Conditions: Leukemia, Acute Lymphoblastic
Keywords: ALL High-risk first relapse B-precursor ALL Precursor Cell Lymphoblastic Leukemia Neoplasms Lymphoproliferative Disorders Immunoproliferative Disorders Antibodies, Bispecific
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 111
Healthy volunteers: no

Brief summary:
B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.

Detailed description:
Patients will be randomized in a 1:1 ratio to receive either one cycle of blinatumomab or one block of standard high-risk consolidation chemotherapy. Blinatumomab is administered as a continuous intravenous infusion (CIVI). One cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab. After completing consolidation therapy, the patients should undergo alloHSCT depending on their bone marrow status. The patients will be followed up until the last subject on study is 36 months following alloHSCT or has died, whichever is first.

Arms:
arm 1: One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day intravenous \[IV\] on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or intramuscularly \[IM\] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses). arm 2: 15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks

Interventions: intervention 1: Blinatumomab intervention 2: Dexamethasone intervention 3: Vincrisitne intervention 4: Daunorubicin intervention 5: Methotrexate intervention 6: Ifosfamide intervention 7: PEG-asparaginase intervention 8: Erwinia-asparaginase
Intervention descriptions: intervention 1: 15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks intervention 2: 10 mg/m\^2/day intravenous (IV) on Days 1-6 intervention 3: 1.5 mg/m\^2/day IV on Days 1 and 6 intervention 4: 30 mg/m\^2 IV over 24 hours on Day 5 intervention 5: 1 g/m\^2 IV over 36 hours on Day 1 intervention 6: 800 mg/m\^2 IV for 1 hour on Days 2-4 intervention 7: 1000 U/m\^2 IV for 2 hours or intramuscularly (IM) on Day 6 intervention 8: In case of allergic reaction to PEG-asparaginase, participants could change to erwinia-asparaginase, 20,000 units/m2 every 48 hours for a total of 6 doses

Protocol document:
Prot_002.pdf: 
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SAP_001.pdf: 
Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 1
STATISTICAL ANALYSIS PLAN
A Randomized, Open-label, Controlled Phase 3 Trial to Investigate the Efficacy, 
Safety, and Tolerability of the BiTEAntibody Blinatumomab as Consolidation 
Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects 
With High-risk First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Protocol Number:
20120215
Version:
2.0
Date:
20 March 2018
Authors:
NCT Number: NCT02393859
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov
-


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................4
1.
Introduction.............................................................................................................5
2.
Objectives...............................................................................................................5
2.1
Primary Objective........................................................................................5
2.2
Secondary Objectives .................................................................................5
3.
Study Overview ......................................................................................................5
3.1
Study Design...............................................................................................5
3.2
Sample Size................................................................................................6
4.
Study Endpoints and Covariates.............................................................................7
4.1
Study Endpoints..........................................................................................7
4.2
Planned Covariates.....................................................................................8
5.
Hypotheses and/or Estimations ..............................................................................8
6.
Definitions...............................................................................................................8
7.
Analysis Subsets ..................................................................................................14
7.1
Primary Analysis Set .................................................................................14
7.2
Safety Analysis Set ...................................................................................14
7.3
Per Protocol Set........................................................................................14
7.4
Pharmacokinetic Analysis Set ...................................................................14
7.5
Interim Analyses Set .................................................................................14
7.6
MRD Evaluable Set...................................................................................15
7.7
HSCT Analysis Set....................................................................................15
7.8
Subgroup Analyses...................................................................................15
8.
Interim Analysis and Early Stopping Guidelines....................................................15
9.
Data Screening and Acceptance...........................................................................16
9.1
General Principles.....................................................................................16
9.2
Data Handling and Electronic Transfer of Data .........................................16
9.3
Handling of Missing and Incomplete Data .................................................17
9.4
Detection of Bias.......................................................................................17
9.5
Outliers .....................................................................................................17
9.6
Distributional Characteristics.....................................................................17
9.7
Validation of Statistical Analyses...............................................................17
10.
Statistical Methods of Analysis..............................................................................17
10.1
General Principles.....................................................................................17
10.2
Subject Accountability ...............................................................................18
10.3
Important Protocol Deviations ...................................................................18
10.4
Demographic and Baseline Characteristics...............................................19


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 3
10.5
Efficacy Analyses......................................................................................19
10.5.1
Analysis of Primary Efficacy Endpoint........................................19
10.5.2
Analysis of Secondary Efficacy Endpoints.................................20
10.5.3
Analyses of Other Efficacy Endpoint(s)......................................20
10.6
Safety Analyses ........................................................................................21
10.6.1
Adverse Events .........................................................................21
10.6.2
Laboratory Test Results ............................................................23
10.6.3
Vital Signs .................................................................................23
10.6.4
Electrocardiogram (ECG) ..........................................................23
10.6.5
Antibody Formation ...................................................................23
10.6.6
Exposure to Investigational Product ..........................................23
10.6.7
Exposure to Other Protocol-specified Treatment .......................24
10.6.8
Exposure to Concomitant Medication ........................................24
10.6.9
100-day Mortality After AlloHSCT..............................................24
10.7
Pharmacokinetic Analysis .........................................................................24
10.7.1
Exposure Response Analysis ....................................................25
11.
Changes From Protocol-specified Analyses..........................................................25
12.
Literature Citations / References...........................................................................26
13.
Appendices...........................................................................................................27
List of Tables
Table 1.  Imputation Rules for Partial or Missing Start Dates.........................................28
List of Appendices
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates for 
Adverse Events and Concomitant Medications.......................................28
Appendix B.  Reference Values/Toxicity Grades ...........................................................30
Appendix C.  List of EOIs (including the search strategies and associated 
algorithms)..............................................................................................32
Appendix D.  Study Design and Treatment Schema......................................................39
Appendix E.  Simulation Results....................................................................................40


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 4
Table of Abbreviations
Abbreviation or Term
Definition/Explanation
AE
adverse event
ALL
acute lymphoblastic leukemia
alloHSCT
allogeneic hematopoietic stem cell transplantation
BiTE
Bi-specific T cell engagers
CDM
clinical data management
CIVI
continuous intravenous infusion
CNS
central nervous system
CR
complete remission
CSR
clinical study report
DMC
data monitoring committee
eCRF
electronic case report form
EFS
event free survival
E-R
event-risk
HC1
high-risk consolidation 1
HC2
high-risk consolidation 2
HC3
high-risk consolidation 3
IPD
important protocol deviation
IVRS
Integrated Voice Response System
KM
Kaplan-Meier
M1
Bone marrow blast percentage < 5%
M2
Bone marrow blast percentage < 25% and ≥5%
MRD
minimal residual disease
OS
overall survival
PCR
polymerase chain reaction
PD
pharmacodynamic
PK
pharmacokinetic
SAP
statistical analysis plan
SOC
standard of care
SSAP
supplementary statistical analysis plan


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
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 20120215
dated 5th December 2017.  The scope of this plan includes the interim analyses and the 
final analysis that are planned and will be executed by the Biostatistics department 
unless otherwise specified. PK analyses will be provided by Clinial Pharmacology, 
Modeling and Simulation (CPMS) group in Department of Medical Sciences. 
2.
Objectives
2.1
Primary Objective
To evaluate event-free survival (EFS) after blinatumomab when compared to standard of 
care (SOC) chemotherapy.
2.2
Secondary Objectives

To evaluate the effect of blinatumomab on overall survival (OS) when compared 
to SOC chemotherapy

To evaluate reduction in minimal residual disease (MRD) after blinatumomab 
when compared to SOC chemotherapy

To evaluate the safety of blinatumomab when compared to SOC chemotherapy

To evaluate the safety of allogeneic hematopoietic stem cell transplantation 
(alloHSCT) after blinatumomab when compared to alloHSCT after SOC 
chemotherapy
3.
Study Overview
3.1
Study Design
This is a Phase 3 randomized, open-label, controlled, multicenter study investigating the 
efficacy and safety profile of blinatumomab versus intensive standard late consolidation 
chemotherapy.  After induction therapy and 2 blocks of high-risk consolidation 
chemotherapy, pediatric subjects with high-risk first relapse B-precursor ALL will be 
randomized in a 1:1 ratio to either blinatumomab or a third block of standard HC3 
chemotherapy. 
Randomization will be stratified by age, marrow status determined at the end of HC2, 
and MRD status determined at the end of induction.  Six strata will be formed from the 
following 2 age categories and 3 marrow/MRD categories:

Age: 1-9 years and other (<1 year and >9 years)

Marrow/MRD:  M1 with MRD level ≥ 10-3, M1 with MRD level < 10-3, and M2


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 6
After a screening period of up to 3 weeks, eligible subjects will be enrolled and 
randomized to one of the following two treatment arms:

Arm 1A:  One consolidation cycle of blinatumomab (15 µg/m2/day), defined 
as a 4-week CIVI of blinatumomab, or  

Arm 2A:  One consolidation cycle of HC3
Most subjects who are in or achieve cytomorphological CR2 (M1 marrow) after 
completing consolidation therapy in any treatment arm will undergo alloHSCT.
The following visit types will be performed:

During screening, assessments will be performed to evaluate eligibility of the 
subject.

During the treatment period, visits will be performed on Day 1, Day 15, 
Day 29/End of Treatment.  The Day 29 visit will have a window of ± 2 days.

A safety follow-up visit will be required within 7 days prior to alloHSCT or, prior to 
any further anti-leukemic treatment administered after end of study treatment. 

Subjects will be followed during a short-term efficacy follow-up period of 
12 months following alloHSCT, followed by a long-term follow-up period that lasts 
until the last subject on study is 36 months following alloHSCT or until death, 
whichever is first. After reaching the primary endpoint, subjects will be directly 
followed by the long-term follow-up period.
o
During the short-term efficacy follow-up period, visits will be performed at 
45 days, 90 days, 6 months, 9 months, and 12 months following 
alloHSCT.
o
During the long-term follow-up period telephone and/or e-mail contact will 
be made to assess disease and survival status every 3 months 
(± 2 weeks) until the last subject on study is 36 months following 
alloHSCT or until death, whichever occurs first.  
During the long-term follow-up period, telephone and/or e-mail contact will be made to 
assess disease and survival status every 3 months (± 2 weeks) until the last subject on 
study has been followed for 36 months after alloHSCT  or until death, whichever occurs 
first.  The overall study design is described by a study schema in Appendix D.
3.2
Sample Size
The target is to observe 94 EFS events in 202 subjects randomized (the Full Analysis 
Set, as described in Section 7).  The following operating characteristics are based on 
5,000 simulations using a 2-sided log-rank test with an overall two-sided type 1 error of 
5%, a 1:1 randomization ratio, and exponentially distributed EFS times for non-cured 
subjects, and a uniform enrollment period of 48 months.


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 7
If the control arm (Arm 2A) has a true cure rate of 40% and median EFS of 7 months 
among non-cured subjects (data on file) and the treatment arm (Arm 1A) has a true cure 
rate of 56.2% and median EFS of 11.1 months among non-cured subjects (a non-cured 
hazard ratio of 0.63) then approximately 84% of the simulations produce a statistically 
significant result (power).  The simulation results for this are shown in Appendix E.
Under the assumption of no treatment effect (40% cure rate and median EFS of 
7 months for all arms), the probability of detecting a significant result in favor of 
blinatumomab (Arm 1A) is approximately 2.3% which is similar to the planned type 1 
error.  The simulation results for this are shown in Appendix E.
4.
Study Endpoints and Covariates
4.1
Study Endpoints
Primary Endpoint

EFS: EFS will be calculated from the time of randomization until the date of relapse 
or M2 marrow after having achieved a CR (complete remission), failure to achieve a 
CR at the end of treatment, second malignancy, or death due to any cause, 
whichever occurs first.  For a more detailed definition please see Section 6.
Key Secondary Efficacy Endpoint

OS: OS will be calculated from time of randomization until death due to any cause.  
For a more detailed definition please see Section 6.
Secondary Efficacy Endpoints

MRD response, defined as MRD level < 10-4 at the end of treatment with 
investigational product(s)

Cumulative incidence of relapse
Secondary Safety Endpoints

Incidence of adverse events (both serious and non-serious), treatment-related 
adverse events, adverse events of interest, clinically significant changes in laboratory 
values

Survival status at 100 days following alloHSCT

Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)

Pharmacokinetic sampling for blinatumomab concentrations for population PK 
analysis

Blinatumomab steady-state concentrations


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 8
4.2
Planned Covariates
The analysis to determine if blinatumomab is superior to the chemotherapy with respect 
to the primary endpoint of EFS will be stratified by the stratification factors at 
randomization: 

Age: 1-9 years and other (<1 year and >9 years)

Marrow/MRD: M1 with MRD level < 10-3, M1 with MRD level ≥ 10-3, and M2
Where specified, analyses of key secondary endpoints will also be stratified by these 
factors. 
If at any point during an analysis, there are less than 2 events in a strata then the strata 
will be combined as follows, with point 1 being the first option and point 4 being the final 
option:
1. Combine M1 with MRD level < 10-3 strata and M1 with MRD level ≥ 10-3 strata  
2. If there are still strata with less than 2 events, combine M1 strata with MRD 
level ≥ 10-3 and M2 strata
3. If there are still strata with less than 2 events, stratify by age only
4. If there are still strata with less than 2 events, stratify by marrow/MRD only.
Exploratory subgroup analyses will be described in Section 7.7.
5.
Hypotheses and/or Estimations
The null hypothesis is that there is no difference between treatment groups with respect 
to EFS versus the alternative hypothesis that the treatment groups differ. The null 
hypothesis will be rejected if the p-value from a two-sided stratified log-rank test is less 
than the value specified by the alpha spending function specified in Section 8 at the 
given analysis (interim or final). In particular, the null hypothesis will be rejected in favor 
of blinatumomab if the log-rank statistic is in the appropriate direction. 
6.
Definitions
Age 
Age will be determined at the time of randomization. In countries where date of birth is 
allowed to be collected, age will be derived using the date of birth and the date of 
randomization. In countries where date of birth is not allowed to be collected, age at 
randomization will be provided by the site.


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 9
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 electronic case report form (eCRF) administered during the long 
term follow-up period of the study. 
Baseline 
For analyzing OS time and EFS time, baseline will be defined as the day of 
randomization. 
For the analysis of other endpoints, baseline will be defined as the value measured on 
day 1 of the first cycle of protocol-specified therapy (either blinatumomab or SOC 
chemotherapy). The protocol specifies that all study procedures on day 1 should be 
completed before the initiation of protocol-specified therapy 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 protocol-specified therapy may 
be used. 
Bone Marrow Assessment
M0 - Representative bone marrow aspirate or biopsy with blasts < 5%, with very low 
cellularity and with no regenerating hematopoiesis.  Also referred to as aplastic bone 
marrow.
M1 - Representative bone marrow aspirate or biopsy with blasts < 5%, with satisfactory 
cellularity and with regenerating hematopoiesis
M2 - Representative bone marrow aspirate or biopsy with at least 5% and < 25% blasts
M3 - Representative bone marrow aspirate or biopsy with at least 25% blasts
Complete Remission
A subject is said to be in complete remission when they have the following:

M1 marrow 

Peripheral blood without blasts

Absence of extramedullary leukemic involvement
Cumulative Dose of Protocol-specified Therapy 
Blinatumomab: The cumulative dose in μg is defined as the following with summation 
over infusions: 
(	
   [	]  	ℎ   ×   [])


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 10
Cumulative dose will be calculated within a cycle and across all cycles. 
SOC Chemotherapy: Provided sites enter the dose of a given chemotherapy drug in the 
same units within and across subjects, the cumulative dose will be calculated. The 
cumulative dose will be the total dose of given chemotherapy drug within a 
chemotherapy regimen. 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 
study CRF in 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. 
Duration of Protocol-specified Therapy 
Blinatumomab: For each infusion episode within a cycle, the duration of exposure will be 
calculated by subtracting the start date and time from the stop date and time. If either a 
start or stop time is missing, only the date portion will be used in calculating the duration 
of a specific infusion. For each cycle, the duration will be the sum of the individual 
infusion durations within that cycle. For the entire study, the duration will be the sum of 
the durations across cycles. The duration will be rounded to the nearest day. 
SOC Chemotherapy: Because many of the drugs within SOC Chemotherapy are given 
only over the course of the first few days of a 3 to 4 week chemotherapy cycle, the 
duration of chemotherapy will not be as informative as the duration of blinatumomab 
which is a continuous infusion over 28 days. Therefore, the number of chemotherapy 
cycles will be emphasized in comparative analyses as opposed to the duration of 
chemotherapy. If duration of a chemotherapy drug does get calculated, it will be defined 
as the time from the first start date of the drug to the last stop date of a drug. The 
duration of a chemotherapy regimen will be earliest start date among the drugs within 
the regimen to the latest stop date among the drugs within a regimen. 
End of Protocol-specified Therapy Date 
For both blinatumomab and SOC chemotherapy groups, the end of protocol-specified 
therapy date is the date the decision was made to end investigational product reported 
on the end of investigational product administration CRF. 


Product:  Blinatumomab
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Dated: 20 March 2018
Page 11
End of Study 
For a subject: a subject ends the study when they die, consent is withdrawn, they are 
lost to follow-up, or they complete the long-term follow-up. The end of study date will be 
captured on the end of study CRF. 
For the study as a whole: the end of study as a whole is defined as the time when the 
last subject is assessed or receives intervention for the purposes of final collection of 
data for the primary (ie, final) analysis of EFS, which will be triggered subject enrolled in 
long-term follow-up is 36 months following alloHSCT or died, whichever occurs first.  At 
the final analysis, the EFS and OS analyses will also be updated with additional 
follow-up data; these analyses will be considered descriptive. If the last subject enrolled 
on study dies or is lost to follow-up before the 36 months following alloHSCT, the 
remainder of the subjects on study will continue to be followed until all subjects on study 
have reached 36 months following alloHSCT, until death or lost to follow-up.
Enrolment Date 
The date of enrolment is the date the subject gets randomized. 
Event Free Survival (EFS) 
EFS will be calculated from the time of randomization until the date relapse or M2 
marrow after having achieved a CR, failure to achieve a CR at the end of treatment, 
second malignancy, or death due to any cause, whichever occurs first.  Subjects who fail 
to achieve a CR following treatment with investigational product or who died before the 
disease assessment at the end of treatment will be considered treatment failures and 
assigned an EFS duration of 1 day.  Subjects still alive and event-free will be censored 
on their last disease assessment date.  If the last disease assessment date is after the 
date that triggers the analysis, the subject will be censored at the analysis trigger date.
MRD Reappearance
A molecular reappearance is a reconversion after molecular remission to reproducible 
MRD positivity at a level ≥10-4. This finding does not fulfil the conditions for the definition 
of subsequent relapse and is not considered a relapse event.
MRD/Molecular Remission 
The occurrence of an MRD level below 10-4 by PCR or flow cytometry. “Complete” MRD 
remission will be defined as the occurrence of an MRD level below the limit of detection. 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 12
Non Response
Persisting M2 marrow at the end of treatment with investigational product(s).
Overall Survival 
OS time will be calculated from time of randomization 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. 
Percent of Intended Dose of Protocol-specified Therapy 
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. 
The planned cumulative dose will be (15 μg x 28 days) = 420 μg for all cycles. The
percent of intended 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. 
SOC Chemotherapy: Given that there are variations in how sites define a SOC 
chemotherapy regimen, it may not be possible to define a planned amount for all drugs 
within a regimen. In which case, the percent of intended dose will not be calculated for 
that drug. If a planned dose can be indentified for certain drugs within a regimen then 
percent of intended dose may be calculated as follows. For a given cycle, the percent of 
intended dose will be the cumulative dose of a given drug within a regimen divided by 
the planned amount of that drug for that cycle. For the entire study, the percent of 
intended dose will be the cumulative dose of a given drug over all cycles divided by the 
planned amount of that drug over all cycles. 
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 arms in the study: One consolidation 
cycle of blinatumomab (treatment arm 1A) or one consolidation cycle of HC3 (treatment 
arm 2A). 


Product:  Blinatumomab
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Randomization Date 
Randomization Date is defined as the date the subject was allocated to a treatment 
group. Per protocol, subjects should initiate their Integrated Voice Response System
(IVRS) assigned protocol-specified therapy within 3 days of the randomization date. 
Relapse
Relapse is defined by the presence of at least one of the following:

Isolated bone marrow relapse
M3 marrow in the absence of extramedullary involvement

Combined bone marrow relapse
M2 or M3 marrow and at least one extramedullary manifestation of ALL

CNS Extramedullary relapse

Testicular Extramedullary relapse

Extramedullary relapse at other sites
Further definitions of CNS extramedullary relapse, testicular extramedullary relapse and 
extramedullary relapse at other sites can be found in the Protocol Appendix G.
Relative Treatment Duration of Protocol-specified Therapy 
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. 
SOC Chemotherapy: Since relative treatment duration is of unique interest to the CIVI 
dosing of blinatumomab, it will not be summarized for the SOC Chemotherapy group. 
Study Day 1 
The day of the first cycle of protocol-specified therapy (either blinatumomab or SOC 
chemotherapy). 
Treatment-emergent Adverse Event 
AEs starting on or after first dose of protocol-specified therapy as determined by the flag 
indicating if the adverse event started prior to the first dose on the Adverse Events 
Summary CRF and up to and including 30 days after the end of protocol-specified 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
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Page 14
therapy. This reporting window also applies to treatment-emergent serious adverse 
events (SAEs). 
7.
Analysis Subsets
7.1
Primary Analysis Set
The primary analysis of efficacy will be performed on all randomized subjects analyzed 
according to their randomized treatment assignment, regardless of the treatment 
received (the Full Analysis Set). 
7.2
Safety Analysis Set
The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received protocol-specified therapy analyzed according to the 
treatment they received. 
7.3
Per Protocol Set
The Per Protocol Set will include all subjects in the Full Analysis Set who did not have 
any important protocol deviations which could have an impact on the efficacy evaluation 
of the subject. The identification of these deviations will be made prior to the data 
analysis. Subjects will be analyzed according to their randomized treatment assignment. 
7.4
Pharmacokinetic Analysis Set
All subjects who received any infusion of blinatumomab and had at least one PK sample 
collected will be included in the Pharmacokinetic Analysis Set. These subjects will be 
evaluated for pharmacokinetics unless significant protocol deviations affect the data 
analysis or if key dosing, dosing interruption, or sampling information is missing.
7.5
Interim Analyses Set
The formal interim analyses of efficacy will include all subjects in the Full Analysis Set 
who were randomized at the time of the database cut-off which will be triggered when 
50% and 75% of the total of 94 events have been observed. The safety reviews are 
scheduled to occur approximately every 6 months, however the timing of safety reviews 
may be adjusted to a degree in order to coincide with when the DMC meets to review 
the interim analyses. The safety reviews will include all subjects in in the Safety 
Analysis Set who were randomized at the time of the database snapshot for a given 
6-month review and the efficacy analysis will include all subjects in the Full Analysis Set.  
The safety reviews are expected to look at basic efficacy (number of EFS and OS 
events) as well as safety.  As there are formal interim analyses at 50% and 75% of the 
94 events have occurred there will be a seperate interim analysis set for each.


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7.6
MRD Evaluable Set
All subjects for whom a baseline MRD marker can be found will be included in the MRD 
Evaluable Set.  The secondary endpoint analysis of MRD Response will be performed 
using this analysis set.
7.7
HSCT Analysis Set
All subjects who undergo an HSCT while in remission without any other anti-leukemic 
therapy will be included in the HSCT Analysis Set. The 100-day mortality after 
AlloHSCT analysis will be performed using this analysis set.
7.8
Subgroup Analyses
As previously mentioned, the randomization will be stratified by age (1-9 years vs. other) 
and marrow/MRD status (M1 with MRD level < 10-3 vs. M1 with MRD level 
≥ 10-3 vs. M2). Exploratory analyses examining the consistency of the treatment effect 
for the primary endpoint and key secondary endpoints will consist of performing 
subgroup analyses of each of the 6 stratum formed by the combination of stratification 
factors (eg, subjects aged 1-9 with M1 and MRD level ≥ 10-3) and for each level of a 
given stratification factor (eg, subjects aged 1-9). Additional subgroup analyses will be 
based on the following factors: 

Sex (male vs. female) 

Race/ethnicity (categories depend on the data, all races with less than 
5% of the total enrolled subjects will be pooled together for summary 
purposes) 

Region (Europe vs. rest of world) 

Occurrence of any genetic abnormality (eg, t(4;11) translocation)

White blood cell count (ANCs or platelets) at screening

Lansky or Karnofsky performance score (dependent on age)

Time from 1st diagnosis to relapse 
8.
Interim Analysis and Early Stopping Guidelines
This study has 2 interim analyses planned to assess benefit when approximately 50% 
and 75% of the total number of EFS events have been observed.  Stopping for benefit 
will be based on the O’Brien-Fleming (1979) member of the family of Lan-DeMets (1983)
alpha spending functions; the critical p-values corresponding to this spending function 
are 0.0031 for the 50% interim analysis, 0.0183 for the 75% interim analysis, and 0.044 
for the primary (ie, final) analysis if the interim analyses occur precisely at 47 (50%) and 
71 (75%) events.


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Approximately 6 to 12 months prior to the completion of the enrollment period, the 
sponsor may assess the event rate aggregated over treatment groups and may revise 
the sample size in order to ensure the study completes with the specified numbers of 
events within a desired time frame.  
An external independent Data Monitoring Committee (DMC) will oversee the interim 
analyses described above. In addition, the DMC will assess safety approximately every 
6 months provided an adequate enrollment rate. The timing of safety reviews may be 
adjusted to a degree in order to coincide with when the DMC meets to review the interim 
analyses. On the basis of their reviews, the DMC will make recommendations to Amgen 
regarding the continuation of the study. The DMC will consist of 3 or more members 
including 2 or more clinicians with relevant specialties and 1 or more statisticians. The 
DMC will be supported by an external independent statistician who is responsible for 
preparing reports that describe the ongoing clinical study data. To minimize the potential 
introduction of bias to the conduct of the study, members of the DMC and the external 
independent statistician will not have any direct contact with study center personnel or 
subjects. Details regarding the responsibilities of the DMC and the independent 
statistician will be described in the DMC Charter.
Records of all meetings will be maintained by the DMC for the duration of the study. 
Records of all meetings will be stored in the Amgen official document management 
system at the conclusion of the study. Further details are provided in the DMC charter. 
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.
9.2
Data Handling and Electronic Transfer of Data 
Amgen’s Clinical Data Management department will provide all data to be used in the 
planned analyses. This study will use the RAVE database. 


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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 endpoint definitions (Section 6) or 
in the description of analyses (Section 10). 
9.4
Detection of Bias 
Methods to detect bias are described in the analyses of particular endpoints 
(Section 10). 
9.5
Outliers
Any suspected outliers will be investigated by the study team and will be included in the 
database unless determined to be an error or there is supporting evidence or 
explanation to justify the exclusion. Any outliers excluded from the analysis will be 
discussed in the Clinical Study Report (CSR), including the reasons for exclusion and 
the impact of their exclusion on the study. 
9.6
Distributional Characteristics
The statistical assumptions for analysis methods will be assessed. If the assumptions 
for the distributional characteristics are not met, these will be described and further 
analyses may be carried out using data transformations or alternative analysis methods.
The use of transformations or alternative analysis methods will be justified in the final 
study report. 
9.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.4 or 
later.  
10.
Statistical Methods of Analysis
10.1
General Principles
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, first and third quartiles, minimum, and maximum. 
Categorical variables will be summarized by the n and percentage in each category.  
Time to event endpoints will be summarized with hazard ratios, Kaplan-Meier (KM) 


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curves, KM proportions at select time points, KM quartiles (when estimable), the number 
of subjects with events, the number of subjects censored, and the pattern of censoring.  
Point estimates for efficacy endpoints will be accompanied by 2-sided 95% confidence 
intervals.
The study will have an overall alpha of 0.05 with 2-sided testing (an alpha of 0.0031 and 
0.0183 for the 50% and 75% interim analyses, respectively, and 0.044 for the primary 
analysis will be used if the efficacy interim analyses occurs at precisely 50% and 75% of 
the total EFS events using the spending function described in Section 8. To preserve 
the overall significance level, statistical testing of the primary and secondary endpoints 
will follow a hierarchical structure.  First, event-free survival (EFS) will be tested.  If 
blinatumomab demonstrates superiority to SOC chemotherapy for EFS then OS will be 
tested. Hierarchical testing will only be carried out at the primary analysis (ie, final 
analysis); testing of overall survival at the interim analysis will be considered descriptive. 
Testing of the other secondary endpoints will be considered descriptive. 
10.2
Subject Accountability
The number and percent of subjects who were screened, randomized, received 
protocol-specified therapy along with the reasons for discontinuing protocol-specified 
therapy and discontinuing study will be summarized by treatment group. The number 
and percent of subjects randomized will be tabulated by the stratification factors. The 
number and percent of subjects randomized will be tabulated by study site. Key study 
dates for the first subject randomized, last subject randomized, and data cut-off date for 
analysis will be presented. The goal will be for Amgen to produce draft TFLs when 45% 
and 75% of the total number of 94 EFS events have been observed.  The 45% draft run 
will be completed in preparation in case the DMC recommends stopping the study early.  
Depending on the rate of enrolment and timing of events these timelines could be 
subject to change.
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 [<1, 1-9, ≥10], sex, race, and ethnicity) and baseline 
disease characteristics will be summarized by treatment group and overall using 
descriptive statistics for the Full Analysis Set and the Safety Analysis Set. If multiple 
races have been reported for a subject, the subject will be categorized as multiple race 
as well as by combination of races. The baseline characteristics to be summarized 
include: 

B-precursor subtype 

Occurrence and type of any genetic abnormality 

Age at diagnosis 

Stratification variables (age and marrow/MRD categories)

Bone marrow assessment

Baseline laboratories including: hemoglobin, ANC, leucocytes, platelet counts, 
and peripheral blasts in blood

Lansky and Karnofsky performance score
10.5
Efficacy Analyses 
10.5.1
Analysis of Primary Efficacy Endpoint 
A 2-sided stratified log-rank test, stratified by the randomization factors, will be used to 
determine if EFS is superior with blinatumomab compared to chemotherapy.  In addition, 
a hazard ratio with a 95% confidence interval will be estimated from a stratified Cox 
regression model.  A Cox regression model will also test for a treatment-by-subgroup 
interaction (an interaction term with a p-value <0.10 may be suggestive of an 
inconsistent treatment effect). KM summaries will be performed by treatment arm 
including the KM proportion at 36 months.  The primary analysis will be performed on the 
Full Analysis Set. A sensitivity analysis will assign the planned study day rather than the 
actual study day to EFS events (other than deaths) to address potential evaluation-time 
bias resulting from the different treatment lengths between study arms. To address the 
potential bias of differing cycle lengths between study arms, EFS event times will be 
grouped into discrete times as follows: As with the primary analysis, subjects who fail to 
achieve or maintain a CR before the disease assessment at the end of the first 
randomized treatment cycle (or before the assessment on day 15 for those subjects on 
the blinatumomab arm) will still be assigned an EFS duration of 1 day.  An additional 
sensitivity analysis will include alloHSCT as a time-dependent covariate in a stratified 
Cox regression model and will test the null hypothesis using the treatment effect from 
that Cox model. To examine the impact of stratification errors (if any occur), the primary 


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analysis will be repeated using the stratification values reported on the CRF rather than 
those obtained through IVRS.
10.5.2
Analysis of Secondary Efficacy Endpoints
Like EFS, a hazard ratio and KM summaries will also summarize OS by treatment arm.  
In addition, a 2-sided stratified log-rank test will be used to describe the difference in OS 
between treatment arms.  The primary analysis will be performed on the Full Analysis 
Set.  
The percentage of subjects in each treatment arm with an MRD response (ie, MRD level 
< 10-4) will be summarized with an exact binomial 95% confidence interval.  In addition, a
2-sided Cochran-Mantel-Haenszel test, which will adjust for the stratification factors at 
randomization, will describe the difference in MRD response between treatment arms. If 
a baseline MRD marker can be found for a subject then that subject will be part of the 
MRD Evaluable Set (as defined in section 7.7). Subjects who are part of the MRD 
Evaluable Set and are missing post-baseline disease assessments will be considered 
not to have achieved a response. The MRD analysis will be performed on the MRD 
Evaluable Set. Sensitivity analyses will be performed on the subset of subjects who 
received investigational product, the subset of subjects who had at least one 
post-baseline disease assessment, and on prospectively defined per protocol analysis 
set.
The cumulative incidence of relapse will be analysed as proposed by 
Fine and Gray’s (1999) extension of the Cox regression model, whereby deaths prior to 
relapse that are not considered related to an otherwise undocumented relapse will be 
treated as a competing risk.  The subdistribution hazard model  will be fitted to the data 
using the PHREG procedure in SAS which will give a hazard ratio, CIF (cumulative 
incidence function) estimate and corresponding p-value for each treatment arm.  This 
analysis will also be repeated using the strata as covariates in the model.  This will be 
presented in both tables and figures as “Duration of hematologic remission”, which is 
evaluated by 1 – cumulative incidence function of hematological relapse with death due 
to other causes as a competing event.
10.5.3
Analyses of Other Efficacy Endpoint(s)
The number of patients receiving transplant, summary statistics of the time to transplant 
and the status at transplant (relapse, M0/M1 status, etc) will be summarized by 
treatment group and overall using descriptive statistics for the Full Analysis Set.


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10.6
Safety Analyses
The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received investigational product analyzed according to the 
treatment they received.  
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred terms.  Tables of fatal adverse events, serious adverse 
events, adverse events by severity, adverse events leading to interruption or withdrawal 
from investigational product or other protocol-specified therapies, and significant 
treatment-emergent adverse events (including adverse events of interest) will also be 
provided. 
The number and percentage of subjects with antibody formation to blinatumomab will 
also be summarized.  
In addition, changes in select vital sign and laboratory parameters will be summarized.  
10.6.1
Adverse Events
The most recent version (at the time of the relevant snapshot) of the Medical Dictionary 
for Regulatory Activities (MedDRA) will be used to code all adverse events (AE) to a 
system organ class and a preferred term.  All adverse event tables will be summarized 
by treatment group.  Treatment-emergent adverse events are events with an onset after 
the administration of the first dose of protocol specified therapy.
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, grade ≥3 AEs, AEs leading to withdrawal or interruption of investigational 
product, fatal AEs, and AEs of interest (EOI).  
Amgen has adopted the Council for International Organizations of Medical Sciences
(CIOMS) definition of an EOI (referred to by CIOMS as Adverse Events of Special 
Interest [AESI]), which is a noteworthy event for a particular product or class of products 
that may warrant careful monitoring. It could be serious or non-serious, and could 
include events that might be potential precursors or prodromes for more serious medical 
conditions in susceptible individuals.” (CIOMS VI, 2005). The process for identifying EOI 
includes, but is not limited to, evaluating information from pre- and non-clinical 
investigations, similar drugs in class, and/or data from clinical trials and/or 
post-marketing experience. Once an EOI has been identified, Amgen utilizes standard 
search strategies to develop a clear specification and an operational definition of the 


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EOI. The definition and search strategy that is applied to an EOI is ideally one that is 
well established such as a Standardized MedDRA Query (SMQ).
For the blinatumomab program, the list of EOIs, including the search strategies and
associated algorithms, if any, can be found in Appendix C. In addition to the EOI search
strategy and algorithm used to define CNS events, the investigator determination as to
whether an event is considered a CNS event (based on the CRF field) will also be used.
The following summary tables will be created for all classes of AEs of special interest:

Overview table using the same classes of AEs as indicated above

Number and percentage of patients with TEAEs, related TEAEs, related TEAEs 
of at least grade 3, serious TEAEs, TEAEs which lead to interruption or 
discontinuation of an investigational product or other protocol-specified
therapiesand serious related TEAEs will be presented by MedDRA SOC and PT 
(sorted by frequency of PT) for all patients

Number and percentage of patients with special AEs by dose and time of onset:
total, cycle 1 day 1-7, cycle 1 day 8, cycle 1 day 9-14, cycle 1 day 15, cycle 1 
day 16-28, cycle 1 day 29 or later, cycle 2 day 1-3, cycle 2 day 4 or later, cycle 3 
day 1-3, cycle 3 day 4 or later,…

Number and percentage of patients with AEs of interest by PT and worst severity

Number of AEs, number and percentage of patients by MedDRA PT

Number and percentage of patients with AEs of interest by PT and outcome 
according to the categories defined below using the hierarchy provided there per 
patient and PT.
The analysis of TEAEs by resolution will be performed on the preferred term level using 
the following categories in the hierarchy given below:

Fatal: at least one fatal TEAE with respective preferred term.

Not recovered/resolved: no fatal TEAE, but at least one TEAE with respective 
preferred term where patient did not recover.

Missing/unknown: no TEAE with respective preferred term where patient did not 
recover or die, but at least one TEAE with respective preferred term where 
outcome was unknown/missing.

Recovered/resolved: only TEAEs with respective preferred term where patient 
recovered with or without sequelae
Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal or interruption of investigational product, and fatal AEs will be tabulated by 
system organ class and preferred term in descending order of frequency.  


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Summaries of treatment-emergent, serious AEs and AEs by severity occurring in at least 
5% of the subjects by preferred term in any treatment arm will be provided in descending 
order of frequency.  
Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade in descending order of frequency.
Subgroup analyses (if there is a medical rationale) will be presented by system organ 
class and preferred term in descending order of frequency. All races (if appropriate) with 
less than 5% of the total enrolled subjects will be pooled together for summary purposes.  
10.6.2
Laboratory Test Results
The summary statistics (n, mean, standard deviation, median, first and third quartiles, 
minimum, and maximum) will be provided at baseline and for select post-baseline 
timepoints by treatment group for subjects in the Safety Analysis Set for the analytes 
listed in Appendix B and for Immunoglobulin Gamma (IgG), Immunoglobulin M (IgM), 
Immunoglobulin A (IgA) and Immunoglobulin E (IgE). For post-baseline summaries, 
both the absolute value and the change from baseline will be presented. In addition, 
shift tables between the worst post-baseline and baseline values will be provided (based 
on the Common Terminology Criteria for Adverse Events using the textbook ranges 
listed in Appendix B). Shift tables between the safety follow-up and baseline values will 
be provided for urinalysis analytes. 
10.6.3
Vital Signs
The analyses of systolic blood pressure, diastolic blood pressure, weight, temperature, 
heart rate and Lansky and Karnofsky performance score will include summary statistics 
at selected time points by treatment group for subjects in the Safety Analysis Set. 
10.6.4
Electrocardiogram (ECG)
There are no ECG measurements collected in this study.
10.6.5
Antibody Formation 
The incidence and percentage of subjects who develop anti blinatumomab antibodies 
(binding and if positive, neutralizing) at any time will be tabulated.   
10.6.6
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group for subjects in the Safety Analysis Set. For both treatment groups, 
the number of cycles of protocol-specified therapy administered will be summarized with 
an additional breakdown of the number of cycles completed, discontinued, and 


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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 for the blinatumomab group and, if calculable, for the high risk consolidation 
chemotherapy group. The number and percent of subjects with dose modifications 
(eg, dose changes, dose interruptions) and reason for modification will be summarized 
for both treatment groups. 
10.6.7
Exposure to Other Protocol-specified Treatment
Descriptive statistics will be produced to describe the required pre-medication 
(dexamethasone) exposure in the Safety Analysis Set.
10.6.8
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 (WHODRUG) dictionary by treatment group 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 WHODRUG 
preferred term for each treatment group in the Full Analysis Set.
10.6.9
100-day Mortality After AlloHSCT
The 100-day mortality after alloHSCT will be summarized with the 100-day KM rate and 
the additional KM summaries described in Section 10.1 by treatment group. For this 
endpoint, OS will be measured starting from the date of alloHSCT. This analysis will be 
performed on the subjects in the HSCT Analysis Set who undergo an alloHSCT while in 
remission without any other anti-leukemic therapy.
10.7
Pharmacokinetic Analysis
All subjects who received any infusion of blinatumomab and had at least one PK sample 
collected will be included in the PK analysis dataset. These subjects will be evaluated 
for PK unless significant protocol deviations affect the data analysis or if key dosing, 
dosing interruption or sampling information are missing. Individual steady state serum 
concentrations (Css) will be summarized by descriptive statistics. Non-compartment 
analysis will be performed to estimate PK parameters.
PK data of blinatumomab may be subject to population PK analysis for covariate 
analysis and exposure-response analyses as needed. If the analyses will be performed, 
a supplemental population PK analysis plan will be generated. Data from multiple 
studies may be used and results will be reported separately.  


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10.7.1
Exposure Response Analysis
Exploratory exposure-efficacy analyses may be performed as needed to evaluate the 
relationship of blinatumomab concentration and clinical response.  Exposure-safety 
analyses may be performed as needed to evaluate the relationship of blinatumomab 
concentration and selected safety endpoint(s).  If the analyses will be performed, a 
supplemental exposure-response analysis plan will be generated. Data from multiple 
studies may be used and results will be reported separately.  
11.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.  


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12.
Literature Citations / References
Fine JP, Gray RJ. A proportional hazards model for the sub-distribution of a competing 
risk. Journal of the American Statistical Association. 1999;94:496–509.
Lan KK, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-663.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35:549-556.


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13.
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, do not impute.


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Appendix B.  Reference Values/Toxicity Grades
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 the table below. 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.
Laboratory Parameter Grades
Laboratory 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Parameter [Unit] 
Lymphocytes 
0.8 - < LLN 
0.5 -< 0.8 
0.2 -< 0.5 
< 0.2 
[G/L) 
Neutrophils [GIL] 
1.5 • < LLN 
1.0 • < 1.5 
0.5 • < 1.0 
< 0.5 
Leukocytes [G/L] 
3.0 -< LLN 
2.0 -< 3.0 
1.0 -< 2.0 
< 1.0 
Platelets [G/L] 
75 -< LLN 
50 -< 75 
25 -< 50 
< 25 
Hemoglobin [g/L]' 
100 • < LLN 
80 -< 100 
65 • < 80 
< 65 
Albumin [g/L] 
30 • < LLN 
20 • < 30 
< 20 
not defined 
AST* 
> ULN- 3*ULN 
> 3*ULN - 5*ULN 
> 5*ULN - 20*ULN 
> 20*ULN 
ALT* 
> ULN- 3'ULN 
> 3'ULN - 5*ULN 
> 5*ULN - 20'ULN 
> 20*ULN 
GGT 
> ULN - 2.5'ULN 
> 2.5'ULN - 5'ULN 
> 5'ULN - 20*ULN 
> 20'ULN 
Bilirubin 
> ULN - 1.5'ULN 
> 1.5'ULN - 3'ULN 
> 3'ULN - 10'ULN 
> 10*ULN 
%change of BL < 
25%-<50% of BL 
50% • <75% of BL 
>= 75% of BL 
FibrinogenA 
25% or 
or 
or 
or< 50mg/dL 
0.75'LLN • < LLN 
< 75*LLN - 0.5*LLN 
< 0.5' LLN - 0.25'LLN 
or< 0.25*LLN 
Calcium [mmol/L]' 2.0 • < LLN 
1.75- < 2.0 
1.5-<1.75 
< 1.5 
Potassium 
not defined 
3.0 -< LLN 
2.5 -< 3.0 
< 2.5 
[mmol/L]' 
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 
A: In case of conflicting criteria the higher grade will be assigned, % change only used when baseline is <LLN 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 31
Vital Signs 
Notable values for vital signs for various ages for the pediatric population are defined 
according to the following table: 
Vital S,i:gns at. V.arious Ages 
A.,ge 
I 
Heart Rate 
Blood Pres.sure (mm 
Re,spi ratory Rate 
(beats!m1i n ), 
Hg1) 
(breath s/miin) 
Prematur,e 120-170: 
5,5-75135-451 
40-70 .t 
0-3 mo 
100-150: 
6,5--85145-55 
35~55 
3-6 mo 
90-'120 
70-90150-65 
30-45 
6-'12 mo 
80-120 
80~ 1 0 D/55-65 
25-40 
1-3 yr 
70-'110 
90--105/55-70 
20-30 
3-6 yr 
165-110 
95--110/60-75 
20-25 
6-'12 yr 
160-95 
100-120/60/75 
14122 
12 : yr 
55-8.5 
11 0-135/65/85 
12-18. 
Re erern:es: Belrumarn, elson Textbook o · Ped'ialJit s: 17t edition . 
.. From Dteckmarnn 
, Brmm stecn 0 , Gausctte-Hill M (eds): Rediatrtt E.duca -on ·or Prehospital 
Professiornals. Sudbury, Mass, Jones & Bartlett, Amerit arn Academy o· RecJiatllics, 2000, p 43-45. 
t From American Heart Associaliu ECC Guidelines, 21!l 
. 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 32
Appendix C.  List of EOIs (including the search strategies and associated 
algorithms)
Events of Interest (EOI) for AMG 103 (blinatumomab) are adverse events that are 
subject to heightened pharmacovigilance based on evidence summarized from basic 
research, information from nonclinical investigations, observed in similar drugs in class, 
epidemiologic data on disease indications and most importantly continuous 
pharmacovigilance during the life cycle of the product.  In order to identify these EOI 
Amgen applies a search strategy that includes the use of SMQs (standardized medical 
dictionary for regulatory activities [MedDRA] queries).  If an SMQ is not available, a 
standardized search strategy is provided by the Amgen Global Medical Coding group 
which contains a pre-specified list of MedDRA preferred terms (PTs).  The Medical 
Coding Group at Amgen centrally maintains all MedDRA SMQs as well as Amgen 
specific EOI search strategies, at the preferred term (PT) level in a roadmap that can be 
accessed for use via the group’s portal in the company intranet.  These SMQs and 
search strategies are updated with each new version of MedDRA when it is released.
The composition of each EOI may be modified and a new EOI may be added based on 
findings from ongoing pharmacovigilance. 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Date: 20 March 2018
Page 33
The following are AMG 103 (blinatumomab) EOI (bold: required for all document. Italic: only required based on safety request)
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Neurologic Events
A wide range of neurological and 
psychiatric signs, symptoms, and 
diagnoses.  These can be the result of 
direct involvement of the nervous 
system by the tumor (ie, CNS 
involvement of leukemia) or a 
consequence of treatment.
High level group terms (HLGTs) 
from the System Organ Classes 
(SOCs) Nervous system 
disorders and Psychiatric 
disorders SOC.  
N/A
standard data output tables
Infections

Any adverse events in the SOC 
Infections and infestations.  Search 
strategy includes any adverse 
events in the Infections and 
infestations SOC.   
Infections and infestations SOC
N/A

standard data output tables.  

possible Additional medical review may 
be performed to further classify the 
infection events into the following four 
categories of infection:
o
Opportunistic Infections (viral, 
fungal and bacterial)
o
Sepsis, Septic Shock, 
Bacteraemia
o
Catheter Site Infections
o
Other Infections
Page 1 of 6
AMGEN® 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Date: 20 March 2018
Page 34
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Cytokine Release 
Syndrome

An exaggerated systemic immune 
response involving the release of 
inflammatory mediators (cytokines, 
chemokines). Cytokine release 
syndrome (CRS) occurring with a 
specific T cell engager (BiTE) such 
as blinatumomab can result in a 
massive release of cellular 
cytokines, which can have 
profound effects on blood 
pressure, vascular integrity and 
myocardial, liver, and lung 
functions.  

Cytokine release syndrome (CRS) 
occurring with a specific T-cell 
engager (BiTE) such as 
blinatumomab can result in a 
massive release of cellular 
cytokines.  In rare cases robust pro 
inflammatory cytokine production 
may trigger macrophage activation 
syndrome (MAS), also known as 
Hemophagocytic 
lymphohistiocytosis (HLH).  

HLH/MAS is a rare condition 
characterised by 
inappropriate immune 
activation and cytokine 
release that typically presents 
with fever and splenomegaly 
in association with 
hyperferritinemia, 
coagulopathy, 
hypertriglyceridemia, 
hypofibringogenemia, and 
cytopenias. 
Cytokine release syndrome 
(EOI search strategy)
Narrow
standard data output tables.  
May require separate search for HLS/MAS 
and descriptive text in the relevant section 
Page 2 of 6
AMGEN® 


Product:  Blinatumomab
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Page 35
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Elevated Liver 
Enzyme
Findings based on laboratory test 
results that indicate an increase in the 
level of AST/ALT/GGT/bilirubin/ALP in 
the blood specimen, as well as 
disorders of the liver, including signs, 
symptoms, radiologic and laboratory 
findings
Liver related investigations, 
signs and symptoms (SMQ)
narrow

standard data output tables SMQ 
Liver related investigations, signs 
and symptoms.
Infusion Reactions

An untoward effect which coincides 
with the timing of the infusion 
(event starts within 24 hours of the 
infusion and ends within 48 hours).  
According to the CTCAE 
version 4.0, an infusion reaction is 
a disorder characterized by an 
adverse reaction to the infusion of 
pharmacological or biological 
substances.  Infusion reactions 
and cytokine release syndrome 
can be clinically indistinguishable 
since blinatumomab is a bispecific 
single-chain antibody construct 
derived from murine monoclonal 
antibodies and pharmacological 
mechanism of action may involve 
cytotoxic T-cell.  
Amgen defined search strategy 
for cytokine release 
syndrome/acute infusion 
reaction with time restriction
narrow
(1) onset <=48 hours and no duration 
restriction. 
Page 3 of 6
AMGEN® 


Product:  Blinatumomab
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Page 36
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Tumor Lysis 
Syndrome
A combination of metabolic 
abnormalities that occur due to the 
release of nuclear and cytoplasmic 
degradation products of malignant 
cells.  Characteristic findings of TLS 
include hyperuricemia, hyperkalemia, 
hyperphosphatemia, and 
hypocalcemia.  TLS can lead to 
downstream effects such as renal 
insufficiency including acute renal 
failure, cardiac arrhythmia, seizures, 
and death (due to multiorgan failure).  
Search strategy:  SMQ Tumour lysis 
syndrome (Narrow and broad). 
Tumor lysis syndrome (SMQ)
narrow
standard data output tables.  
An algorithm will be further applied to broad 
search output based on the recommendation 
by CIOMS SMQ Working Group for SMQ 
Tumour lysis syndrome +  apply 5-day 
window for events from category B and C  in 
the search strategy and algorithm
Data outputs:  standard data output tables, 
plus additional output based on broad search 
result applying algorithm.
Capillary Leak 
Syndrome
A disorder characterized by leakage of 
intravascular fluids into the 
extravascular space.  Search strategy:  
Amgen-defined search strategy for 
capillary leak syndrome (narrow and 
broad).  
Capillary leak syndrome (EOI 
Search Strategy)
narrow
standard data output tables.  
Medication Errors 
Any preventable event that may 
cause or lead to inappropriate 
medication use or harm to a 
patient 
(http://www.fda.gov/ForConsumers
/ConsumerUpdates/ucm048644.ht
m).

In Legacy study protocols 
MT103-211 (version 2) and 
MT103-205 (version 2), any 
overdose (> 10% of the intended 
dose) was required to be reported 
as an SAE, even if no untoward 
medical effect was observed 
following the overdose.  
Medication Errors and Product 
Use Issue  EOI
(EOI Search Strategy)
standard data output tables
Decreased 
Immunoglobulins

Diminished levels of 
immunoglobulins (Ig) in the blood.  
Decreased immunoglobulins 
(EOI Search Strategy)
Narrow
standard data output tables.  
Page 4 of 6
AMGEN® 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Date: 20 March 2018
Page 37
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Embolic and 
thrombotic events 
(including DIC)
Thrombotic disorders characterized 
by formation of a thrombus that 
obstructs vascular blood flow 
locally or detaches and embolize to 
occlude blood flow downstream. 
Embolic and thrombotic events 
(SMQ)
Narrow
standard data output tables
Leukoencephalopathy 
White matter changes first 
described in children with leukemia, 
associated with radiation and 
chemotherapy injury, often 
associated with methotrexate; 
pathologically characterized by 
diffuse reactive astrocytosis with 
multiple areas of necrotic foci 
without inflammation.  
Progressive multifocal 
leukoencephalopathy (EOI 
Search Strategy) 
Broad
Standard data output tables
Neutropenia and 
Febrile neutropenia
Neutropenia (EOI Search 
Strategy)
Narrow
Standard data output tables.  
Maybe covered by cytopenias output. 
Lymphopenia
Lymphopenia (EOI Search 
Strategy)
Narrow
Standard data output tables.  
Maybe covered by cytopenias output. 
Immunogenicity
Immunogenicity (EOI Search 
Strategy)
Narrow
Standard data output tables. 
Minimum Critical 
Toxicities
Bone marrow  toxicity 
(cytopenias)
A reduction, hypocytosis, or a lack 
of cellular elements in the 
circulating blood.
Hematopoietic cytopenias SMQ 
narrow

standard data output tables.
Hepatotoxicity
Drug related hepatic disorders 
SMQ
Additional Hepatotoxicity may 
be evaluated by medical review 
of potential cases of Hy’s Law:  
ALT or AST > 3.0 ULN; TBL 
>=2.0 ULN, ALP <2.0 ULN; and 
no other confounding factors 
including preexisting or acute 
liver disease (FDA, 2009).
narrow

Additional output maybe requested by 
applying laboratory criterion for potential 
Hy’s law cases and patient profile output
Page 5 of 6
AMGEN® 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Date: 20 March 2018
Page 38
EOI
Case Definition
Search Strategy
Type of Search
Data output/Notes
Nephrotoxicity
Acute renal failure SMQ
narrow
standard data output tables
QT Prolongation
Cardiac arrythmias SMQ, 
Convulsions SMQ, Torsade de 
pointes-QT prolongation SMQ
narrow
standard data output tables
Page 6 of 6
AMGEN® 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 39
Appendix D.  Study Design and Treatment Schema
C 
C 
0 
0 
N 
N 
I 
s 
s 
s 
F 
N 
0 
0 
C 
ARM 1A 
0 
D 
L 
L 
R 
71 
L 
u 
I 
I 
E 
BLI NATUMOMAB 
H 
L 
C 
D 
D 
E 
s 
0 
T 
A 
A 
N 
C 
w 
I 
T 
T 
I 
ARM2A 
T 
0 
I 
I 
N 
u 
N 
0 
0 
G 
HC 3 
p 
N 
N 
1 
2 
Arm lA: A si ngle consol idation cycle of 
bl inatumomab (15 µg/m 2/day) 
Arm 2A: A si ngle consol idation cycle HC3 
HC = high risk consolidation; HSCT = hematopoietic stem cel l transplantation; R = randomization 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 40
Appendix E.  Simulation Results
IA at 50% 
IA at 75% 
Rnal Analysis 
Rej--HO: 25.3% 
. -----
Operating characteristics from 5000 sirrulations assuning: 
Truth is H1 
NC median blin v control: 11.1 v 7 mths: HR=0.63 
Cure rate blin v control: 0.562 vs 0.40 
Ranned final number of events/subjects: 94/202 (rv'ax events under truth is 105) 
No stopping for futility nor adapting 
Overall A-ob of Rejecting HO: 83.9% 
Average N: 179 
Continue 
~ ej-HO: 38.6% 
. ~j-HO: 19.9% 
Continue 
Fail to Rej HO: l6>l ~ • 


Product:  Blinatumomab
Statistical Analysis Plan:  20120215
Dated: 20 March 2018
Page 41
IA at 50% 
~
}H0: 0.1% 
IA at 75% 
Final Analysis 
Operating characteristics from 5000 sinulations assuning: 
Truth is HO 
NC median blin v control: 7 v 7 nths: HR=1 .00 
Cure rate blin v control: 0.40 vs 0.40 
Flanned final number of events/subjects: 94/202 (rvlax events under truth is 121) 
No stopping for futility nor adapting 
Overall A-ob of Rejecting HO: 2.3% 
Average N: 195 
Continue 
~
j-HO: 0.7% 
• !3-ej,ttO: 1.4 % 
Continue 
Fail to Rej HO: 97>7~ •