who achieve CR/CRh* and those who achieve 
CR/CRh*/CRi.   
 
CR rate within 2 cycles of treatment with blinatumomab:  CR rate is defined as the 
proportion of subjects who achieve CR within 2 cycles of treatment with 
blinatumomab.  Subjects without response assessment will be accounted for in the 
denominator when calculating the response rate. 
 
CR/CRh*/CRi rate within 2 cycles of treatment with blinatumomab:  CR/CRh*/CRi 
rate is defined as the proportion of subjects who achieve CR/CRh*/CRi within 
2 cycles of treatment with blinatumomab.  Subjects without response assessment will 
be accounted for in the denominator when calculating the response rate. 
 
AlloHSCT rate:  AlloHSCT rate is defined as the proportion of subjects undergoing 
alloHSCT among who achieve CR/CRh* after treatment with blinatumomab.   
 
Overall survival (OS):  OS time will be calculated from the time of first infusion of 
blinatumomab until death due to any cause.  Subjects still alive will be censored at 
the date last known to be alive.  If the date last known to be alive is after the date 
that triggers the analysis, the subject will be censored at the analysis trigger date. 
 
MRD response rate within 2 cycles of treatment of blinatumomab:  MRD response 
rate is defined as the proportion of subjects who achieve MRD response within 
2 cycles of treatment with blinatumomab.  Subjects without response assessment will 
be accounted for in the denominator when calculating the response rate. 
 
100 day mortality after alloHSCT:  The 100-day mortality after alloHSCT will be 
summarized with the 100-day KM rate among the subjects who achieve CR/CRh* 
without intervening therapy after blinatumomab and undergo alloHSCT. 
 
Time to a 10 point decrease from baseline in global health status/ QoL using the 
EORTC QLQ-C30:  Time to a 10 point decrease will be calculated from baseline to 
the time of first 10 point decrease in terms of global health status/QoL using EORTC 
QLQ-C30.  Subjects still alive and no occurrence of 10 point decrease will be 
censored at the date of last assessment of EORTC QLQ-C30.  This analysis will be 
performed on subjects with a non-missing baseline and at least 1 non-missing 
post-baseline result of any EORTC QLQ-C30 scales/item. 
For the time to event endpoints such as RFS , OS, and time to a 10 point decrease from 
baseline in global health status/Quality of Life (QoL) using the EORTC QLQ-C30, the 
endpoints will be summarized descriptively with hazard ratio, KM curves, KM quartiles 
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(when estimable), the number of subjects with events, the number of subjects censored, 
and the pattern of censoring.  
The CR rate, CR/CRh*/CRi rate, alloHSCT rate and MRD response rate will be 
calculated and the exact binomial 95% confidence interval will be generated for the 
rates. 
The primary analysis will be based on the Primary Analysis Set.   
10.4.4 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be determined with non-compartmental analysis 
method with PK Analysis Set.  PK parameters such as Css, volume of distribution, 
clearance, and elimination half-life will be estimated for subjects who have sufficient 
evaluable PK data.  Summary statistics of PK parameters and data listings of individual 
blinatumomab concentration data will be provided. 
PK data may be subjected to exploratory population PK analysis with an integrated 
dataset of multiple studies.  If the analysis is performed, nonlinear mixed effects 
modeling will be used.  Effect of covariates on exposure will be determined.  These may 
include age, body weight, body surface area, renal function, liver function, and sex.  
Other covariates may be analyzed if necessary.  The results will be reported separately. 
Exposure-response relationships for selected efficacy and safety endpoints may be 
assessed as appropriate.  The results will be reported separately. 
10.4.5 
Safety Endpoints 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading withdrawal from blinatumomab, treatment-emergent adverse 
events of interest, will also be provided.  The number and percentage of subjects with 
antibody formation to blinatumomab will be summarized.  In addition, changes in vital 
sign and laboratory parameters will be summarized.  
Subject incidence of all disease related events, fatal disease related events, serious 
disease related events, and disease related events leading to withdrawal from 
blinatumomab, will also be provided.  Subject incidence of fatal disease related events 
will be tabulated by system organ class and preferred term. 
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Extent of exposure to blinatumomab will be summarized using descriptive statistics.  
Percentage of subjects and number of cycles with doses held and dose reductions will 
be calculated. 
These analyses will be performed using subjects in the SAS. 
10.4.6 
Exploratory Endpoints 
These analyses will be detailed in the SAP. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Global Clinical Trial Manager to the 
investigator.  The written informed consent document 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 or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
The Investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the Investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the Investigator will be acting in that capacity, the Investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
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retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  Refer to International Council on 
Harmonisation-Good Clinical Practice (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 eCRF 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 Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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 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 eCRFs 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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the eCRFs 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 eCRFs. 
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 eCRFs, 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 Quality, Compliance & Audit (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 eCRFs must be maintained and 
readily available. 
 
Updates to eCRFs 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 eCRF, 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 subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
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Schedule of Assessments (Table 9), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
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 encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states (August 2013 
revision): 
 
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; (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. 
Approved 
 
 


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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. 
Approved 
 
 


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13. 
REFERENCES 
Baoan Chen, Zhihu Huang, Xiaoping Zhang, et al.  An epidemiological investigation of 
leukemia incidence between 2003 and 2007 in Nanjing, China.  J Hematol Oncol.  
2010;3:21 
Berg SL, Blaney SM, Devidas M, et al.  Phase II study of nelarabine (compound 
506U78) in children and young adults with refractory T-cell malignancies:  a report from 
the Children´s Oncology Group.  J Clin Oncol.  2005;23:3376-3382. 
Blinatumomab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Cheson BD, Pfistner B, Juweid ME, et al.  Revised response criteria for malignant 
lymphoma.  J Clin Oncol.  2007;25:579-586. 
DeAngelo DJ, Yu D, Johnson JL, et al.  Nelarabine induces complete remissions in 
adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or 
lymphoblastic lymphoma:  cancer and leukemia group B study 19801.  Blood.  
2007;109(12):5136-5142. 
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.  Int J Cancer.  2002;100(6):690-697. 
Fielding AK, Richards SM, Chopra R, et al.  Outcome of 609 adults after relapse of acute 
lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study.  Blood.  
2007;109(3):944-950. 
Gökbuget N, Hoelzer D.  Salvage therapy of adult acute lymphoblastic leukemia.  In:  
Faderl S, Kantarjian H, eds.  Leukemias:  Principles and Practice of Therapy.  Oxford, 
UK:  Wiley-Blackwell; 2011 
Gökbuget N, Hoelzer D.  Treatment of adult acute lymphoblastic leukemia.  Semin 
Hematol.  2009; 46(1):64-75.  
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2006.  http://www.icmje.org/ 
Jabbour EJ, Faderl S, Kantarjian HM.  Adult acute lymphoblastic leukemia.  Mayo Clin 
Proc.  2005;80:1517-1527. 
Jeha S, Gaynon PS, Razzouk BI, et al.  Phase II study of clofarabine in pediatric patients 
with refractory or relapsed acute lymphoblastic leukemia.  J Clin Oncol.  2006; 
24:1917-1923. 
Kantarjian HM, Thomas D, Ravandi F, et al.  Defining the course and prognosis of adults 
with acute lymphocytic leukemia in first salvage after induction failure or short first 
remission duration.  Cancer.  2010;116(24):5568-5574. 
Larson RA.  Acute lymphoblastic leukemia:  Older patients and newer drugs.  
Hematology Am Soc Hematol Educ Program.  2005;131-136. 
Liu L, Jiao W, Zhang Y, Wu D, et al.  Efficacy of low-dose cytarabine and aclarubicin in 
combination with granulocyte colony-stimulating factor (CAG regimen) compared to 
Hyper-CVAD regimen as salvage chemotherapy in relapsed/refractory Philadelphia 
chromosome-negative acute lymphoblastic leukemia.  Leuk Res.  2015;39:323-328 
Liu YH, Zhang Yan, Ge FM, et al.  FLAG regimen in the treatment of adult refractory or 
relapsed acute lymphoblastic leukemia.  Cancer Research and Clinic, January 2013, 
Vol.25, No.1. 
Approved 
 
 


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Löffler A, Kufer P, Lutterbüse R, et al.  A recombinant bispecific single-chain antibody, 
CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated 
T lymphocytes.  Blood.  2000;95:2098-2103. 
NCCN Practice Guidelines in Oncology, Acute Lymphoblastic Leukemia.  NCCN.org 
Version 2.0, 2014.  
Ni Xiong, Shen Zhixiang, Chen Fangyuan, et al.  Trend in the incidence and geographic 
variations of acute lymphoblastic leukemia in Shanghai, China from 2002 to 2006.  Chin 
Med J.  2011; 124(16):2406-2410. 
O'Brien SM, Aulitzky W, Ben Yehuda D, et al.  Phase II study of marqibo in adult patients 
with refractory or relapsed Philadelphia chromosome negative (Ph-) acute lymphoblastic 
leukemia (ALL).  J Clin Oncol.  2010;28:15s, (suppl; abstr 6507). 
O´Brien S, Thomas D, Ravandi F, et al.  Outcome of adults with acute lymphocytic 
leukemia after second salvage therapy.  Cancer.  2008;113:3186-3191. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655.  
Oriol A, Vives S, Hernández-Rivas JM, et al.  Outcome after relapse of acute 
lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials 
by the PETHEMA Study Group.  Haematologica.  2010;95:589-596. 
Pui CH, Evans WE.  Acute lymphoblastic leukemia.  N Engl J Med.  1998;339:605-615. 
Tavernier E, Boiron JM, Huguet F, et al.  Outcome of treatment after first relapse in 
adults with acute lymphoblastic leukemia initially by the LALA-94 trial.  Leukemia.  
2007;21:1907-1914. 
Thomas DA, Kantarjian H, Smith TL, et al.  Primary refractory and relapsed adult acute 
lymphoblastic leukemia:  characteristics, treatment results, and prognosis with salvage 
therapy.  Cancer.  1999;86:1216-1230. 
Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA.  BiTEs:  bispecific antibody 
constructs with unique anti-tumor activity.  Drug Discov Today.  2005;10:1237-1244. 
Yan CH, Wang JZ, Huang XJ, et al.  Chemotherapy followed by modified donor 
lymphocyte infusion as a treatment for relapsed acute leukemia after haploidentical 
hematopoietic stem cell transplantation without in vitro T-cell depletion:  superior 
outcomes compared with chemotherapy alone and an analysis of prognostic factors.  
Eur J Haematol.  2013;91:304-314. 
Zhang Tao, Zhang YQ, Chen XQ, et al.  FLAG regimen in the treatment of refractory or 
relapsed adult acute lymphoblastic leukemia.  Modern Oncology.  2010;18(11); 
2235-2238. 
Zhang Xian, Meng FY, Xu Bin, et al.  Fludarabine combined cytarabine in the treatment 
of 25 patients with refractory/ relapsed acute lymphoblastic leukemia.  The Journal of 
Practical Medicine.  2008;24(16). 
Approved 
 
 


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14. 
APPENDICES 
Approved 
 
 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 for adverse event grading and information.  The CTCAE scale is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments Reporting 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases 
of concurrent AST or ALT and TBL and/or INR elevation according to the criteria 
specified in Section 6.5 require the following: 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations have 
been concluded). 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed and 
sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
Approved 
 
 


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Appendix B.  Sample Serious Adverse Event Report Form 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets  
Approved 
 
 


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Approved 
 
 


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Appendix D.  Expected Disease-related Adverse Events by System Organ Class 
(SOC) 
System Organ Class 
Disease-Related Adverse Events 
Blood and lymphatic system 
disorders 
Febrile neutropenia, anemia, neutropenia, 
thrombocytopenia, leukopenia, lymphadenopathy 
Gastrointestinal disorders 
Abdominal distension, abdominal pain, constipation, 
diarrhea, gingival pain, nausea 
General disorders and 
administration site conditions 
Fatigue, pyrexia, malaise, bone and joint pain 
Infections and infestations 
Infectiona,b 
Investigations 
White blood cell count decreased, hemoglobin 
decreased, platelet count decreased 
Metabolism and nutrition disorders 
Decreased appetite, weight loss 
Musculoskeletal and connective 
tissue disorders 
Skeletal pain, muscular pain, arthralgia, neck pain 
Nervous system disorders 
Dizziness, headache, lethargy, meningismus, syncope 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea, epistaxis 
Other 
Hemorrhagec 
a Represents preferred terms under infections and infestations primary SOC 
b Progressive multifocal leukoencephalopathy (PML) is excluded from the list of DRE and must be reported 
to Amgen in an expedited manner  
c Represents hemorrhage preferred terms under multiple SOCs 
Approved 
 
 


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Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all selfcare, but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC et al.:  Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group.  Am J Clin Oncol 1982; 5: 649-655 
Approved 
 
 


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Appendix F.  EORTC Quality of Life Questionnaire 
 
Approved 
 
 


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Approved 
 
 


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Amendment 6 
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
Amgen Protocol Number 20130316 
NCT Number:  NCT03476239 
Amendment Date: 
09 March 2020 
Rationale: 
The protocol is being amended to: 
 
Clarify the primary completion date definition for individual subjects. 
Approved 
 
 


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Amendment 5
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTEAntibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
Amgen Protocol Number Blinatumomab 20130316
NCT Number:  NCT03476239
Amendment Date:
27 August 2019
Rationale:
The protocol is being amended to:

align laguage related to the interim analysis with the statistical analysis plan

clarify the end of study visit definition for individual subjects

clarify reporting procedures for serious disease-related events
Approved 
 
 


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Date:  30 November 2018
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CONFIDENTIAL
Amendment 4
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTE® Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
Amgen Protocol Number (Blinatumomab) 20130316
Amendment Date:
30 November 2018
Rationale:
This protocol is being amended to:

Clarify that neurologic abnormalities during the study will be monitored by
neurologic adverse events that may be related to blinatumomab.  This monitoring
will be continuous throughout the study and will be reported with start and stop
time of the adverse event and CTCAE Version 4.03 grade

Update the treatment procedures by increasing the time interval that
dexamethasone can be given as pre-medication since dexamethasone has a
long half life

Clarify the definition of primary analysis that it includes either when all the
enrolled subjects have finished at least 2 cycles of blinatumomab and the safety
follow-up visit (if subjects discontinue treatment after 2 cycles), or discontinued
the treatment of blinatumomab and complete the safety follow-up visit, whichever
occurs first

Make minor administative changes and clarification throughout the document
Approved 
 
 


Product:  Blinatumomab 
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Date:  22 August 2018 
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CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTE® Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
 
Amgen Protocol Number (Blinatumomab) 20130316 
 
Amendment Date: 
22 August 2018 
Rationale: 
This protocol is being amended to: 
• 
highlight and clarify the treatment requirement for subjects who develop isolated 
CNS leukemia during the study. 
• 
clarify that the B precursor phenotype will be confirmed by the local laboratory 
using flow cytometry rather than immunocytochemistry (ICC). 
• 
clarify that bone marrow aspiration/biopsy and lumbar puncture are standard of 
care procedures, are not considered study specific procedures, and may be 
performed prior to informed consent and used to determine eligibility. 
• 
update exclusion criterion 209 and 221 to exclusion criterion 226 and 227, 
respectively.  Changes were made to these exclusion criterions during protocol 
amendment 2 but were never renumbered.  Therefore, these exclusion criterions 
were renumbered in order to ensure continuity between the protocol and CRF. 
• 
describe an additional ad hoc Interim Analysis. 
• 
clarify that ‘bands or stabs’ are optional laboratory analytes. 
• 
clarify that intrathecal prophylaxis needs to be administered within 14 days prior 
to starting treatment with blinatumomab.  This aligns therapy with standard of 
care in China. 
• 
Update end of study and safety language to align with the new protocol template. 
• 
Clarify that the therapy name, indication, dose, unit, frequency, start date and 
stop date will be collected for all concomitant therapies used during the study. 
• 
make administrative and editorial updates. 
Approved 
 
 


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CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
Blinatumomab 
Amgen Protocol Number (Blinatumomab) 20130316 
 
Amendment Date: 
20 February 2018 


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Page 2 of 48 
CONFIDENTIAL 
 
 
Rationale: 
This protocol is being amended to: 
• 
Increase the number of participating sites from 20 to 25 
• 
Update Exclusion criteria 221 to align with program level contraceptive language 
• 
Update Exclusion criteria 209 to align with the instruction to calculate eGFR  
• 
Replace local Safety Review Committee with Data Review Team 
• 
Add a time window for PK sample collection  
• 
Incorporate updated blinatumomab program level guidelines for  
− 
Dose Modifications (Interruptions, Withholdings, and Criteria for Restarting 
Treatment) 
− 
Criteria for Conditional Withholding of Blinatumomab and Other Protocol-required 
Therapies due to Potential Hepatotoxicity 
• 
Remove serum cytokine concentrations from secondary endpoints 
• 
Add quantification and characterization of serum cytokines and chemokines to 
exploratory endpoints 
• 
Move 100-day mortality after alloHSCT from safety endpoints to secondary 
endpoints 
• 
Clarify visit window for long term follow-up  
• 
Remove references to maintenance phase as there is no maintenance phase for this 
study 
• 
Clarify dexamethasone dose for CNS-related adverse events 


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Amendment 01 
Protocol Title:  An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and 
Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
Blinatumomab 
Amgen Protocol Number (Blinatumomab) 20130316 
 
 
Date: 
29 July 2015 
Amendment Date: 
07 December 2016 
 
Approved 
 
 


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Rationale: 
The following changes are being made to the study for the reasons indicated: 
• 
The Chinese Food and Drug Administration (CFDA) is open to have interim 
analysis in our study for early NDA filing which was discussed at CDE formal 
consultation meeting in March 2016. 
• 
The interim analysis is planned at 75% (90 subjects) enrollment, strong efficacy 
is provided at IA by using OBF alpha-spending function where CR/CRh* rate has 
to be equal to or greater than 42.2%.  
• 
In terms of safety, although study may have the chance for early NDA filing at the 
time of interim analysis, the study won't stop enrollment and will continue to enroll 
the remaining 30 patients.  The 120 subjects’ safety data will be provided to 
CFDA. 
• 
Change in exploratory objectives and endpoints:  the acute lymphoblastic 
leukemia symptom scale (ALLSS) was removed as this scale was not validated. 
• 
Change in the statistical hypothesis: Considering the available efficacy data in 
available treatment for adult relapsed/refractory B-precursor acute lymphoblastic 
leukemia (R/R ALL), the lower limit of 95% CI of CR/CRh* rate of blinatumomab 
was increased to 30%. 
• 
Number of subjects:  The number of subjects was increased from 100 to 120 to 
ensure 90% power to detect a significant difference between historical control of 
30% and blinatumomab of 45% in CR/CRh* rate at 2.5% one-sided significance 
level. 
• 
Interim analysis:  For R/R ALL patients, there is no good choice of treatment and 
new effective drugs are urgently needed.  If the efficacy result of interim analysis 
is compelling and with a clear benefit-risk, early filing with interim analysis data 
could meet clinical needs. 
• 
Inclusion Criteria:  According to the global studies data, different prior salvage 
therapies have different clinical benefits.  Based on clinical practice in China, the 
patient population needs to be refined to avoid bias on study results. 
• 
Laboratory analytes and biomarker tests:  Clarifications were made to some of 
the protocol required procedures and provided additional detail as needed; 
biomarker testing that was not allowed in China was removed. 
• 
Combine Safety Data Review Committee (SDRC) with Data Review Team 
(DRT):  The DRT will review the safety data during the interim analysis; 
therefore, there is no need for an SDRC.  
Approved 
 
 

SAP_001.pdf: 
Product:  Blinatumomab 
Statistical Analysis Plan:  20130316 
Dated:  18 September 2019 
Page 1 
STATISTICAL ANALYSIS PLAN 
An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety 
of the BiTE® Antibody Blinatumomab in Chinese Adult Subjects With 
Relapsed/refractory B-precursor Acute Lymphoblastic Leukemia (ALL) 
Protocol Number: 
20130316 
Version: 
Version 4.0 
Date: 
18 Sep 2019 
Authors: 
 
NCT Number: NCT03476239
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Blinatumomab 
Statistical Analysis Plan:  20130316 
Dated:  18 September 2019 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 4 
1. 
Introduction .............................................................................................................. 5 
2. 
Objectives ................................................................................................................ 5 
2.1 
Primary ......................................................................................................... 5 
2.2 
Secondary .................................................................................................... 5 
2.3 
Safety ........................................................................................................... 5 
2.4 
Exploratory ................................................................................................... 5 
3. 
Study Overview ........................................................................................................ 6 
3.1 
Study Design ................................................................................................ 6 
3.2 
Sample Size ................................................................................................. 7 
4. 
Study Endpoints and Covariates .............................................................................. 7 
4.1 
Study Endpoints ........................................................................................... 7 
4.2 
Planned Covariates ...................................................................................... 7 
5. 
Hypotheses and/or Estimations ................................................................................ 8 
6. 
Definitions ................................................................................................................ 8 
7. 
Analysis Sets .......................................................................................................... 12 
7.1 
Primary Analysis Set (PAS) ........................................................................ 12 
7.2 
Safety Analysis Set (SAS) .......................................................................... 13 
7.3 
Pharmacokinetic Analysis Set (PKS) .......................................................... 13 
7.4 
Interim Analyses Set ................................................................................... 13 
7.5 
Subgroup Analyses .................................................................................... 13 
8. 
Planned Analyses .................................................................................................. 13 
8.1 
Interim Analysis and Early Stopping Guidelines ......................................... 13 
8.2 
Primary Analysis ......................................................................................... 14 
8.3 
Final Analysis ............................................................................................. 14 
9. 
Data Screening and Acceptance ............................................................................ 14 
9.1 
General Principles ...................................................................................... 14 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 15 
9.3 
Handling of Missing and Incomplete Data .................................................. 15 
9.4 
Outliers ....................................................................................................... 15 
9.5 
Distributional Characteristics ...................................................................... 15 
9.6 
Validation of Statistical Analyses ................................................................ 15 
10. 
Statistical Methods of Analysis ............................................................................... 16 
10.1 
General Principles ...................................................................................... 16 
10.2 
Subject Accountability ................................................................................ 16 
10.3 
Important Protocol Deviations .................................................................... 16 


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10.4 
Demographic and Baseline Characteristics ................................................ 17 
10.5 
Efficacy Analyses ....................................................................................... 17 
10.5.1 
Analysis of Primary Efficacy Endpoint ........................................ 17 
10.5.2 
Analyses of Secondary Efficacy Endpoints ................................ 18 
10.6 
Safety Analyses .......................................................................................... 18 
10.6.1 
Adverse Events .......................................................................... 18 
10.6.2 
Laboratory Test Results ............................................................. 19 
10.6.3 
Vital Signs ................................................................................... 20 
10.6.4 
Antibody Formation .................................................................... 20 
10.6.5 
Exposure to Investigational Product ........................................... 20 
10.6.6 
Exposure to Other Protocol-specified Treatment ....................... 20 
10.6.7 
Exposure to Concomitant Medication ......................................... 20 
10.7 
Other Analyses ........................................................................................... 20 
10.7.1 
Pharmacokinetic Analysis ........................................................... 20 
10.7.2 
Analyses of Exploratory Endpoints ............................................. 21 
10.7.3 
Analyses of Health Related Quality of Life Endpoints ................ 21 
10.7.4 
Exploratory Biomarker Endpoints Analysis ................................. 22 
11. 
Literature Citations / References ............................................................................ 23 
12. 
Appendices ............................................................................................................ 24 
List of Tables 
Table 1.  Imputation Rules for Partial or Missing Start Dates .......................................... 25 
Table 2.  Grading of Select Laboratory Parameters ........................................................ 27 
Table 3.  Notable Abnormalities of Vital Signs ................................................................ 28 
List of Appendices 
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates for 
Adverse Events and Concomitant Medications ....................................... 25 
Appendix B.  Laboratory Grading and Notable Vital Sign Values ................................... 27 
 
 


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Statistical Analysis Plan:  20130316 
Dated:  18 September 2019 
Page 4 
 
Table of Abbreviations 
Term or Abbreviation 
Description 
BM 
CDM 
Bone Marrow 
Clinical Data Management 
CSR 
Clinical study report 
CRF 
Case Report Form 
EOI 
Event Of Interest 
E-R 
Exposure-Response 
IBG 
Independent Biostatistics Group 
IPD 
Important Protocol Deviation 
KM 
Kaplan-Meier  
MedDRA 
Medical Dictionary for Regulatory Activities 
SAP 
Statistical Analysis Plan 
SSAP 
Supplemental Statistical Analysis Plan 
PK 
Pharmacokinetic or Pharmacokinetics 
QL2 
Global Health Status/Quality of Life Scale Score from the 
EORTC QLQ-C30 
WHODRUG 
World Health Organization Drug dictionary 
 


Product:  Blinatumomab 
Statistical Analysis Plan:  20130316 
Dated:  18 September 2019 
Page 5 
 
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 blinatumomab study 20130316 
Amendmend 5 dated 27 August 2019. The scope of this plan includes the interim 
analysis, the primary analysis and final analysis that are planned and will be executed by 
the Biostatistics department or designee unless otherwise specified. The analysis of 
Health-related Quality of Life endpoints will be described in a separate supplemental 
SAP (SSAP). PK data analyses will be provided by Clinical Pharmacology Modeling and 
Simulation group. Exploratory biomarker endpoints will be analyzed in a separate 
Contributing Scientific Report by scientists from the Clinical Biomarkers and Diagnostics 
(CBD) group. 
2. 
Objectives 
2.1 
Primary 
• 
To evaluate the rate of hematological response (complete remission/complete 
remission with partial hematological recovery [CR/CRh*]) induced by blinatumomab 
in Chinese adult subjects with relapsed/refractory B-precursor acute lymphoblastic 
leukemia (ALL). 
2.2 
Secondary 
• 
To evaluate pharmacokinetics (PK) of blinatumomab 
• 
To evaluate the effect of blinatumomab on overall survival (OS)  
• 
To evaluate the relapse-free survival (RFS) induced by blinatumomab  
• 
To evaluate minimal residual disease (MRD) response induced by blinatumomab 
• 
To evaluate the incidence of allogeneic hematopoietic stem cell transplantation 
(alloHSCT) and 100-day mortality following HSCT in blinatumomab treated subjects  
• 
To estimate the effect of blinatumomab on patient reported outcomes of global health 
status/quality of life (QoL) using the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) 
(analyses described in a SSAP). 
2.3 
Safety 
• 
To evaluate the safety of blinatumomab in Chinese subjects with relapsed/refractory 
B-precursor ALL 
2.4 
Exploratory 
• 
To evaluate central nervous system (CNS) symptoms and explore potential 
predictive factors for CNS events associated with blinatumomab 


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3. 
Study Overview 
3.1 
Study Design 
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and 
safety of the BiTE antibody blinatumomab in Chinese adult subjects with 
relapsed/refractory B-precursor ALL.  
The study will consist of a screening period, a treatment period, and a follow-up period. 
Treatment will consist of up to 5 cycles of blinatumomab (for details see Section 6.2.2 of 
the protocol). Subjects who have achieved a BM response (≤ 5% BM blasts) or 
CR/CRh*/CRi within 2 induction cycles of treatment may continue to receive up to 3 
additional consolidation cycles of blinatumomab. Thirty days (± 3 days) after end of the 
last dose of protocol-specified therapy, subjects will have a safety follow-up visit. 
Following this, there will be long term (efficacy/survival) follow-up portion of the study for 
disease status and overall survival. Subjects will be followed via clinic visit or telephone 
contact every 3 months (± 1 month) after their safety follow-up visit until death has been 
observed or a maximum of 2 years after start of treatment, whichever occurs first. 
If subjects are suitable for alloHSCT after treatment with blinatumomab, they may 
undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab. It 
is recommended to administer at least 2 cycles of blinatumomab before alloHSCT. The 
subjects should complete the safety follow-up visit before undergoing a transplant, and 
these subjects will continue to be followed in the long term follow-up phase of the study. 
In order to enroll representative and balanced adult ALL subjects in terms of the number 
of prior salvage treatments, the study requires that approximately 50% of subjects are 
receiving salvage treatment for the first time. 
Salvage treatment will be categorized in the interactive voice response 
system/interactive web response system (IVRS/IWRS) in order to monitor the number of 
subjects enrolled in each category. Subjects will be categorized to: 
(a) those expecting to receive blinatumomab as a first salvage treatment or 
(b) those expecting to receive blinatumomab as a second or greater salvage treatment. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 


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3.2 
Sample Size 
The overall sample size of 120 subjects, calculated using the exact method for a single 
proportion, was estimated in order to ensure 90% power to detect a significant difference 
in terms of CR/CRh* rate between historical control with 30% CR/CRh* rate and 
blinatumomab assuming 45% CR/CRh* rate in the alternative hypothesis, at the 2.5% 
one-sided significance level. 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
Primary Endpoint 
• 
CR/CRh* rate within 2 cycles of treatment with blinatumomab 
Secondary Endpoints  
• 
CR rate within 2 cycles of treatment with blinatumomab  
• 
CR/CRh*/CRi (complete remission with incomplete hematological recovery) rate 
within 2 cycles of treatment with blinatumomab  
• 
Pharmacokinetic parameters  
• 
Overall survival  
• 
Relapse-free survival  
• 
MRD response rate within 2 cycles of treatment with blinatumomab  
• 
Proportion of subjects undergoing allogeneic HSCT among those who achieved 
CR/CRh* after treatment with blinatumomab  
• 
100-day mortality after allogeneic HSCT 
• 
Time to a 10 point decrease from baseline in global health status/Quality of Life 
(QoL) using the EORTC QLQ-C30. 
Safety Endpoints 
• 
Overall incidence and severity of adverse events 
• 
Incidence of anti-blinatumomab antibody formation 
Exploratory Endpoints 
• 
Neurological adverse events 
• 
Quantification and characterization of peripheral blood lymphocyte subsets 
• 
Quantification and characterization of serum cytokines and chemokines 
4.2 
Planned Covariates 
The following covariates may be used to examine key efficacy and/or safety in 
subgroups or covariates analyses: 
• 
Sex (female vs. male) 
• 
Age (< 35 vs ≥ 35 to < 55 vs ≥ 55) 


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• 
Prior salvage therapy (yes vs. no) 
• 
Prior alloHSCT (yes vs. no) 
• 
Bone marrow blast at baseline (<50% vs. ≥50%) 
• 
Disease status (primary refractory vs first relapse vs second or later relapse)  
• 
Refractory to last previous therapy (yes vs. no) 
5. 
Hypotheses and/or Estimations 
The clinical hypothesis is that blinatumomab will have clinically meaningful anti-tumor 
activity better than 30% as measured by CR/CRh* rate within 2 cycles in Chinese adult 
subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia. The 
anticipated CR/CRh* rate of blinatumomab within 2 cycles will be 45%.  
6. 
Definitions 
Age 
Age will be determined by sites at day 1 of the first infusion of blinatumomab.  
AlloHSCT rate 
AlloHSCT rate is defined as the proportion of subjects undergoing alloHSCT among 
whom achieve CR/CRh* after treatment with blinatumomab.  
Anti-cancer therapies during long term follow-up 
Anti-cancer therapies during long term follow-up will be those therapies entered in the 
anti-cancer therapy case report form (CRF) administered during the long term follow-up 
period of the study. 
Baseline 
For data analyses, baseline will be defined as the value measured on day 1 of the first 
infusion of blinatumomab. The protocol specifies that all study procedures on day 1 
should be completed before the initiation of blinatumomab which will be the assumption 
in the analysis unless the time of the assessment is recorded. If a day 1 value is not 
available, the latest value before the day of the start of blinatumomab may be used. 
Blast Free Hypoplastic or Aplastic Bone Marrow 
Defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and 
insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or 
ANC ≤ 500/µl.  
Complete cycle 
A complete cycle is defined as undergoing ≥ 90% of a planned cycle’s duration (in days). 


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Complete Remission (CR) 
A CR is defined as having ≤ 5% blasts in the bone marrow , no evidence of disease, and 
full recovery of peripheral blood counts (platelets > 100,000/μL, and absolute neutrophil 
count [ANC] > 1,000/μL). CR rate is defined as the proportion of subjects who achieve 
CR within 2 cycles of treatment with blinatumomab. Subjects without response 
assessment will be accounted for in the denominator when calculating the response 
rate. 
Complete Remission with Partial Hematological Recovery (CRh*) 
CRh* is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and partial 
recovery of peripheral blood counts: platelets > 50,000/µl, and ANC > 500/µl. 
Complete Remission with Incomplete Hematological Recovery (CRi) 
CRi is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and 
incomplete recovery of peripheral blood counts: platelets > 100,000/µl or ANC > 1,000/μl 
(but not both). 
CR/CRh* 
CR/CRh* is defined as having either CR, or CRh*. CR/CRh* rate is defined as the 
proportion of subjects who achieve CR/CRh* within 2 cycles of treatment with 
blinatumomab. Subjects without response assessment will be accounted for in the 
denominator when calculating the response rate, ie, these subjects will be counted as 
non-responders.  
CR/CRh*/CRi 
CR/CRh*/CRi is defined as having either a CR, CRh*, or CRi. CR/CRh*/CRi rate is 
defined as the proportion of subjects who achieve CR/CRh*/CRi within 2 cycles of 
treatment with blinatumomab. Subjects without response assessment will be accounted 
for in the denominator when calculating the response rate.  
Cumulative Dose of Blinatumomab 
Blinatumomab: The cumulative dose in µg is defined as the following with summation 
over infusions: 
g/day]
[ 
received
 
dose
 
 
received
 
dose
each 
for 
 
[days]
infusion 
 
of
duration 
µ
×
∑
 
Cumulative dose will be calculated within a cycle and across all cycles. 
Death Date 
For subjects who die during the study, the death date will be recorded on the end of 


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study CRF as the end of study date. For deaths collected after a subject has ended 
study (eg, through public records or as part of adverse event (AE) reporting post end of 
study date), the death date will be recorded on the long term follow-up CRF in the 
subject status date or on the AE CRF in the AE end date for a grade 5 AE. 
End of Blinatumomab Therapy Date 
The end of Blinatumomab therapy date is the date the decision was made to end 
investigational product reported on the end of investigational product administration 
CRF.  
End of Study (Primary Completion) 
For a subject: a subject ends the study when they die, consent is withdrawn, or they are 
lost to follow-up. The end of study date will be captured on the end of study CRF. 
For the study as a whole: the primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. The primary 
completion date is when data for the primary endpoint are last collected for the purposes 
of conducting the primary analysis. If the study concludes prior to the primary completion 
date originally planned in the protocol (ie, early termination of the study), then the 
primary completion will be the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit). 
End of Study 
The end of study date is defined as the date when all the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, longterm follow-up), as applicable. 
Enrollment Date  
The date of enrollment is the date the subject gets first infusion of blinatumomab . 
Overall Survival (OS) 
OS time will be calculated from the time of first infusion of blinatumomab until death due 
to any cause. Subjects still alive will be censored at the date last known to be alive up 
until the data cut-off date.  


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Relapse event 
A relapse event is any one of the following: 
• 
Hematological relapse: proportion of blasts in bone marrow > 5% or blasts in 
peripheral blood after documented CR or CRh* or CRi 
• 
Extramedullary relapse: extramedullary lesion that is new or increased by 50% from 
nadir as assessed by Cheson criteria (Cheson et al, 2007)  
Relapse-free survival (RFS)  
RFS time will be calculated from the first onset of CR/CRh* within the 2 cycles until the 
documented hematological relapse, extra-medullary disease, or death due to any cause, 
whichever occurs first. The analysis is restricted to subjects who achieve CR/CRh* 
within 2 cycles of treatment. The subjects still alive and relapse-free will be censored at 
the date of last disease assessment up until the data cut-off date. Sensitivity analyses of 
RFS will be calculated similarly for those who achieve CR/CRh* and those who achieve 
CR/CRh*/Cri at anytime during the study. 
Last Dose Date of Blinatumomab: 
The stop date of the last infusion of blinatumomab administered.   
MRD Response 
MRD response is defined as favorable if MRD < 1 x 10-4 leukemic cells detectable 
measured by flow cytometry, within 2 cycles of blinatumomab treatment. The presence 
of a low number of leukemic cells that are not detectable by light microscopy after 
induction therapy and/or consolidation therapy is an independent prognostic factor for 
poor outcome of ALL. Subjects whose MRD persists during induction and consolidation 
of front-line treatment or who become MRD-positive following treatment, have a poor 
leukemia free survival.  
MRD response rate is defined as the proportion of subjects who achieve MRD response 
within 2 cycles of treatment with blinatumomab among subjects who achieved CR/CRh* 
within 2 cycles of treatment with blinatumomab and had evaluable MRD assessment.  
Percent of Intended Dose of Blinatumomab: 
For a given cycle, the percent of intended dose of blinatumomab will be the cumulative 
dose in that cycle divided by the planned cumulative dose for that cycle. For the first 
cycle, the planned cumulative dose will be (9 µg/day x 7 days) + 
(28 µg/day x 21 days) = 651 µg. For subsequent cycles, the planned cumulative dose 
will be (28 µg/day x 28 days) = 784 µg. For the entire study, the percent of intended 


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dose of blinatumomab will be the sum of the cumulative doses across cycles divided by 
the sum of the planned cumulative doses across the cycles started. Re-started cycles 
will have the planned cumulative dose counted both for the period before the re-start and 
for the period after the re-start in the calculation of the percent of intended dose. 
Prior Salvage Regimens 
Prior salvage regimens are those medications recorded on the prior anti-cancer 
therapies CRF where the line of therapy field indicates salvage chemotherapy. 
Protocol-specified Therapy 
Protocol-specified therapy refers to the treatment blinatumomab. The protocol also uses 
the term “protocol required therapy” but for consistency protocol-specified therapy will be 
used throughout this document. 
Relative Treatment Duration of Blinatumomab: 
For each cycle, the relative treatment duration will be duration of blinatumomab infusion 
for that cycle divided by 28 days, the planned duration of infusion. For the entire study, 
the relative treatment duration will be the duration of blinatumomab infusion for the entire 
study divided by 28 times the number of cycles started. Re-started cycles will count as 
28 days for the period before the re-start and 28 days for the period after the re-start in 
the calculation of planned duration. 
Study Day 1 
The first day of the infusion of blinatumomab. 
Treatment-emergent Adverse Event 
AEs starting on or after first dose of blinatumomab as determined by the flag indicating if 
the adverse event started prior to the first dose on event page of CRF and up to and 
including 30 days after the end of blinatumomab. This reporting window also applies to 
treatment-emergent serious adverse events (SAEs). 
7. 
Analysis Sets 
7.1 
Primary Analysis Set (PAS) 
This dataset consists of all enrolled subjects who received at least one infusion of 
blinatumomab. Primary analysis will be performed when all the enrolled subjects have 
finished at least 2 cycles of blinatumomab and the safety follow-up visit (if subjects 
discontinue treatment after 2 cycles), or have discontinued the treatment of 
blinatumomab and complete the safety follow up visit, whichever occurs first.  


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7.2 
Safety Analysis Set (SAS)  
All enrolled subjects who received at least one infusion of blinatumomab. The definition 
is the same as PAS.  
7.3 
Pharmacokinetic Analysis Set (PKS) 
All subjects who received any infusion of blinatumomab and had at least one PK sample 
collected will be included in the Pharmacokinetic Analysis Set. These subjects will be 
evaluated for pharmacokinetics unless significant protocol deviations affect the data 
analysis or if key dosing, dosing interruption, or sampling information is missing. 
7.4 
Interim Analyses Set 
The Interim Analysis Set is defined as the first 90 subjects (75% of the expected total) 
who have had the opportunity to be treated with at least 2 cycles of blinatumomab and to 
finish the safety follow-up visit (if subjects discontinue treatment after 2 cycles), or have 
discontinued the treatment of blinatumomab and complete the safety follow-up visit, 
whichever occurs first. The interim analysis will assess blinatumomab efficacy and safety 
and will be based on this Interim Analysis Set.  
7.5 
Subgroup Analyses 
Subgroup analyses will be performed to explore the consistency of the treatment effect. 
This includes logistic regression or Cox regression that will estimate odds ratio or hazard 
ratio and its corresponding 95% confidence interval for treatment effect between 
subgroups. The following covariates may be used to examine efficacy and/or safety in 
subgroups or covariates analyses:  
• 
Sex (female vs. male) 
• 
Age (< 35 vs ≥ 35 to < 55 vs ≥ 55) 
• 
Prior salvage therapy (yes vs. no) 
• 
Prior alloHSCT (yes vs. no)  
• 
Bone marrow blast at baseline (<50% vs. ≥50%) 
• 
Disease status (primary refractory vs first relapse vs second or later relapse)  
• 
Refractory to last previous therapy (yes vs. no) 
8. 
Planned Analyses 
8.1 
Interim Analysis and Early Stopping Guidelines 
The interim analysis will assess blinatumomab efficacy and safety and will be based on 
the Interim Analysis Set. The efficacious benefit assessment will be based on an 
O’Brien-Fleming alpha spending function (O’Brien and Fleming, 1979) with the critical 
boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh* 


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rate. If the interim analysis showed statistically efficacious and overall benefit-risk 
analysis is promising, then the interim analysis will become the primary analysis of this 
study. In addition, the study will still continue its enrollment until 120 subjects are 
enrolled and continue to complete the protocol specified procedures. 
The interim analysis will be reviewed by an Amgen internal Data Review Team (DRT) 
including medical scientist, biostatistician, safety scientist, pharmacologist. The interim 
analysis will be performed by the independent biostatistician and the programmers 
supporting the DRT. The DRT and independent biostatistician and programmer are 
independent from the Clinical Study Team, which allows the study integrity to be 
maintained. The DRT will also review safety data at the time of interim analysis. 
Additional ad hoc Interim Analyses may be performed descriptively without alpha 
spending. Pharmacokinetic samples collected at specific timepoints may be analyzed 
and reported. The purpose of this analysis is just to provide descriptive analyses of PK, 
safety, and efficacy information (including 95% confidence intervals) for regulatory 
submissions and interactions.  
8.2 
Primary Analysis 
Primary analysis will be performed when all enrolled subjects have finished at least 
2 cycles of blinatumomab and the safety follow-up visit (if subjects discontinue treatment 
after 2 cycles) or have discontinued the treatment of blinatumomab and complete the 
safety follow up visit, whichever occurs first. 
8.3 
Final Analysis 
Final analysis will be performed at the end of the study when all the enrolled subjects 
have finished all the follow-up visits or have withdrawn from the study, whichever occurs 
first. The analyses of RFS, OS, alloHSCT rate after achieving CR/CRh*, and safety will 
be updated. 
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses. The 
database will be subject to edit checks outlined in the data management plan by Amgen 
Clinical Data Management (CDM) department. Any outstanding data issues will be 
communicated to CDM for resolution before the database is locked. 


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9.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. 
9.3 
Handling of Missing and Incomplete Data 
The descriptive statistics will identify the extent of missing data. Rules for handling 
missing data related to endpoints are described in the description of analyses 
(Section 10). The handling of incomplete and partial dates for adverse events and 
concomitant medications are described in Appendix A. Handling of missing or 
incomplete data for exposure-response analysis will be described in the E-R SSAP or 
associated documents to support population PK/PD dataset generation and E-R 
analysis. 
9.4 
Outliers 
Any suspected outliers will be investigated by the study team and will be included in the 
database unless determined to be an error or there is supporting evidence or 
explanation to justify the exclusion. Any outliers excluded from the analysis will be 
discussed in the Clinical Study Report (CSR), including the reasons for exclusion and 
the impact of their exclusion on the study. 
9.5 
Distributional Characteristics 
The statistical assumptions for analysis methods will be assessed. If the assumptions for 
the distributional characteristics are not met, these will be described and further 
analyses may be carried out using data transformations or alternative analysis methods. 
The use of transformations or alternative analysis methods will be justified in the final 
study report. 
9.6 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.4 or 
later. For the exposure–response analysis, refer to the E-R SSAP for software used. 


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10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The binomial endpoints including CR/CRh* rate, CR rate, CR/CRh*/CRi rate, alloHSCT 
rate and MRD response rate will be calculated and the Clopper-Pearson formula 
(Clopper and Pearson, 1934) will be used to derive the exact 95% confidence intervals 
of binomial rates for primary and secondary endpoints.The time-to-event endpoints 
including RFS and OS will be summarized with hazard ratio, Kaplan-Meier (KM) curves, 
KM proportions at selected time points, KM quartiles (when estimable), the number of 
subjects with events, the number of subjects censored, and the pattern of censoring. 
Continuous variables will be summarized by the non-missing sample size, mean, 
standard deviation, median, first and third quartiles, minimum, and maximum. 
Categorical variables will be summarized by the percentage in each category.  
Subgroup analyses will be performed to explore the consistency of the treatment effect 
for subgroups described in Section 7.5; this includes: 
• 
 Logistic regression for CR/CRh* rate, CR rate, CR/CRh*/CRi rate, alloHSCT rate 
and MRD response rate, that will estimte the odds ratio and its 95% confidence 
intervals between subgoups. 
• 
Cox regression for RFS and OS that will estimte the hazard ratio and its 95% 
confidence intervals between subgoups. 
The analyses of biomarker will be separately documented.  
10.2 
Subject Accountability 
The number and percent of subjects who were screened, received protocol-specified 
therapy along with the reasons for discontinuing protocol-specified therapy and 
discontinuing study will be summarized. The number and percent of subjects receiving 
first infusion of blinatumomab will be tabulated. The number and percent of subjects 
infused will be tabulated by study site. Key study dates for the first subject infused, last 
subject infused, and data cut-off date for analysis will be presented. 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes and descriptions 
will be used during the course of the study.  
Eligibility deviations are defined in the protocol.  


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10.4 
Demographic and Baseline Characteristics 
Demographic (ie, age, age group [<35, ≥35 to <55, ≥55], geriatric age group 
[<65, ≥65 to <75 and ≥75] and sex) and baseline disease characteristics will be 
summarized using descriptive statistics for the Primary Analysis Set. The baseline 
characteristics to be summarized include: 
• 
B-precursor subtype 
• 
Occurrence and type of any genetic abnormality 
• 
Age at diagnosis 
• 
White blood cell count at diagnosis 
• 
Time to CR following first line treatment 
• 
MRD status following first line treatment 
• 
Relapse/refractory status at baseline 
o Refractory to first line treatment 
o Refractory to salvage therapy 
o In second or greater relapse 
o In relapse after alloHSCT 
• 
Number and type of prior salvage regimens 
• 
Occurrence of prior alloHSCT 
• 
Baseline bone marrow blast count  
• 
Baseline laboratories including: hemoglobin, ANC, leucocytes, platelet counts, and 
peripheral blasts in blood 
• 
Baseline CD19 status (percentage and absolute number of CD19 positive cells) 
• 
Baseline CD3 status (percentage and absolute number of CD3 positive cells) 
10.5 
Efficacy Analyses 
10.5.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the CR/CRh* rate within 2 cycles of treatment with 
blinatumomab. The response rate will be calculated and the exact binomial 95% 
confidence interval will be generated for the response rate. Similar analyses will be 
provided for CR/CRh* rate during the treatment. Subgroup analyses will be performed to 
explore the consistency of the treatment effect for subgroups described in Section 7.5; 
this includes a logistic regression that will estimte the odds ratio and its 95% confidence 
intervals between subgoups. The results will be presented by forest plot. 
The primary analysis will be based on the Primary Analysis Set.  


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10.5.2 
Analyses of Secondary Efficacy Endpoints 
The secondary efficacy endpoints include relapse-free survival (RFS), CR rate, 
CR/CRh*/CRi rate, alloHSCT rate, overall survival, MRD response rate, 100 day 
mortality after alloHSCT, and time to a 10 point decrease from baseline in global health 
status/Quality of Life (QoL) using the EORTC QLQ-C30.  
The CR rate, CR/CRh*/CRi rate, alloHSCT rate and MRD response rate will be 
calculated and the exact binomial 95% confidence interval will be generated for these 
response rates.  
Subgroup analyses of the CR rate will be performed to explore the consistency of the 
treatment effect for subgroups described in Section 7.5; this includes a logistic 
regression that will estimte the odds ratio and its 95% confidence intervals between 
subgoups. The results will be presented by forest plot. The above subgroup analysis will 
apply to CR/CRh*/CRi rate, alloHSCT rate and MRD response rate. Subgroup analyses 
of the RFS and OS will be performed to explore the consistency of the treatment effect 
for subgroups described in Section 7.5; this includes a Cox regression that will estimte 
the hazard ratio and its 95% confidence intervals between subgoups. The results will be 
presented by forest plot. 
The 100-day mortality after alloHSCT will be summarized with the 100-day KM rate 
among the subjects who achieve CR/CRh* and remain in remission without intervening 
therapy after blinatumomab and undergo alloHSCT. 
The RFS time, CR rate, CR/CRh*/CRi rate, MRD response rate, the OS time and the 
alloHSCT rate will be analyzed based on the Primary Analysis Set. Time to a 10 point 
decrease from baseline in global health status/Quality of Life (QoL) using the EORTC 
QLQ-C30 will be performed on the EORTC QLQ-C30 Analysis Set. 
10.6 
Safety Analyses 
10.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term. AEs 
of interest (EOI) categories will be based on search strategies defined by medical 
coding. Treatment-emergent adverse events are events with an onset after the 
administration of the first dose of Blinatumomab. 
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, AEs leading to withdrawal of Blinatumomab, fatal AEs and EOI.  


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Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of IP, and fatal AEs will be tabulated by system organ class and preferred 
term in descending order of frequency; similar summaries will be repeated for EOIs. 
Time to onset of selected EOIs (infection, cytokine release syndrome and neurologic 
events) may also be summarized with descriptive statistics. Duration of selected 
EOIs will be summarized by KM methods and the descriptive statistics for 
resolved events (number of subjects; number of events; number of days 
experiencing events: mean, SD, median, Q1, Q3, min, max) and unresolved events 
(number of subjects,  number of events) of selected EOIs should also be provided.  
A summary of treatment-emergent AEs will be tabulated by system organ class, 
preferred term, and worst grade. 
Subgroup analyses (if there is a medical or regulatory rationale) will be presented by 
system organ class and preferred term in descending order of frequency. 
The number and percentage of subjects with antibody formation to blinatumomab will be 
summarized. In addition, changes in vital sign and laboratory parameters will be 
summarized.  
Subject incidence of all disease related events, fatal disease related events, serious 
disease related events, and disease related events leading to withdrawal from 
blinatumomab, will also be provided.  
Extent of exposure to blinatumomab will be summarized using descriptive statistics. 
Percentage of subjects and number of cycles with doses held and dose reductions will 
be calculated.  
These analyses will be performed using subjects in the SAS.  
10.6.2 
Laboratory Test Results 
Shift tables between the worst post-baseline and baseline grades for select laboratory 
parameters defined in Appendix B. Plots or other summaries overtime will be presented 
for select laboratory parameters including immunoglobin, platelets, and liver parameters 
(alanine transaminase, aspartate transaminase, γ-glutamyl transferase, alkaline 
phosphatase, and total bilirubin) for subjects in the Safety Analysis Set. The subject 
incidence of potential cases of Hy’s Law will be summarized.  


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10.6.3 
Vital Signs 
The number and percentage of subjects with abnormal changes (defined in Appendix B) 
in systolic blood pressure, diastolic blood pressure and heart rate will summarized for 
subjects in the Safety Analysis Set. 
10.6.4 
Antibody Formation 
The incidence and percentage of subjects who develop anti blinatumomab antibodies 
(binding and if positive, neutralizing) at any time will be tabulated. 
10.6.5 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to blinatumomab group 
for subjects in the Safety Analysis Set. The number of cycles of blinatumomab group 
administered will be summarized with an additional breakdown of the number of cycles 
completed, discontinued, and re-started. In addition, the duration of therapy, the relative 
treatment duration, the cumulative dose, and the percent of intended dose will be 
summarized by cycle and overall. The number and percent of subjects with dose 
modifications (eg, dose changes, dose interruptions) and reason for modification will be 
summarized.  
10.6.6 
Exposure to Other Protocol-specified Treatment 
Descriptive statistics will be produced to describe the required pre-medication 
(dexamethasone) exposure in the Safety Analysis Set. 
10.6.7 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug (WHO DRUG) dictionary in the Safety Analysis Set. In 
addition, the number and proportion of subjects receiving anti-cancer therapies during 
long term follow-up will be summarized by WHO DRUG preferred term in the Full 
Analysis Set.  
10.7 
Other Analyses 
10.7.1 
Pharmacokinetic Analysis 
Blinatumomab serum samples will be taken as listed in Schedule of Assessment of the 
protocol. The Clinical Data Interchange Standards Consortium (CDISC) Analysis Data 
Model (ADaM) standard will be adopted to create the Analysis Dataset for 
Pharmacokinetics Concentrations (ADPC). The ADPC dataset includes the following 
variables: 1) subject level information (eg., subject ID, country, planned treatment, actual 


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treatment received, population flags); 2) PK variables (eg., concentration, actual and 
scheduled PK sampling time); 3) Dosing variables (eg., planned and actual dose(s), start 
time, stop time and duration of drug infusion, time relative to first infusion start); 
4) Physical measurement variables (eg., demographics, selected baseline 
characteristics and laboratory measurements) and 5) Miscellaneous variables (eg., study 
specific variables).  
Pharmacokinetic parameters will be determined with non-compartmental analysis 
method with PK Analysis Set. PK parameters such as steady state concentration (Css), 
volume of distribution, clearance, and elimination half-life will be estimated for subjects 
who have sufficient evaluable PK data. Summary statistics of PK parameters and data 
listings of individual blinatumomab concentration data will be provided. 
PK data may be subjected to exploratory population PK analysis with an integrated 
dataset of multiple studies. If the analysis is performed, nonlinear mixed effects modeling 
will be used. Effect of covariates on exposure will be determined. These may include 
age, body weight, body surface area, renal function, liver function, and sex. Other 
covariates may be analyzed if necessary. The results will be reported separately. 
Exposure-response relationships for selected efficacy and safety endpoints may be 
assessed as appropriate. If the analysis is performed, the results will be reported 
separately. 
10.7.2 
Analyses of Exploratory Endpoints 
Listings and summary statistics of selected CNS events will be generated to explore 
possible relation with blinatumomab. 
For a subgroup of patients, samples for analysis of lymphocyte subsets will be taken at 
baseline (before first dose on Cycle 1 D1), at cycle 1 (24 hours after the beginning of the 
infusion [D2] and at the end of the infusion), and at the SFU visit as described in the 
Schedule of Assessments of the study protocol. If B cells have not recovered (number of 
CD19-positive cells is 90 to 570 per μL) at the safety follow-up visit lymphocyte subsets 
will also be collected 6 months (+3 months) after the safety follow-up visit. Analysis will 
be provided in a Contributing Scientific Report by the Clinical Biomarker and Diagnostics 
group. 
10.7.3 
Analyses of Health Related Quality of Life Endpoints 
The analyses of health related quality of life endpoints will be described in a SSAP. 


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10.7.4 
Exploratory Biomarker Endpoints Analysis 
The investigation of lymphocytes subset, cytokines, and chemokines measurement will 
be part of a separate biomarker analysis plan by scientists from the Clinical Biomarkers 
and Diagnostics (CBD) group. 


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11. 
Literature Citations / References 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25:579-586. 
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial, Biometrika. 1934; 26(4):404-413. 
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. 
Biometrics. 1979;35:549-556. 


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12. 
Appendices 
 


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Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates for Adverse 
Events and Concomitant Medications 
The following data will be imputed using the following algorithm:  
• 
Adverse Events  
• 
Concomitant Medications 
Table 1.  Imputation Rules for Partial or Missing Start Dates 
 Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial:  
yyyymm 
Partial:  
yyyy 
missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
Imputation rules for partial or missing stop dates: 
Initial imputation 
• 
For partial stop date mmyyyy, impute the last of the month. 
• 
For partial stop date yyyy, impute December 31 of the year. 
• 
For completely missing stop date, do not impute. 
• 
If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date. 
• 
If the stop date imputation leads to a stop date that is before the start date, then 
there is a data error and do not impute the stop date. (ie. set the stop date as 
missing). 


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Imputation rules for partial or missing death dates: 
• 
If death year and month are available but day is missing: 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date to the day 
after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date to the first 
day of the death month. 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error and do not 
impute. 
• 
If both month and day are missing for death date or a death date is totally missing, 
the death date will be imputed as the day after the date last known to be alive.  
Note that the last contact date refers to the last contact (ie, a visit or an assessment) 
with patient instead of family members. Last contact date would be derived from the 
latest patient visit/assessment date. 
 


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Appendix B.  Laboratory Grading and Notable Vital Sign Values 
Laboratory Values 
Safety laboratory values below a distinct limit (eg. detection limit, documented as 
“< [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “> [limit]”) will be substituted by the limit itself for all analyses. 
A Grade (based on CTC AE version 4.0 [v4.03: June 14, 2010]) will be assigned to each 
laboratory result as detailed in Table 2. Depending on the toxicity definition, the same 
result may be assigned to two grading for deviations towards higher or lower values. In 
case no lower limit of normal is provided for the absolute lymphocyte, neutrophils or 
leukocyte counts it will not be differentiated between grade 1 and grade 0 results for 
these parameters. Values not meeting any of the criteria will be assigned a grade 0. 
Table 2.  Grading of Select Laboratory Parameters 
Laboratory 
Parameter [Unit] 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lymphocytes 
[G/L] 
0.8 - < LLN 
0.5 - < 0.8 
0.2 - < 0.5 
< 0.2 
Neutrophils  
[G/L] 
1.5 - < LLN 
1.0 - < 1.5 
0.5 - < 1.0 
< 0.5 
Leukocytes 
[G/L] 
3.0 - < LLN 
2.0 - < 3.0 
1.0 - < 2.0 
< 1.0 
Platelets [G/L] 
75 - < LLN 
50 - < 75 
25 - < 50 
< 25 
Hemoglobin 
[g/L]* 
100 - < LLN  
80 - < 100 
< 80 
 not defined 
Albumin [g/L] 
30 - < LLN 
20 - < 30 
< 20 
not defined 
AST* 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
ALT * 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
GGT  
> ULN – 
2.5*ULN 
>2.5*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
Bilirubin 
> ULN – 
1.5*ULN 
>1.5*ULN – 3*ULN 
> 3*ULN – 10*ULN 
> 10*ULN 
Fibrinogen^ 
%change of BL 
<25% or 
0.75*LLN - < 
LLN 
25%- <50% of BL 
 or  
< 75*LLN – 0.5*LLN 
50% - <75% of BL  
or 
< 0.5* LLN – 0.25*LLN 
>= 75% of BL 
or < 50mg/dL 
or < 
0.25*LLN 
Corrected 
Calcium 
[mmol/L]* 
2.0 - < LLN 
1.75 - < 2.0 
1.5 - < 1.75 
< 1.5 
Potassium 
[mmol/L]* 
not defined 
3.0 - < LLN 
2.5 - < 3.0 
< 2.5 
Lipase 
> ULN – 
1.5*ULN 
> 1.5*ULN – 
2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
Amylase  
> ULN – 
1.5*ULN 
> 1.5*ULN – 
2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
BL: baseline value, LLN: Lower limit of normal, ULN: Upper limit of normal 
*: Clinical criteria from CTC AE 4.0 grading were not considered in order to assign grades 
^: In case of conflicting criteria the higher grade will be assigned, % change only used when baseline is <LLN  


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Vital Signs 
Notable values for vital signs are defined according to the following table: 
Table 3.  Notable Abnormalities of Vital Signs 
Vital Sign 
 
Notable Abnormalities 
Pulse rate (bpm) 
 
>120 
<50 
Blood pressure (mmHg) 
Systolic 
≥160 
≤90 
 
Diastolic 
≥105 
≤50 
Weight (kg) 
 
change from baseline ≥10% (in both directions) 
Body temperature (°C) 
 
> 39