Clinical trial NCT04524455
Conditions: Acute Lymphoblastic Leukemia
Keywords: Blinatumomab AMG 404 Leukemia
Sponsor: Amgen
Start date: 2020-10-02; Completion date: 2023-01-24
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this phase 1b study is to evaluate the safety and tolerability of blinatumomab and AMG 404 in combination in adults with R/R B-ALL and to estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMG 404 when combined with continuous intravenous infusion (cIV) blinatumomab.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Blinatumomab intervention 2: AMG 404 intervention 3: Dexamethasone Premedication
Intervention descriptions: intervention 1: Blinatumomab will be administered as a continuous intravenous infusion (cIV). intervention 2: AMG 404 will be administered as an intravenous infusion (IV). intervention 3: Dexamethasone will be administered orally or intravenously prior to blinatumomab treatment, as needed.

Protocol documents:
Prot_000.pdf: 
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Cohort 1
Blinatumomab (28d CIV)
AMG 404 (240 mg) 
Day 11 and Day 39 of C1, C3, C5; 
Day 25 for C2 and C4
De-escalate
Escalate
Cohort 2a
Blinatumomab start  D3 of C1 (28d CIV)
AMG 404 (480 mg) 

Cycle 1: C1D1, C1D29

Cycle 2: D13 & 41; 

Cycle 3: D27; 

Cycle 4: D13 & 41; 

Cycle 5: D27
Cohort 2b
Blinatumomab start  D3 of C1 (28d CIV)
AMG 404 (240 mg) 

Cycle 1: C1D1, C1D29

Cycle 2: D13 & 41; 

Cycle 3: D27; 

Cycle 4: D13 & 41; 

Cycle 5: D27
Dose expansion*
Blinatumomab (28d CIV)
AMG 404 (RP2D)
RP2D of AMG 404 will be determined in 
the dose exploration part
Cohort 1c
Blinatumomab start  D3 of C1 (28d CIV)
AMG 404 (120 mg) 

Cycle 1: C1D1, C1D29

Cycle 2: D13 & 41; 

Cycle 3: D27; 

Cycle 4: D13 & 41; 

Cycle 5: D27
De-escalate if 
DLT in Cohort 2a  
using mTPI-2
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SAP_001.pdf: 
Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 1 of 40 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b Open-label Study Investigating the 
Safety, Tolerability, Pharmacokinetics, and Efficacy 
of Administration of Blinatumomab in Combination 
With AMG 404 for the Treatment of Adults With 
Relapsed or Refractory B Cell Precursor Acute 
Lymphoblastic Leukemia (ALL) 
Short Protocol Title: 
Blinatumomab in Combination With AMG 404 for the 
Treatment of Adults with Relapsed or Refractory B 
cell Precursor ALL 
Protocol Number: 
20190177 
NCT Number 
NA 
Authors: 
 Global Biostatistical 
Science 
 Global Biostatistical 
Science 
 Global Biostatistical Science 
 Global Biostatistical Science 
 Clinical Pharmacology Modeling and 
Simulation 
Sponsor: 
Amgen 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: (805) 447-1000 
SAP Date: 
Document Version 
Date 
Amendment 1 (v2.0) 
20 September 2021 
NCT Number: NCT04524455
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 2 of 40 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
03AUG2020 
NA 
Amendment 1 (v2.0) 
20SEP2021 
The SAP is amended due to the protocol 
amendment 3 dated 01Jun2021. Below 
are the key updates -  
 
Changes to study design: 
Updated dosing schedule for AMG 
404 in relation to blinatumomab 
cycle. 
 
Included new cohorts 1c, 2a, and 
2b. 
 
Updated DLT window. 
 
Included minimal residual disease 
(MRD) assessment by Next 
Generation Sequencing (NGS) 
and flow cytometry or Quantitative 
polymerase chain reaction (Q-
PCR) in Cohorts 1c, 2a, and 2b. 
 
Updated duration of safety follow-
up visit and end of study visit 
 
Updated following definitions (SAP 
Section 5) 
o Baseline 
o Study day 
o Treatment emergent 
adverse event  
 
Included Treatment-emergent 
Adverse Event including 
Extended Period definition (SAP 
Section 5)  
 
Updated ECG 
(Electrocardiogram) analysis in 
relation to the changes in 
schedule of ECG post-baseline 
assessments per protocol 
amendment 3 (SAP Section 9.6.6 
and Section 10) 
 
Added EOIs (Events of Interest) 
for AMG 404 in Appendix E. 
 
 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 3 of 40 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size .............................................................................................. 15 
3.3 
Adaptive Design ........................................................................................ 16 
4. 
Covariates and Subgroups ................................................................................... 16 
4.1 
Planned Covariates ................................................................................... 16 
4.2 
Subgroups ................................................................................................. 16 
5. 
Definitions ............................................................................................................. 16 
5.1 
General Definitions .................................................................................... 16 
5.2 
Study Points of Reference ......................................................................... 17 
5.3 
Study Dates .............................................................................................. 17 
5.4 
Endpoints .................................................................................................. 18 
6. 
Analysis Sets ........................................................................................................ 19 
6.1 
Safety Analysis Set ................................................................................... 20 
6.2 
Dose-limiting toxicity Analysis Set ............................................................. 20 
6.3 
Pharmacokinetic Analyses Set(s) .............................................................. 20 
7. 
Planned Analyses ................................................................................................. 20 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 20 
7.2 
Primary Analysis ....................................................................................... 22 
8. 
Data Screening and Acceptance ........................................................................... 22 
8.1 
General Principles ..................................................................................... 22 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 22 
8.3 
Handling of Missing and Incomplete Data ................................................. 22 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 23 
9. 
Statistical Methods of Analysis.............................................................................. 23 
9.1 
General Considerations ............................................................................. 23 
9.2 
Subject Accountability ............................................................................... 23 
9.3 
Important Protocol Deviations ................................................................... 24 
9.4 
Demographic and Baseline Characteristics ............................................... 24 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 4 of 40 
CONFIDENTIAL  
 
 
9.5 
Efficacy Analyses ...................................................................................... 24 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 24 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 24 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 25 
9.6 
Safety Analyses ........................................................................................ 25 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 25 
9.6.2 
Adverse Events ......................................................................... 25 
9.6.3 
Laboratory Test Results ............................................................ 26 
9.6.4 
Vital Signs ................................................................................. 27 
9.6.5 
Physical Measurements ............................................................ 27 
9.6.6 
Electrocardiogram ..................................................................... 27 
9.6.7 
Antibody Formation ................................................................... 27 
9.6.8 
Exposure to Investigational Product .......................................... 27 
9.6.9 
Exposure to Other Protocol-required Therapy ........................... 27 
9.6.10 
Exposure to Concomitant Medication ........................................ 27 
9.7 
Other Analyses ......................................................................................... 28 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 28 
9.7.2 
Analyses of Biomarker Endpoints .............................................. 28 
10. 
Changes From Protocol-specified Analyses.......................................................... 28 
11. 
Literature Citations / References ........................................................................... 30 
12. 
Prioritization of Analyses....................................................................................... 33 
13. 
Data Not Covered by This Plan............................................................................. 33 
14. 
Appendices ........................................................................................................... 34 
Appendix A.  Reference Values/Toxicity Grades ................................................... 34 
Appendix B.  Technical Details and Supplemental Information 
Regarding Statistical Procedures .............................................................. 35 
Appendix C. Toxicity Management Guidelines ...................................................... 37 
Appendix D.  ECOG Performance Status and NYHA Classification ...................... 38 
Appendix E.  Adverse Events of Interest Search Strategy and Rules .................... 39 
 
List of Table 
Table 3-1.  mTPI-2 Decision Rules ................................................................................ 13 
Table 7-1.  Stopping Boundary with Batch Size 3, Posterior Probability of 
80% and DLT limit of 30% ...................................................................... 21 
Table 7-2. Operating Characteristics with Batch Size 3, Posterior Probability 
of 80% and DLT limit of 30% .................................................................. 21 
Table 14-1.  Notable Abnormalities of Vital Signs and Physical Measurement ............... 34 
Table 14-2.  Management of Infusion-related Reactions With AMG 404 ........................ 37 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 5 of 40 
CONFIDENTIAL  
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
ALL 
AUC 
alloHSCT 
BM 
cIV 
CI 
CL 
CPMS 
CR 
CRF 
CRh 
CRS 
Css 
Cmax 
CTCAE 
DLRM 
DLRT 
DLT 
ECG 
ECOG 
eCRF 
EOI 
EOS 
GSO   
HSCT  
IP 
IV 
irAE 
MedDRA 
MRD 
MTD 
mTPI-2 
NT 
Adverse event 
Acute lymphoblastic leukemia 
Area under the concentration-time curve 
Allogenic hematopoietic stem cell transplant 
Bone marrow 
Continuous intravenous infusion 
Confidence Interval 
Clearance 
Clinical Pharmacology Modeling and Simulation 
Complete remission 
Case report form 
Complete remission with partial hematological recovery 
Cytokine release syndrome 
Steady state concentrations 
Maximum observed concentration 
Common Terminology Criteria for Adverse Events 
Dose level review meeting 
Dose level review team 
Dose limiting toxicity 
Electrocardiogram 
Eastern Cooperative Oncology Group 
Electronic case report form 
Events of interest 
End of study 
Global Safety Officer 
Hematopoietic stem cell transplant 
Investigational Product 
Intravenous 
Immune-related adverse event 
Medical Dictionary for Regulatory Activities 
Minimal residual disease 
Maximum tolerability dose 
Modified toxicity probability interval method 
Neurotoxicity 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 6 of 40 
CONFIDENTIAL  
 
 
PD 
PK 
PT 
𝑝𝑇 
QTcB 
RO 
RP2D 
R/R B-ALL 
SAP 
SAE 
SC 
SFU 
SOC 
TEAE 
TLS 
T1/2 
WHO 
 
Pharmacodynamic(s) 
Pharmacokinetic(s) 
Preferred Term 
Target dose limiting toxicity rate 
Bazett-corrected QT Interval (QTcB)  
receptor occupancy 
Recommended Phase 2 Dose 
Relapsed or Refractory B cell Precursor Acute Lymphoblastic 
Leukemia 
Statistical Analysis Plan 
Serious adverse Event 
Subcutaneous(ly) 
Safety follow up 
System Organ Class 
Treatment-emergent adverse event 
Tumor lysis syndrome 
Terminal half-life 
World Health Organization 
 
 
 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 7 of 40 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for study 20190177, 
Blinatumomab and AMG 404 dated  01 June 2021.  The scope of this plan includes the 
primary analysis that is planned and will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified. PK/PD and biomarker analyses will be 
performed by Clinical Pharmacology, Modeling and Simulation (CPMS) group and Clinical 
Biomarkers and Diagnostics group. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of blinatumomab in 
combination with AMG 404 in adults 
with relapsed or refractory B- cell 
precursor Acute Lymphoblastic 
Leukemia (R/R B-ALL) 
 
To estimate the Maximum Tolerated 
Dose (MTD) and Recommended 
Phase 2 Dose (RP2D) of AMG 404 
when combined with continuous 
intravenous infusion (cIV) 
blinatumomab 
 
Dose-limiting toxicities (DLTs). 
 
Treatment-emergent adverse 
events (TEAEs), serious 
TEAEs, treatment-related 
TEAEs and adverse events of 
interest (EOI) 
Secondary 
 
To evaluate the efficacy of 
blinatumomab and AMG 404 
combination therapy in the treatment 
of R/R B-ALL 
 
Complete remission/ complete 
remission with partial 
hematological recovery 
(CR/CRh) within the first 2 
cycles and across all cycles 
 
CR within the first 2 cycles and 
across all cycles 
 
Duration of CR 
 
Duration of CR/CRh 
 
To 
characterize 
pharmacokinetic 
(PK) following blinatumomab and 
AMG 404 combination therapy 
 
Blinatumomab PK parameters 
 
AMG 404 PK parameters 


Product:  Blinatumomab and AMG 404 
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CONFIDENTIAL  
 
 
 
To evaluate the immunogenicity of 
blinatumomab and AMG 404 
following blinatumomab and 
AMG 404 combination therapy 
 
Anti-blinatumomab antibodies 
 
Anti-AMG 404 antibodies 
 
 
 
Exploratory 
 
To evaluate the 
pharmacodynamic (PD) profiles 
for B- and T-lymphocytes, and 
cytokine levels over time following 
treatment with blinatumomab and 
AMG 404 
 
PD parameters of B- lymphocytes 
and T- lymphocytes and cytokines 
following administration of 
blinatumomab and AMG 404 
 
To evaluate lymphocyte subsets 
and serum cytokine 
concentrations in relation to 
outcome 
 
CR/CRh and minimal residual 
disease (MRD) response in 
relation to  
B-cell clearance, T-cell kinetics 
and serum cytokine concentration 
levels 
 
To evaluate MRD response 
following blinatumomab and 
AMG 404 combination therapy 
 
Complete MRD response within 
the first 2 cycles and across all 
cycles 
 
2.2 
Hypotheses and/or Estimations 
This is a phase 1b study and no formal statistical hypothesis will be tested. 
3. 
Study Overview 
3.1 
Study Design 
This is a multicenter, non-randomized, open-label, Phase 1b trial in adults with R/R B-
ALL, evaluating safety, tolerability, PK and efficacy of blinatumomab and AMG 404 
combination therapy. The study will consist of up to a 3-week screening and pre-phase 
period, a treatment period, a safety follow-up (SFU) visit 30 (+ 7) days after last dose of 
blinatumomab, and an end of study (EOS) visit 140 + 7 days after the last administration 
of AMG 404. 
Subjects in this study will receive at least 2 and up to 5 cycles blinatumomab and AMG 
404 in combination (Blin + AMG 404).  
Cohort 1: 
Each cycle will be 42 days and includes a 14-day blinatumomab treatment-free interval 
between Days 29 and 42. In extenuating circumstances, the treatment-free interval 
may be prolonged by up to 7 days, if deemed necessary by the investigator. 


Product:  Blinatumomab and AMG 404 
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Blinatumomab cIV will be given on Day 1 to Day 28.  In Cycle 1, blinatumomab will be 
administered at 9 µg/day on Day 1 to Day 7, then at 28 µg/day on Day 8 to Day 28 for 
subjects ≥45 kg and 5 µg/m2/day, not to exceed 9 µg/day, on Day 1 to Day 7, then 15 
µg/m2/day  on Day 8 to Day 28 for subjects < 45 kg, not to exceed 28 µg/day.  In Cycle 
2 to Cycle 5, blinatumomab will be administered at a dose of 28 µg/day for subjects ≥45 
kg and 15 µg/m2/day for subjects < 45 kg, not to exceed 28 µg/day on Day 1 to Day 28.  
AMG 404 will be administered intravenously (IV) over approximately 30 minutes starting 
on Day 11 of Cycle 1 and dosed every 4 weeks (Q4W) thereafter AMG 404 should be 
administered on Day 11 of Cycle 1; however, dosing may be delayed by up to 4 days 
(Day 11 + 4 days) in the event of any adverse or safety event leading to interruption of 
blinatumomab infusion or any other clinical events making AMG 404 dosing on Day 11 
unsafe. The allowed ± 4-day delay will apply to any AMG 404 dose. For cycle 1, if 
blinatumomab infusion is interrupted, AMG 404 will be dosed on Day 11 after re-initiation 
of blinatumomab infusion and not Day 11 of the cycle. For example, if blinatumomab 
infusion is interrupted on day 3 for 2 days, the restart day for blinatumomab will be day 4 
and the AMG 404 should be given on Day 11 of blinatumomab infusion. 
With this dosing schedule AMG 404 will be dosed on Day 11 and Day 39 of Cycles 1, 3, 
and 5 and Day 25 of Cycles 2 and 4.   
Cohorts 1c, 2a, and 2b: 
In Cohorts 1c, 2a, and 2b, Cycle 1 will be 44 days and each subsequent cycles will 
be 42 days.  In Cycle 1, blinatumomab will be administered at 9 g/day on Day 3 to 
Day 9, then at 28 g/day on Day 10 to Day 30 for subjects  45 kg.  Blinatumomab 
cIV will be administered at 5 g/m2/day (not to exceed 9 g/day), on Day 3 to Day 9, 
then 15 g/m2/day (not to exceed 28 g/day) on Day 10 to Day 30 for subjects  45 
kg.  In all cohorts, Cycle 2 to Cycle 5, blinatumomab will be administered at a dose 
of 28 g/day on Day 1 to Day 28 for subjects 45 kg and 15 g/m2/day (not to exceed 
28 g/day) for subjects  45 kg.  Each cycle will include a 14-day blinatumomab 
treatment free interval: between Days 31 and 44 for cycle 1 and between Days 29 
and 42 for subsequent cycles.  The treatment-free interval may be prolonged by up 
to 7 days, in all the cohorts if deemed necessary by the investigator.   AMG 404 will 
be administered IV over approximately 30 minutes starting on Day 1 of Cycle 1 and 
dosed Q4W thereafter.  After completion of the dose of AMG 404 (Day 1 and Day 29) 
in Cycle 1, the subsequent doses may be given within a  4 day window.  For cycle 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
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1, if blinatumomab infusion is interrupted, AMG 404 will be dosed on the day of the 
cycle and not the day of the blinatumomab infusion (See protocol Figure 4-1)  
The planned doses of AMG 404 in Cohorts 1 and 2a will be 240 and 480 mg, 
respectively.   Other cohorts may be considered to evaluate different dosing 
schedules of AMG 404 in relation to the blinatumomab infusion (see protocol Figure 
4-2). 
With this dosing schedule AMG 404 will be dosed on Day 1 and 29 of Cycle 1, Day 
13 and 41 of cycles 2 and 4 and day 27 of cycles 3 and 5. Dose escalation (or de-
escalation) decisions for AMG 404 will be guided primarily by observed safety and 
tolerability of combination therapy with cIV blinatumomab and AMG 404.  Bone marrow 
(BM) evaluations will be performed at Day 29 ( 7 days) of each cycle in cohort 1 on Day 
31  7 days of cycle 1 in cohorts 1c, 2a, and 2b and at Day 29 ( 7 days) of cycles 2-
5 in cohorts 1c, 2a, and 2b.  Subjects will be hospitalized starting on day 1 until day 
11 of the Cohorts 1c, 2a, and 2b cycle 1 (see protocol Figure 4-2). 
Expansion phase:  
For the expansion phase, the recommended dose and schedule will be estimated 
by the Dose Level Review Team (DLRT) using the totality of the clinical and 
laboratory data from the dose exploration stage. 
Dexamethasone 20 mg IV will be given within 6 hours prior to start of the first dose of 
blinatumomab.  In addition, dexamethasone up to 24 mg daily may be used as treatment 
for any cytokine release syndrome (CRS) and/or neurotoxicity (NT) associated with 
blinatumomab infusion.  If dexamethasone treatment becomes necessary it should be 
administered for up to 3 days, and if treatment is required for longer than 3 days then 
dexamethasone should be tapered over 4 days. 
Subjects will discontinue therapy if they fail to achieve a blast count < 5% after 2 cycles, 
relapse or experience disease progression, are suitable for a hematopoietic stem cell 
transplantation (HSCT) or are intolerant to blinatumomab and AMG 404 combination 
therapy.   
A Safety follow-up (SFU) visit will occur 30 (+ 7) days after the last dose of blinatumomab, 
or before HSCT or any other non-protocol specified anti-tumor therapy, whichever is 
earlier. An end of study (EOS) will occur  140 (+ 7) days after the last administration of 
AMG 404. 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
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CONFIDENTIAL  
 
 
Infusion related reactions and immune-mediated toxicity attributed to AMG 404 by the 
investigator(s) will follow immune-related adverse events (irAE) management under 
National Comprehensive Cancer Network (NCCN) guidelines (Section 11.9 of Protocol, 
Appendix C; Thompson JA et al, 2019). 
The study will consist of 2 stages, dose exploration and dose expansion.  
Dose Exploration 
 
In the dose exploration stage, subjects will be enrolled in groups of 3 to 6.  The Dose Level 
Review Team (DLRT) will meet after all subjects in each group are DLT evaluable to 
determine if additional subjects need to be enrolled into the cohort, if it is appropriate to 
dose escalate or de-escalate, or to stop the study for safety concerns. A maximum of 
9 subjects overall may be enrolled at each dose level during dose exploration.   
The planned dose levels for blinatumomab are: 
Cohort 1 cycle 1:  Administer 9 µg/day on Day 1 to Day 7 and 28 µg/day on Day 8 to 
Day 28 for subjects ≥45 kg. Administer 5 µg/m2/day, not to exceed 9 µg/day, on Day 1 
to Day 7, then 15 µg/m2/day on Day 8 to Day 28 for subjects < 45 kg, not to exceed 28 
µg/day 
Cohort 1 Cycle 2-5:  Administer 28 g/day for subjects 45 kg and 15 g/m2/day for 
subjects  45 kg, not to exceed 28 g/day. 
Cohorts 1c, 2a, and 2b cycle 1:  Administer 9 g/day on Day 3 to Day 9 and 
28 g/day on Day 10 to Day 30 for subjects 45 kg.   Administer 5 g/m2/day, not 
to exceed 9 g/day, on the first 7 days (Day 3 to Day 9), then 15 g/m2/day 
thereafter for subjects  45 kg, not to exceed 28 g/day (Day 10 to Day 30).  
Cohorts 1c, 2a, and 2b cycle 2-5:  Administer 28 g/day on Day 1 to Day 28 for 
subjects  45 kg.  Administer 15 g/m2/day on Day 1 to Day 28 for subjects  45 kg, 
not to exceed 28 g/day. 
For cycle 1 the dose levels for AMG 404 are: 
 
Cohort 1: 240 mg Q4W starting on Day 11 of Cycle 1 
 
Cohort 2a: 480 mg Q4W starting on Day 1 of Cycle 1  
 
Cohort 2b: 240 mg Q4W starting on Day 1 of Cycle 1  
 
Cohort 1c: 120 mg Q4W starting on Day 1 of Cycle 1  
 


Product:  Blinatumomab and AMG 404 
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 
Cohort 2*:  480 mg Q4W starting on Day 11 of Cycle 1 
 
Cohort 1b*:  120 mg Q4W starting on Day 11 of Cycle 1 
 
*After completion of cohort 1, cohorts 2a, 2b, and 1c will replace previous 
dose cohorts of 2 and 1b defined in the protocol dated 19 May 2020.  The 
new cohorts, 2a, 2b, and 1c will administer AMG 404 on day 1 of cycle 1.  
Cohort 2b may be considered if cohort 2a is considered unsuitable (see 
protocol Figure 4-2). 
Dose exploration will begin with Cohort 1.  After the DLT evaluation period, the DLRT will 
evaluate all available safety, laboratory, PK and pharmacodynamic (PD) data as well as 
rules generated from a modified toxicity probability interval (mTPI-2) algorithm to guide 
their dose finding decisions.   
The following decision may occur:   
1) Dose escalation to Cohort 2a,  
2) Additional enrollment to Cohort 1,  
3) De-escalation to Cohort 1c 
4) De-escalation to Cohort 2b based on safety results from cohort 2a.  
Table 3-1 shows the mTPI-2 escalation/de-escalation guideline with a target toxicity 
probability of 0.30, acceptable toxicity probability interval of (0.25, 0.35).  A dose level will 
be considered unsafe, with no additional subjects enrolled at that dose level, if it has an 
estimated 95% or more probability of exceeding the target DLT rate 𝑝𝑇 (ie, P [DLT > 𝑝𝑇 | 
data] > 95%) with at least 3 subjects treated and evaluated at that dose level.  If 2 subjects 
have DLT prior to the third subject enrolling, only 2 subjects will be evaluated in this cohort.  
The MTD will be defined as the dose for which the estimate of the toxicity rate from an 
isotonic regression (Yan et al, 2017) is closest to the target toxicity rate.  If there are ties, 
the higher dose level when the estimate is lower than the target toxicity rate will be 
selected and the lower dose level when the isotonic estimate is greater than or equal to 
the target toxicity rate will be selected.  The RP2D will be estimated by the DLRT using 
the totality of the clinical and laboratory data from dose exploration stage. 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
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Table 3-1.  mTPI-2 Decision Rules 
Number of 
DLTs 
Number of Evaluable Subjects 
n=1a 
n=2a 
n=3 
n=4 
n=5 
n=6 
n=7 
n=8 
n=9 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
2 
. 
DU 
D 
D 
D 
S 
S 
S 
S 
3 
. 
. 
DU 
DU 
D 
D 
D 
D 
D 
4 
. 
. 
. 
DU 
DU 
DU 
D 
D 
D 
5 
. 
. 
. 
. 
DU 
DU 
DU 
DU 
DU 
D = de-escalate to the next lower dose level; DLT = dose-limiting toxicity; DU = current dose is unacceptably 
toxic; E = escalate to the next higher dose level; mTPI = modified toxicity probability interval; S = stay at 
the current dose level. 
a The columns indicating the actions based on data from 1 or 2 subjects are included to reflect the 
completeness of the mTPI design. However, in this study, a minimum of 3 subjects will be enrolled at each 
dose level, unless unacceptable toxicity is seen. 
 
Dose exploration will continue until any of the following events occur: 
 
The maximum planned dose (480 mg) to be tested is determined to be safe and 
tolerable 
 
The lowest planned dose (120 mg) is determined to be unacceptably toxic  
 
The maximum sample size of 24 DLT evaluable subjects has been reached for 
dose exploration phase  
Dose-limiting Toxicity  
The DLT-evaluable period (DLT window) will begin with the first AMG 404 dose and 
include 28 days after the second AMG 404 dose is administered.  The DLT window may 
also be extended to assess events starting within the window in case the DLT definition is 
time dependent. 
The subject will be DLT evaluable if he/she has completed the DLT window as described 
above or experienced a DLT any time during the DLT window.  A subject will not be DLT 
evaluable if he/she drops out before completion of the DLT-evaluable period for reasons 
other than a DLT. Exception: if a subject has not completed the DLT evaluable 
window but has received the planned doses of blinatumomab in cycle 1 (28 days) 
and the second dose of AMG 404 (day 29) but drops out due to disease non 
response or disease progression then, that subject will be considered 
DLT-evaluable and will not be replaced. All available safety data for subjects who are 
not DLT-evaluable will still be evaluated and considered in DLRT recommendations. 


Product:  Blinatumomab and AMG 404 
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An adverse event (AE) will be considered related to study treatment (possibly, probably, 
or definitely related to the study treatment) if there is a suspected “reasonable causal 
relationship” to the study treatment and not only a lack of an alternative explanation for 
the toxicity.  All toxicities will be graded using the Common Terminology Criteria for 
Adverse Events version 5.0 (CTCAE5). 
DLT is defined as any of the following occurrences related to study drug 
 
Grade ≥ 4 neutropenia or thrombocytopenia lasting more than 42 days from the 
cycle start in the absence of active leukemia 
 
Grade 4 CRS or Grade 3 that does not resolve to ≤ Grade 1 in 7 days 
 
Grade 4 tumor lysis syndrome (TLS) not resolving within 7 days 
 
Grade ≥ 3 nonhematological laboratory abnormalities that last for > 3 days 
 
Grade 3 abnormalities in creatinine, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, amylase, or lipase occurring outside the 
setting of CRS and that last for > 3 days 
 
Grade 4 neurologic events 
 
Grade 3 neurologic events that do not resolve to Grade ≤ 1 within 7 days in spite 
of intervention/treatment interruption 
 
Recurrent seizures (if second seizure occurs after restart of blinatumomab and/or 
administration of antiseizure medication) 
 
Grade ≥ 3 infusion-related reactions 
 
Immune-mediated toxicities 
➢ Recurrent grade ≥ 2 pneumonitis 
➢ Grade ≥ 3 pneumonitis 
➢ Grade 4 colitis/diarrhea 
➢ Grade ≥3 Hepatitis 
➢ Encephalitis (any grade)  
➢ Grade 4 bullous dermatoses (including Stevens-Johnson syndrome [SJS] 
and toxic epidermal necrolysis [TEN]) 
➢  Grade 4 nephritis   


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
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➢ Grade ≥ 3 myocarditis  
➢ Grade 4 immune-mediated adverse reactions not otherwise specified  
➢ Recurrent grade ≥ 3 immune-mediated adverse reactions  
➢ Grade ≥ 3 endocrinopathies, not responsive to replacement therapy ≤ 3 
days 
Dose expansion 
Additional subjects will be enrolled to the RP2D determined from dose exploration to 
further assess safety, PK, PD, and efficacy.  Up to a total of 15 subjects at RP2D, not 
exceeding 27 total in the study will be enrolled (including dose exploration and dose 
expansion).  The DLRT will be convened in the dose expansion stage of the study to 
review safety and efficacy data and will assess safety after the first 6 subjects treated at 
the RP2D have completed the DLRT window (i.e., 28 days after the second  AMG 404 
dose is administered  with (see exception rule in protocol Section 6.2.1.1.2 ) additional 
reviews occurring after every 3 RP2D subjects having completed the study up to the 
planned maximum of 15 subjects. 
The overall study design is described by a study schema in Section 1.2 of the protocol.  
The endpoints are defined in Section 2.1.  Please see Section 6.2.1.1.2  and Section 
6.2.1.2  of the protocol for details on DLT and dose expansion respectively. 
3.2 
Sample Size 
Up to 27 evaluable subjects will be enrolled in the study.  
The number of subjects to be enrolled for dose exploration will depend upon the toxicities 
observed. With a minimum of 3 subjects and a maximum of 9 subjects enrolled at each 
dose level, up to 18 evaluable subjects can be enrolled for 2 planned dose levels. A third 
cohort may be necessary to evaluate the administration of AMG 404 at 240 mg/day 
starting at D1 of cycle. Once the dose exploration has completed per the modified toxicity 
probability interval (mTPI-2) algorithm or the highest protocol defined dose is evaluated, 
an RP2D will be selected and additional subjects will be enrolled in dose expansion to 
further assess safety, PK, PD, and efficacy.  Up to a total of 15 evaluable subjects at RP2D 
(counting both dose exploration and dose expansion) or 27 evaluable subjects total in the 
study will be enrolled.  
The sample size in the dose escalation is based on practical considerations and is 
consistent with conventional oncology studies with the objective to estimate the MTD.  
With 3 subjects per cohort, there is a 27% to 70% probability of observing at least 1 DLT 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
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if the true DLT rate is 10% to 33% and with 6 and 9 subjects per cohort, there is a 47% to 
91% and 61% to 97% probability. With the dose expansion cohort, 15 evaluable subjects 
will provide a 54%, 80%, and 99.5% probability of observing at least 1 AE with a true 5%, 
10%, and 30% incidence rate. 
3.3 
Adaptive Design 
The modified toxicity probability interval method (mTPI-2) will be used to guide dose 
escalation (see Section 7.1 for details).  
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
This phase 1b study has no prespecified covariates. The relationship between 
covariates and endpoints may be explored if appropriate. 
4.2 
Subgroups 
This phase 1b study has no prespecified subgroups. 
5. 
Definitions 
5.1 
General Definitions 
Age at Enrollment 
Subject age at enrollment will be collected in years in the clinical database. 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to blinatumomab in combination 
with AMG 404. 
Cumulative Dose of Blinatumomab, AMG 404 
Blinatumomab: The cumulative dose in µg is defined as the following with summation over 
infusions:  
∑ (duration of infusion [days] for each dose received x dose received [µg/day]) 
AMG 404: The cumulative dose in mg is calculated by summation over all received dose 
in mg.  
Cumulative dose will be calculated within a cycle and across all cycles. Cumulative dose 
will be summarized for blinatumomab and AMG 404 separately. 
 


Product:  Blinatumomab and AMG 404 
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Bazett-corrected QT Interval (QTcB)  
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: QTcB=QT/ (RR/1000)1/2. 
5.2 
Study Points of Reference 
Baseline 
For the analysis of all endpoints, baseline will be defined as the value measured on day 1 
of the first cycle of investigational product. The protocol specifies that 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 most recent value before the day of the start of any protocol-
specified therapy may be used. 
Change from Baseline 
Change from baseline is the arithmetic difference between post-dose assessment and 
baseline. 
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value)  
Percent Change from Baseline 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline  
Value] x 100 
5.3 
Study Dates 
Inform Consent Date 
The date on which the subject signs the inform consent form. 
Enrollment Date 
Date of enrollment collected in the case report form (CRF). 
End of Study (primary completion) 
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). 
Safety Follow-up (SFU)  
Upon permanent discontinuation from the study treatment for any reason, SFU visit will 
be performed 30 (+7) days after the end of the last dosing interval of blinatumomab.  
 


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End of Study (EOS)  
Defined as the date when the last subject across all sites is assessed or receives an 
intervention for evaluation in the study (i.e., last subject last visit), following any additional 
parts in the study (e.g., long-term follow-up, additional antibody testing), as applicable. 
The EOS date is the same as the primary completion date for each subject. 
End of Study for Individual Subject 
Defined as the date when an individual subject completed all protocol specified 
procedures. The date will be recorded on the End of Study CRF page. 
End of Investigational Product (IP) Administration Date 
Defined as the last infusion of blinatumomab/AMG404 reported on the End of IP 
Administration CRF. 
Death Date  
For subjects who die during the study, the death date will be recorded on the end of study, 
event and survival status CRF. The earliest date will be used if the dates are inconsistent 
among these CRF pages.  
Study Day 
Study Day 1 is defined as the day of first dose of blinatumomab or AMG 404, 
whichever is earlier. 
And Study Day is defined as: 
Pre study day 1: study day = (date – date of study day 1) 
Post study day 1: study day = (date - date of study day 1) + 1  
5.4 
Endpoints 
Treatment-emergent Adverse Event (TEAE) 
Treatment-emergent Adverse Event refers to the adverse event starting on or after 
first dose of blinatumomab or AMG 404  as determined by "Did event start before 
first dose of investigational product" equal to "No" or missing on the Events eCRF 
and up to and including 30 days after the last dose of blinatumomab or AMG 404 
(whichever is later) excluding events reported after End of Study date. 
 This reporting window also applies to treatment-emergent serious adverse events 
(SAEs). 


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CONFIDENTIAL  
 
 
Treatment-emergent Adverse Event including Extended Period (TEAEEP) 
Treatment-emergent Adverse Event including Extended Period refers to the 
adverse event starting on or after first dose of blinatumomab or AMG 404  as 
determined by "Did event start before first dose of investigational product" equal 
to "No" or missing on the Events eCRF and up to the End of Study date. 
Dose Limiting toxicity (DLT) 
Investigators will determine whether an adverse event qualifies as a DLT per protocol 
Section 6.2.1.1.2. 
Treatment Response 
Treatment response is defined in Section 8.2.2.1 of the Protocol. The data will be 
recorded on Treatment Response CRF page. 
Duration of CR/CRh 
Calculated only for subjects who achieve a CR/CRh within first 2 cycles. The duration will 
be calculated from the date a CR/CRh is first achieved within first 2 cycles until the earliest 
date of a disease assessment indicating a relapse event or death, whichever occurs first. 
Subjects who do not have a relapse event 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.  
Duration of CR 
Calculated only for subjects who achieve a CR within first 2 cycles. The duration will be 
calculated from the date a CR is first achieved within first 2 cycles until the earliest date 
of a disease assessment indicating a relapse event or death, whichever occurs first. 
Subjects who do not have a relapse event 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.  
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined in Section 6.1 


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6.1 
Safety Analysis Set 
Safety Analysis Set is defined as all subjects that are enrolled and receive at least 1 
dose of blinatumomab. The analysis of all endpoints, unless noted otherwise, will be 
conducted on the Safety Analysis Set.  
6.2 
Dose-limiting toxicity Analysis Set 
Dose-limiting toxicity Analysis Set is defined as DLT-evaluable subjects in the Safety 
Analysis Set (see definition of DLT-evaluable in Section Error! Reference source not 
found. of the protocol).  The analysis of DLTs will be conducted on the DLT Analysis Set. 
6.3 
Pharmacokinetic Analyses Set(s) 
Pharmacokinetic (PK) Analysis Set is defined as all subjects in the Safety Analysis Set 
who have at least 1 PK sample collected.  These subjects will be evaluated for PK analysis 
unless the number of data points required for analysis is not enough, or significant protocol 
deviations have affected the data, or if key dosing or sampling information is missing. 
7. 
Planned Analyses 
The planned Analysis is described in the following sections.  
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis using as-is database snapshot.  The 
DLRT will review all accumulating data after each group in dose exploration or all subjects 
in dose-expansion complete the DLT evaluation period.  The mTPI-2 will be used to guide 
dose exploration.  The target toxicity rate for the MTD is 0.3, with the acceptable toxicity 
probability interval of (0.25, 0.35). 
Up to 15 subjects will be treated at RP2D (counting both dose exploration and dose 
expansion). The DLRT will assess safety after the first 6 subjects treated at the RP2D 
have completed the DLRT window (i.e., 28 days after the second cycle AMG 404 dose is 
administered  with additional reviews occurring after every 3 RP2D subjects having 
completed study up to the planned maximum of 15 subjects. All subjects treated at RP2D 
both from the dose exploration and dose expansion phases will be included in these 
interim safety analyses.  Safety reviews could occur more frequently if necessary to 
address emerging safety concerns.  The stopping rules presented in 
 use a 
Bayesian approach (Thall et al, 1995) to terminate the study if there is posterior probability 
greater than 80% that DLT rate is greater than 30% (the target toxicity rate used in the 
dose escalation phase of the study). The stopping boundaries assume a prior beta 
distribution of (1, 1).  The operating characteristics in 
 provide the probability of 


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stopping the trial early for given hypothetical true DLT rates.  Calculations were performed 
using Multc Lean Software. 
Table 7-1.  Stopping Boundary with Batch Size 3, Posterior Probability of 80% and 
DLT limit of 30%  
Number of subjects 
Number of DLT for Stopping 
6 
≥3 
9 
≥4 
12 
≥5 
15 
Study completes 
Table 7-2. Operating Characteristics with Batch Size 3, Posterior Probability of 
80% and DLT limit of 30% 
DLT rate 
Probability of stopping 
Average Sample Size 
0.20 
14% 
14 
0.25 
25% 
13 
0.30 
38% 
12 
0.35 
52% 
11 
0.40 
65% 
10 
The DLRT will also review totality of all data including efficacy. For study stopping rules 
for futility, the DLRT may consider response rate using the upper limit of confidence 
interval (CI) to be lower than 42%. Forty two percent is the response rate from the TOWER 
study.  Response rate is defined as CR/CRh within 2 cycles of blinatumomab.  The DLRT 
may consider stopping the study for futility if 0 out of 7 subjects (95% CI 0%, 41%) or less 
than 1 out of 11 subjects (95% CI 0.2%, 41%) responds.  This rule will apply only to 
evaluable subjects (dose exploration and dose expansion) who received the RP2D. 


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7.2 
Primary Analysis 
The primary analysis will occur when all subjects complete EOS or terminate the study 
early.  The data will be analyzed once they have been entered, cleaned, and locked. The 
purpose of this analysis is to summarize efficacy and safety after all subjects have 
complete follow-up.  
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
Subjects without hematological response assessments will be considered as non-
responders. Otherwise, only non-missing data will be analyzed.  
 
Incomplete adverse event and concomitant medication dates will be imputed 
per Appendix B 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations following 
Amgen SOP. 
8.5 
Outliers 
Details of detecting outliers can be found in the DMP or other data management 
document. In addition, outliers may be identified via the use of descriptive statistics. All 
confirmed outlier data will be included in the analyses presented in this statistical analysis 
plan unless there is sufficient scientific justification to exclude them. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. Data distribution will be explored, if required, data transformations or 
alternative non-parametric methods of analyses will be utilized. 


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8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance with 
current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported versions 
of statistical analysis software; for example, the SAS System version 9.4 or later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
The analysis will be performed by cohorts, for subjects treated at RP2D and for all 
subjects. 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic, efficacy and biomarker data by dose, dose schedule, and time as 
appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations and ranges, while categorical data will be summarized using 
frequency counts and percentages.  Response rates will be presented with 95% exact CI 
proposed by Clopper-Pearson (1934).  Time-to-event endpoints will be summarized using 
the Kaplan-Meier method.  Graphical summaries of the data may also be presented. When 
data are summarized by time, the scheduled time points listed in the protocol Table 1-1 
will be used. For statistical analyses comparing change from baseline, only subjects with 
both baseline and at least one post-baseline assessment will be included. When 
assessing minimum/maximum increases or decreases over the study, all assessments, 
including unscheduled assessments will be used. 
The primary analysis will be triggered when target enrollment is complete and all subjects 
complete the study or withdraw from the study. 
9.2 
Subject Accountability 
The number and percent of subjects who were screened, received at least one dose of 
blinatumomab, completed investigational product, discontinued from investigational 
product (including reasons for discontinuing), completed study, discontinued the study 
(including reasons for discontinuing) will be summarized. 
Key study dates for the first subject enrolled, last subject enrolled, and date that the last 
subject ended investigational product and ended study will be presented.  


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9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, subcategory codes, and descriptions 
will be used during the course of the study.  Eligibility deviations are defined in the protocol. 
The final IPD list is used to produce the list of subjects with IPDs. In addition, a separate 
listing of all inclusion and exclusion deviations will be provided. 
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized using 
descriptive statistics. If multiple races have been reported for a subject, the subject will be 
categorized as multiple race as well as by the combination of race.  
The baseline characteristics to be summarized include:  
 
Sex: Male, Female 
 
Age: <55, ≥ 55 to < 65, ≥ 65 
 
Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other 
 
ECOG performance status 
 
Prior HSCT: Yes, No 
 
Criteria for entry to study: primary refractory, refractory to salvage therapy, first 
relapse with remission duration of less than 12 months, untreated second or 
greater relapse, relapse any time after allo-HSCT 
 
White blood cell count  
 
Platelet count 
 
Percentage of bone marrow blast 
 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
No efficacy parameter is considered in primary endpoints 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The number and percentage of subject with CR/CRh within first 2 cycles of treatment 
initiation and across all cycles will be summarized by dose level along with corresponding 
95% exact confidence interval (CI) using the Clopper-Pearson method (Clopper and 
Pearson, 1934). Similar analysis will be provided for CR rate within first 2 cycles of 
treatment initiation and across all cycles. 


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For subjects treated at the MTD and/or RP2D, the Kaplan-Meier summaries will be 
performed for 1) duration of CR 2) duration of CR/CRh. Time to event curve, median time 
to event and percentiles with 95% CI will be estimated.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
This analysis will be provided by clinical biomarker team in a Contributing Scientific 
Report, the detailed statistical analysis method will be described within. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Subject incidence of DLT will be summarized by cohort in the dose escalation stage. The 
DLT summary will be based on the DLT analysis set. 
The statistical analysis methods for TEAE, serious TEAE, treatment-related TEAE, and 
adverse events are described in Section 9.6.2. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term.  
Subject incidence of all, serious, grade 3 and above, leading to withdrawal of 
investigational product, leading to interruption of investigational product, fatal, treatment-
related, treatment-related serious, and treatment-related grade 3 and above treatment-
emergent adverse events will be tabulated by system organ class and preferred term in 
descending order of frequency. In addition, treatment-emergent adverse events will be 
summarized by preferred term, by system organ class, preferred term, and grade; and by 
preferred term only in descending order of frequency. Also SAEs by preferred term will be 
presented. Subject incidence of TEAEEPs will be tabulated by SOC and preferred 
term. In addition, summary of fatal AE, SAEs and treatment-related TEAEEPs  will 
also be provided.  
Treatment-emergent events of interest (EOIs), treatment-emergent serious EOI, 
treatment-emergent grade 3 and above EOI, treatment-emergent EOI leading to IP 
interruption, treatment-emergent EOI leading to IP discontinuation, treatment-emergent 
fatal EOI will be summarized by EOI category and preferred term.  In addition, for each 
EOI category, the subject incidence of all, serious, grade 3 and above, grade 4 and 
above, fatal, leading to withdrawal of investigational product, leading to interruption of 
investigational product will be summarized.  Time to onset, duration, number of resolved 


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events for select EOIs (infection, neurologic events, and CRS) may also be summarized. 
In addition, summary of AMG 404 event of interest (EOI) TEAEEPs will also be 
provided.  
9.6.3 
Laboratory Test Results 
Summary statistics over scheduled visits for actual values, changes from baseline of 
selected laboratory parameters listed below will be presented.  
 
Lymphocytes 
 
Neutrophils 
 
Leukocytes 
 
Platelets 
 
Hemoglobin 
 
Albumin 
 
AST 
 
ALT 
 
GGT 
 
Bilirubin 
 
Corrected calcium 
 
Potassium 
 
Lipase 
 
Amylase 
 
ALP 
 
IgG 
 
Creatinine 
Shift tables between the worst post-baseline and baseline grades for select laboratory 
parameters below. 
 
Lymphocytes 
 
Hemoglobin 
 
Corrected calcium 
 
Potassium 
 
Neutrophils 
 
Leukocytes 
 
Platelets 
 
Albumin 


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 
AST 
 
ALT 
 
GGT 
 
Bilirubin 
 
Lipase 
 
Amylase 
 
Creatinine 
The subject incidence of potential cases of Hy’s Law will be summarized. 
9.6.4 
Vital Signs 
The number and percentage of subjects with abnormal changes (defined in Appendix A, 
Table 14-1) in systolic blood pressure, diastolic blood pressure, temperature and heart 
rate will be summarized.  
9.6.5 
Physical Measurements 
The number and percentage of subjects with abnormal changes (defined in Appendix A, 
Table 14-1) in weight will also be summarized.  
9.6.6 
Electrocardiogram 
All on-study ECG data will be listed. 
9.6.7 
Antibody Formation 
The number and percentage of subjects who have developed anti-blinatumomab 
antibodies (binding and if positive, neutralizing) and anti-AMG 404 binding antibodies at 
any time will be summarized. 
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment. The number of cycles, number of doses of investigational product and the 
total dose will be summarized by treatment. 
9.6.9 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe pre-medication (dexamethasone) 
exposure in the Safety Analysis.  
9.6.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term as coded by the World Health Organization Drug (WHO 
DRUG) dictionary. 


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9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Nominal sampling times will be used for individual concentration-time plots and tables. 
Actual dose administered, and actual sampling times will be used for the calculation of 
PK parameters for each subject. The reasons for excluding any sample from the 
analyses will be provided. 
Individual concentration-time data will be tabulated and presented graphically. Summary 
of PK concentration over time and PK parameters will be provided.  Mean concentration-
time profiles for each dose will be provided.  
Blinatumomab PK parameters such as steady state concentrations (Css) may be 
analyzed.  AMG 404 PK parameters such as maximum observed concentration (Cmax), 
time to maximum concentration (tmax) and area under the plasma concentration-time 
curve (AUC) will be analyzed.  Pharmacokinetic parameters will be estimated using 
standard non-compartmental approaches based on the PK Analysis Set and 
summarized by dose level using descriptive statistics including, but not limited to means, 
standard deviations, medians, minimums, and maximums.  Based on the review of the 
data, analyses to describe the relationship between blinatumomab and AMG 404 
exposure and either PD effect and/or clinical outcome may also be performed.  Above 
analyses will be conducted by Amgen Clinical Pharmacology Modeling and Simulation 
(CPMS). 
9.7.2 
Analyses of Biomarker Endpoints 
Below exploratory biomarker endpoints will be analyzed by Clinical Biomarkers and 
Diagnostics in a Contributing Scientific Report, detailed analyses method will be 
described within. 
 
PD parameters of B lymphocytes and T lymphocytes and cytokines following 
administration of blinatumomab and AMG 404.  
 
CR/CRh and MRD response in relation to B-cell clearance, T cell kinetics and 
serum cytokine concentration levels. 
 
Complete MRD response within the first 2 cycles. 
10. 
Changes From Protocol-specified Analyses 
Per protocol amendment 2, the ECG data will be completed at baseline while for rest of 
the days, ECG data will be collected as clinically indicated. Due to this, ECG data may not 


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CONFIDENTIAL  
 
 
be consistently collected across same post-baseline visits for all subjects. Hence, 
summaries over time and/or changes from baseline over time for all ECG parameters and 
post-baseline summaries for QTcF will not be provided as described in protocol section 
9.4.2.3.6.  


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Literature Citations / References 
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Oncol Hematol.  2004;50:223-261. 
Brahmer JR, Lacchetti C, Schneider BJ, et al.  Management of Immune-Related Adverse 
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American 
Society of Clinical Oncology Clinical Practice Guideline.  J Clin Oncol.  
2018;36(17):1714-1768. 
Brischwein K, Schlereth B, Guller B, et al.  MT110: a novel bispecific single-chain 
antibody construct with high efficacy in eradicating established tumors.  Mol Immunol. 
2006 Mar;43(8):1129-43. 
Dreier T, Lorenczewski G, Brandl C, et al.  Extremely potent, rapid and 
costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed 
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Feucht J, Kayser S, Gorodezki D, et al.  T-cell responses against CD19+ pediatric acute 
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contrarily by PD-L1 and CD80/CD86 on leukemic blasts.  Oncotarget.  
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Gökbuget N, Dombret H, Ribera JM, et al.  International reference analysis of outcomes 
in adults with B-precursor Ph-negative relapsed/refractor y acute lymphoblastic 
leukemia.  Haematol.  2016;101(12):1524-1533. 
Gökbuget N, Stanze D, Beck J, et al.  Outcome of relapsed adult lymphoblastic leukemia 
depends on response to salvage chemotherapy, prognostic factors, and performance of 
stem cell transplantation.  Blood.  2012;120(10):2032-2041. 
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;ch17. 
 


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Goldstein R, Goyos A, Li C, et al.  AMG 701 induces cytotoxicity of multiple 
myeloma cells and depletes plasma cells in cynomolgus monkeys.  Blood Adv. 
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Gong J, Chehrazi-Raffle A, Reddi S, Salgia R.  Development of PD-1 and PD-L1 
inhibitors as a form of cancer immunotherapy: a comprehensive review of registration 
trials and future considerations.  J Immunother Cancer.  2018;6(1):8.  
Guo W, Wang SJ, Yang S, Lynn H, Ji Y.  A Bayesian interval dose-finding design 
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Kantarjian H, DeAngelo DJ, Stelljes M, et al.  Inotuzumab Ozogamicin versus Standard 
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Remissions in Leukemia.  N Engl J Med.  2014;371:1507-1517. 
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Socinski MA, Jotte RM, Cappuzzo F, et al.  Atezolizumab for first-line treatment of 
metastatic nonsquamous NSCLC.  N Engl J Med.  2018;378:2288-2301.  
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12. 
Prioritization of Analyses 
There is no Prioritization of Analyses 
13. 
Data Not Covered by This Plan 
None 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
used. 
Refer to protocol Sections 6.2.1.1.2, 11.9 , Error! Reference source not found.11.3 
and SAP  Table 14-2. 
Notable values for vital signs and physical measurements are defined in the following 
table. 
Table 14-1.  Notable Abnormalities of Vital Signs and Physical Measurement 
 
Vital Signs or Physical Measurements 
Notable Abnormalities 
Heart rate (bpm) 
 
> 120 
 
 
< 50 
Blood pressure (mmHg)  Systolic 
≥ 160 
 
 
≤ 90 
 
Diastolic 
≥105 
 
 
≤ 50 
Body temperature (°C) 
 
> 39 
Weight (kg) 
 
Change from baseline ≥ 10% (in both 
directions) 
 
 
 


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Appendix B.  Technical Details and Supplemental Information Regarding 
Statistical Procedures 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.   
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.  
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start 
Date 
 
1st 
Dose 
1st 
Dose 
1st 
Dose 
yyyymm 
1st 
Dose 
yyyymm 
1st 
Dose 
yyyy 
1st 
Dose 
yyyy 
Partial: 
yyyymm 
1st 
Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
 1st 
Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
1st 
Dose 
yyyy 
3 
1 
3 
1 
N/A 
1 
1 
 1st 
Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1  Impute the date of first dose 
2  Impute the first of the month 
3  Impute January 1 of the year 
4  Impute January 1 of the stop year 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 36 of 40 
CONFIDENTIAL  
 
 
Note:  
 
For subjects who were never treated (first dose date is missing), partial start 
dates will be set to the first day of the partial month. 
 
If the start date imputation leads to a start date that is after the stop date, then 
do not impute the start date 
 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 37 of 40 
CONFIDENTIAL  
 
 
Appendix C. Toxicity Management Guidelines 
Table 14-2.  Management of Infusion-related Reactions With AMG 404 
Severity (CTCAE 
Grade Version 5.0) 
AMG 404 Dose 
Modification 
Management 
Premedication at 
Subsequent 
Dosing 
Grade 1 (mild transient 
reaction; infusion 
interruption not 
indicated; intervention 
not indicated) 
Interrupt or 
slow the rate of 
the infusion. 
 
 
 
 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 Treat per institutional 
guidelines. 
None 
Grade 2 (therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDS,  
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours) 
Interrupt or 
slow the rate of 
the infusion.  
For subjects 
who develop 
grade 2 
infusion-related 
reaction despite 
adequate 
premedication, 
permanently 
discontinue 
AMG 404. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 Treat per institutional 
guidelines.  Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, and 
narcotics. 
Subject may be 
premedicated 
1.5 hours  
(± 30 minutes) prior 
to infusion of  
AMG 404 with:  
 Diphenhydramine 
50 mg orally (or 
equivalent dose of 
antihistamine). 
 Acetaminophen 
500-1000 mg 
orally (or 
equivalent dose of 
antipyretic). 
Grade 3 (prolonged [eg, 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion]; recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae) 
 
OR 
 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
study drug. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 Hospitalization may be 
indicated. 
 Treat per institutional 
guidelines.  Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, 
narcotics, oxygen, 
vasopressors, 
corticosteroids, and 
epinephrine.  In cases 
of anaphylaxis, 
epinephrine should be 
used immediately. 
No subsequent 
dosing 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NSAIDS = nonsteroidal 
anti-inflammatory drugs. 
 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 38 of 40 
CONFIDENTIAL  
 
 
Appendix D.  ECOG Performance Status and NYHA Classification 
Eastern Cooperative Oncology Group 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 self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
Source:  Oken et al, 1982 
ECOG = Eastern Cooperative Oncology Group 
New York Heart Association Functional Classification 
Class I  
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation or dyspnea. 
Class II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea. 
Class III 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation or dyspnea. 
Class IV 
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased.  
 
 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 39 of 40 
CONFIDENTIAL  
 
 
Appendix E.  Adverse Events of Interest Search Strategy and Rules 
Event of Interest (EOI) 
 Search Strategy 
EOI Search Scope 
Blinatumomab 
Capillary Leak Syndrome 
Capillary leak syndrome 
(AMQ) 
Narrow 
Cytokine Release 
Syndrome 
Cytokine release syndrome  
(AMQ) 
Narrow 
Decreased 
Immunoglobulins 
Decreased 
immunoglobulins (AMQ) 
Narrow 
Elevated Liver Enzyme 
Liver related investigations, 
signs and symptoms 
(SMQ) 
Narrow 
Embolic and thrombotic 
events 
Embolic and thrombotic 
events (SMQ) 
Narrow 
Immunogenicity 
Immunogenicity 
Narrow 
Infections 
Infections and infestations 
(SOC) 
Infections and infestations 
(SOC) 
Infusion Reactions without 
considering duration 
Infusion reaction (AMQ) 
Narrow search with event 
onset within 48 hours of 
drug start and no duration 
restriction 
Leukoencephalopathy 
Progressive multifocal 
leukoencephalopathy 
(AMQ) 
 
Broad (including all terms) 
Progressive multifocal 
leukoencephalopathy 
(AMQ) 
 
Medication Errors (SMQ) 
Broad (including all terms) 
Neurologic Events                 Central neuropsychiatric 
events due to direct 
neurotoxicities  
(AMQ)  
Narrow 
Neutropenia and Febrile 
neutropenia 
Neutropenia (AMQ) 
 
Narrow 
Pancreatitis 
Acute pancreatitis (SMQ) 
Narrow 


Product:  Blinatumomab and AMG 404 
Protocol Number:  20190177 
Date:  20 September 2021 
   Page 40 of 40 
CONFIDENTIAL  
 
 
Tumor Lysis Syndrome 
Tumor lysis syndrome 
(SMQ) 
Narrow 
AMG 404 
Non-infectious diarrhea  
Non-infectious diarrhea 
(SMQ) 
Broad 
Haemorrhages 
SMQ  broad 
Haemorrhages (SMQ) 
Broad