Clinical trial NCT03541369
Conditions: Relapsed/Refractory Acute Myeloid Leukemia (AML)
Sponsor: Amgen
Start date: 2018-09-14; Completion date: 2023-02-21
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Evaluate the safety and tolerability of AMG 427 in adult subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML). Estimate the maximum tolerated dose (MTD) and / or a biologically optimal dose (eg, recommended phase 2 dose \[RP2D\]).

Detailed description:
Evaluate the safety and tolerability of AMG 427 in adult subjects with relapsed/refractory AML. Estimate the maximum tolerated dose (MTD) and / or a biologically optimal dose (eg, recommended phase 2 dose \[RP2D\]). Approximately 80 subjects will be enrolled.

Arms: arm 1: AMG 427 Dose-finding phase of the study arm 2: AMG 427 MTD identified in dose escalation phase (or lower) will be administered to subjects.
Interventions: intervention 1: AMG 427
Intervention descriptions: intervention 1: AMG 427 will be administered as an intravenous (IV) infusion in adult subjects with relapsed/refractory AML.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 1 of 189 
CONFIDENTIAL 
 
Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With Acute 
Myeloid Leukemia 
AMG 427 
Amgen Protocol Number 20170528 
IND number BB-IND 138440 
NCT Number:  NCT03541369 
Eudra CT:  2018-001389-40 
 
Clinical Study Sponsor: 
Amgen Inc. 
1 Amgen Center Drive 
Thousand Oaks, CA 91320  
Phone:  1 805 447 1000 
Key Sponsor 
Contact(s): 
 MD 
Medical Director, Early Development 
Phone:  
E-Mail:  
 
Senior Global Early Clinical Development Manager 
Phone: 
E-mail:  
  
Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
22 March 2018 
08 June 2018 
30 April 2019 
26 November 2019 
Amendment 4 Date: 
17 February 2020 
Amendment 5 Date: 
17 September 2020 
Amendment 6 Date: 
24 March 2021 
Amendment 7 Date: 
16 March 2022 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 2 of 189 
CONFIDENTIAL 
 
  
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: 1-800-77-AMGEN; Amgen’s general number 
in the US (1-805-447-1000). 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 3 of 189 
CONFIDENTIAL 
 
Investigator’s Agreement 
I have read the attached protocol amendment entitled “A Phase 1 First-in-human Study 
Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy 
of AMG 427 in Subjects With Acute Myeloid Leukemia,” dated 16 March 2022, and 
agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 4 of 189 
CONFIDENTIAL 
 
Protocol Synopsis 
Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 427 in Subjects With Acute Myeloid Leukemia 
Study Phase:  1   
Indication:  Acute Myeloid Leukemia (AML) 
Primary Objectives:   
 
Evaluate the safety and tolerability of AMG 427 in adult subjects with 
relapsed/refractory (R/R) AML or minimal/measurable residual disease-positive (MRD) AML 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically optimal dose 
(eg, recommended phase 2 dose [RP2D]) 
 
Evaluate the safety and tolerability of extended intravenous (eIV) administration of 
AMG 427 
Secondary Objectives:   
 
Characterize the pharmacokinetics (PK) of AMG 427 
 
Evaluate the anti-leukemia activity of AMG 427  
Exploratory Objectives:  
Hypotheses:  AMG 427 will demonstrate evidence of anti-leukemic activity at a safe and well 
tolerated dose in subjects with MRD or R/R AML. 
Primary Endpoints:   
 
Safety:  
 
Dose limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs) and 
treatment-related adverse events (TRAEs) 
Secondary Endpoints:   
 
AMG 427 PK parameters including, but not limited to, maximum serum concentration (Cmax), 
minimum serum concentration (Cmin), area under the concentration-time curve (AUC), and if 
feasible, half-life (t½) of AMG 427 
 
Efficacy parameters for (R/R) AML:  subject response to treatment with AMG 427 (response 
defined as complete response/remission [CR]/complete response/remission with incomplete 
recovery of peripheral blood counts [CRi]/morphologic leukemia-free state, partial remission 
[per modified International Working Group (IWG) criteria], complete response/remission with 
partial hematologic recovery [CRh]), and duration of response (duration of response will only 
be measured for subjects in the expansion cohort) 
 
Efficacy parameters for MRD AML:  subject response to treatment with AMG 427 (response 
refers to conversion from MRD status to MRD- status), relapse free survival, and overall 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 5 of 189 
CONFIDENTIAL 
 
survival (relapse free survival, and overall survival will only be measured for subjects in 
expansion cohort) 
Exploratory Endpoints:   
Study Design:   
This is a first-in-human (FIH), open-label, phase 1 dose escalation study.  AMG 427 will be 
administered as a short intravenous (IV) infusion (eIV infusion may apply) in adult subjects with 
MRD or R/R AML.  The study will be conducted at approximately 15 sites in the United States 
(US), Australia, Canada, Japan, South Korea, and Germany.  Additional countries or sites may be 
added if necessary.   
The dose-escalation cohorts will determine the MTD, safety, tolerability, PK, and PD of AMG 427.  
Planned dose levels (dose per infusion) the dose escalation cohorts are as follows: 
 
 g.  The starting 
dose for the
cohort will be
g administered as short term IV infusions on day 1 (D1) and 
day 5 (D5).  The doses administered for the cohorts following cohort  will be recommended by 
the Dose Level Review Team (DLRT).  The initial several cohorts will receive 2-3 doses (1 each 
on D1, D3 [if applicable], and D5, and D8 [if applicable]).  After reviewing the emerging PK, safety 
and efficacy data, the DLRT may recommend the administration of additional doses on D3 and 
D8, to comprise a 2-week cycle with doses on D1/D3/D5/D8.  The study will consist of 3 groups: 
 
FIH Group:  AMG 427 administered as short term IV infusions in R/R AML subjects.   
 
(CLOSED) Etanercept (Enbrel) substudy:  Etanercept will be administered for CRS 
prophylaxis 2 days prior to each cycle of AMG 427 short term IV infusions in R/R AML 
subjects in the US.  (Etanercept may be implemented to FIH expansion groups based on 
emerging data). 
 
eIV Infusion Group:  AMG 427 eIV infusions administered on days 1 and 2, and 3, with 
short term IV infusions on days 5 and 8 in R/R AML subjects.  (eIV infusion may be 
implemented to FIH expansion groups based on emerging data). 
 
MRD Group:  AMG 427 administered in short term IV infusions in MRD AML subjects. 
The study will have 3 alternative dosing schedules.  
 
(CLOSED) Schedule A  
 
D1/D5 or D1/D5/D12/D19 (dexamethasone prophylaxis) 
 
(CLOSED) Schedule B:  Etanercept Substudy (R/R AML) 
 
D1/D5 or D1/D5/D12/D19 (etanercept 2 days prior to each cycle) 
Etanercept substudy used etanercept 2 days prior to infusion of each cycle D1, and if 
applicable, 2 days prior to infusion on D12.  
 
 
 
Schedule C (Table 16 through Table 21):  FIH, eIV (R/R AML); MRD Group (MRD AML) 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 6 of 189 
CONFIDENTIAL 
 
 
D1/D3/D5/D8 or D1/D3/D5/D8/D12/D19 (dexamethasone prophylaxis) 
Note: 
 
The MRD group will use Schedule C for all cycle collections and Table 22 for additional 
whole blood MRD collection, or Table 23, as applicable. 
After reviewing additional PK, safety, and efficacy data, the DLRT may recommend the 
administration of additional doses on day 12 and 19, to comprise a 4-week cycle with doses on 
either D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19.  Once the DLRT recommends a 4 or 6 dose 
schedule (D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19), all subsequent cohorts will be treated with 
a 4 or 6 dose schedule.  If on Schedule A (CLOSED) or C, all subjects will be pre-treated with an 
8 mg dose of IV dexamethasone within 1 hour prior to D1, D3 (if applicable), D5, and D8 (if 
applicable) AMG 427 doses and each dose step.  A dose step is any AMG 427 dose that is 
higher for a given subject than the subject has previously received.  A dose step will be triggered 
by the observation of CRS or infusion related reaction at the first dose (see example in Figure 2).  
Dose steps may occur at the D3, D5, D8, D12, or D19.  Each cycle will last for approximately 
14 days for cohorts receiving 2 or 4 doses (D1/D5 or D1/D3/D5/D8), and approximately 28 days 
for cohorts receiving 4 or 6 doses (D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19).  Subjects will be 
assessed for DLTs for 28 days.  Cycles will be followed by a treatment-free interval for 1-2 weeks 
(depending on response), which may be extended for up to 7 weeks or longer for the cohorts at 
higher doses, based on a dose level review meeting (DLRM) recommendation.  The D3, D5, 
D8 doses, and the D12, D19 doses (if applicable) may be at the same dose as the preceding 
dose or may be at a higher dose level (dose step).  This will be based on tolerability of the lower 
dose level and other clinical signs, pharmacological, and PD results and will be recommended by 
the DLRT.  For a schematic description of the different dose step options see Figure 2 in 
Section 3.1.  For logistical reasons, there is a  1 – 3 day window for dosing days.  
Dose Escalation Cohorts 
Dose escalation will be conducted in 2 stages:  a single subject stage and a multiple subject 
stage.  Single subjects will be enrolled at initial dose levels.  Multiple subject cohorts, which will 
enroll 2 – 4 subjects per cohort, will be triggered by any evidence of pharmacologic activity, 
including, but not limited to infusion reactions, CRS, tumor lysis syndrome (TLS), or depletion of 
peripheral blasts and/or white blood cells.  The Bayesian logistic regression model (BLRM) 
design will be used to guide dose escalation.  The actual dose selected at each dose cohort may 
be at or below the model’s recommended dose as recommended by the DLRT after considering 
all information.  Subjects will be assessed for DLTs for 28 days.  Subjects in the etanercept 
(Enbrel) substudy (CLOSED) can intra-subject dose escalate after 1 cycle to the 
first-in-human (FIH) study (eg, move from schedule B to schedule C), if subjects show evidence 
of disease progression after discussion with the Sponsor (eg, use of hydroxyurea to control 
increasing WBC).  Subjects who complete the DLT period may proceed to a higher dose level for 
the following treatment cycle once the next dose cohort has been deemed safe by the DLRT, 
after consultation with the sponsor, if no DLT was reported during or after the completion of the 
DLT period for that subject. 
Estimation of initial and target MTDs 
It is anticipated that 2 to 3 MTDs may be estimated: 1 for the initial dosing and 1 - 3 for the 
subsequent dosing.  Should the initial dose be limited by adverse events related to first dose 
effects and/or cytokine release syndrome, the second MTD (dose step) for the target dose will be 
estimated after giving the initial dose at MTD1.  Each MTD will be estimated following the dose 
escalation guided by BLRM described above.  A second dose step may also be implemented in a 
cycle if this was considered appropriate and necessary to allow further dose escalation.  This 
second dose step would be performed the same way as described above.  In this case, a third 
MTD would be estimated for the dose to be administered after the second dose step. 
Once the dose escalation phase has determined a final MTD, tocilizumab may be evaluated as 
an alternative prophylaxis to prevent/reduce the severity of CRS.  A cohort of 3 subjects may be 
treated with AMG 427 at the final MTD dose level and a single dose of 8 mg/kg IV tocilizumab will 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 7 of 189 
CONFIDENTIAL 
 
be administered prior to the dose of AMG 427 replacing pretreatment with dexamethasone.  If no 
DLTs are observed, 3 additional subjects will be included in this cohort.  The use of tocilizumab 
may be further explored based on observed tolerability and other clinical and pharmacological 
data.  
Expansion Cohort 
At completion of the dose escalation cohorts, approximately 90 additional subjects (approximately 
40 R/R AML subjects in the FIH cohorts and 50 MRD AML subjects in the MRD cohorts) will be 
enrolled in a dose expansion cohort to gain further clinical experience, safety, and efficacy data in 
subjects administered AMG 427.  The dose to be evaluated will be at or below the MTD 
estimated in the dose escalation cohorts.  Based on emerging safety data, the planned dose level 
and dose schedule may be modified during the conduct of the expansion phase.  Additionally, 
enrollment to dose expansion will be paused and possibly terminated if safety stopping rules 
and/or efficacy futility rules are met (see Section 10.3 for details).  
A final estimate of the MTD and RP2D will be evaluated and confirmed utilizing all DLT-evaluable 
subjects from the dose escalation and the dose expansion cohorts. 
Sample Size:   
It is anticipated that approximately 200 subjects will be enrolled in this study, with approximately 
110 subjects enrolled in the dose escalation cohorts and 90 subjects in the dose expansion 
cohorts:   
Dose escalation cohorts: 
 
FIH (R/R AML):  approximately 90 subjects 
 
(CLOSED) etanercept substudy (R/R AML):  approximately 25 subjects  
 
eIV (R/R AML):  approximately 10 subjects 
 
MRD Group (MRD):  approximately 10 subjects  
Dose expansion cohorts: 
 
FIH (R/R AML):  approximately 40 subjects 
 
MRD Group (MRD):  approximately 50 subjects  
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 2 subjects per 
cohort, there is a 19 to 55 probability of observing at least 1 DLT.  With 3 subjects per cohort, 
there is a 27 to 70 probability of observing at least 1 DLT if the true DLT rate is 10 to 33 
and with 4 subjects per cohort, there is a 34 to 80 probability. 
In the dose expansion cohort, a subject number of 40 will provide an 87 probability of observing 
at least 1 adverse event with 5 incidence rate and 99 probability of observing at least 
1 adverse event with 10 incidence rate.  A subject number of 50 will provide a 92.3 probability 
of observing at least 1 adverse event with 5 incidence rate and 99.5 probability of observing 
at least 1 adverse event with 10 incidence rate.  These probabilities will be 64 and 88 
respectively with a subject number of 20.  An exact 80 binomial CI will be provided for response 
rate.  With the 20 subjects and 20 response rate, the expected 80 CI would be 9 to 36.  
With 40 subjects and 20 response rate, the expected 80 CI would be 12 and 30.  With 
50 subjects and a 40 response rate, the expected 80 CI would be 30.6 and 50.1. 
Summary of Subject Eligibility Criteria:   
Male or female subjects  18 years of age at the time of signing informed consent who have AML 
as defined by 2016 World Health Organization (WHO) Classification (Appendix D); for R/R AML 
subjects only, persisting or recurring following 1 or more treatment courses (choice of treatment 
courses may be at investigator discretion), and must have 5 blasts in bone marrow.  Patients 
with acute promyelocytic leukemia (APML) are not eligible for this trial.  For MRD AML subjects 
and for a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2. 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 8 of 189 
CONFIDENTIAL 
 
Investigational Product  
Amgen Investigational Product Dosage and Administration:   
AMG 427 will be manufactured and packaged by Amgen Inc., or its agents, and distributed using 
Amgen or its agents’ clinical study drug distribution procedures.  
AMG 427 is supplied as a sterile, preservative-free lyophilized powder for administration after 
reconstitution with sterile Water for Injection (WFI).  After reconstitution with 
 mL of sterile WFI, 
the
mg/mL AMG 427 drug product is formulated with 
 mM glutamic acid,  (w/v) sucrose, 
and 
 polysorbate 80, pH 
.  The final container is a single-use, 6R glass vial and contains 
a target extractable amount of
mg AMG 427.   
The intravenous solution stabilizer (IVSS) is supplied as a sterile solution in a 
-cc glass vial 
containing 
 mL deliverable product.  The IVSS does not contain an active pharmaceutical 
ingredient and is a buffered, preservative-free solution (
 mM citric acid, 
 M lysine 
hydrochloride, 
 [w/v] polysorbate 80, pH 
).  The IVSS is intended for pre-treatment of 
IV bags prior to dilution of AMG 427 drug product.  
AMG 427 solution will be prepared in bags for short or eIV infusion and delivered through infusion 
lines.   
The first eIV group will start at a DLRT-approved dose level from the FIH group, eg, if DLRT 
approves as safe and tolerable, the following dosing regimen will be administered: 
 
Days 1 and 2:  eIV of 
 g (over approximately 48 hours, with approximately 12-hour bag 
changes) 
 
Day 3:  eIV of 
 g (over approximately 24 hours, with approximately 12-hour bag 
changes) 
 
Day 5:  short IV of 
 g (over approximately 90 minutes) 
 
Day 8:  short IV of 
 g (over approximately 90 minutes) 
Subsequent eIV cohorts will use the same dose levels as the FIH (short IV) cohorts (Table 4). 
The infusion-free interval prior to the start of the following treatment cycle will have a duration of 
1 to 5 weeks (depending on treatment response and adverse events), but may be extended to up 
to 7 weeks in case of prolonged marrow aplasia and aleukemic cytopenias after consultation with 
the sponsor.  It may also be extended for up to 3 days from the planned duration if necessary for 
logistical reasons.  The DLRT may recommend on changes of the duration of the infusion-free 
interval for future cohorts after evaluation of emerging data.  
Subjects will be hospitalized for a minimum of 8 or 11 days from the first dose in cycle 1 (ie, at 
least 72 hours after the day 5 or day 8 dose, depending on the schedule) and for a minimum of 
72 hours following day 12 and day 19 doses in cycle 1 (if applicable).  If the subject receives a 
second cycle of AMG 427 at the same dose, hospitalization will be for a minimum of 8 or 11 days 
from the start of the day 1 dose (ie, at least 72 hours after the day 5 or day 8 dose, depending on 
the schedule) in cycle 2.  Hospitalization following day 12 and day 19 doses (if applicable) in 
cycle 2 and onwards will be at the discretion of the treating physician.  For subjects receiving 
 2 cycles, hospitalization for cycle 3 onwards for all doses will be at the treating physician’s 
discretion.  However, in case of intra-subject dose escalation (ISDE), subjects will be hospitalized 
as per the guidance for the first cycle.  After re-start of treatment, following an interruption due to 
an adverse event(s), the subject will be hospitalized for a minimum of 72 hours.  Subjects can be 
hospitalized for a longer time period at the discretion of the investigator.  A nurse trained in 
emergency procedures or a physician must be available when the dose of AMG 427 is started for 
immediate intervention in case of complications.  
The planned dose levels for the dose escalation cohorts are: 
 
 g.  Lower intermediate doses may be 
implemented based on BLRM and DLRT recommendations.  The MTD or a lower dose will be 
administered in the dose expansion cohort. 
A total of up to 12 total treatment cycles can be administered as long as in the judgment of the 
investigator the subject is deriving benefit and does not meet the criteria for permanent 
discontinuation of the drug (Section 6.2.1.4).   


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 9 of 189 
CONFIDENTIAL 
 
Procedures:   
After providing informed consent, eligible subjects will undergo the following assessments during 
this study:  physical examination, Eastern Cooperative Oncology Group (ECOG) status, height, 
weight, vital signs, pulse oximetry, electrocardiogram (ECG) triplicate measurements, laboratory 
assessments (including serum pregnancy test, if applicable, coagulation, hematology, chemistry, 
urinalysis, hepatitis serology, and 
), biomarker and PK assessments, 
and bone marrow assessments.  For a full list of study procedures, including the timing of each 
procedure, please refer to Section 7 of the study protocol and the Schedule of Assessments 
(Table 10 to Table 23).  
Statistical Considerations:   
All subjects who are enrolled and receive at least 1 administration of the investigational product 
(AMG 427) will be included in the analysis, unless otherwise specified.  The primary analysis will 
occur when target enrollment is complete and each subject either had the opportunity to receive 
up to 12 cycles of treatment or terminated the study early.   
Descriptive statistics will be provided for selected demographics, safety, PK, PD, 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.  Graphical summaries of the data may 
also be presented. 
The number and percentage of subjects reporting any treatment-emergent adverse events will be 
tabulated.  Clinical laboratory test, ECG, physical examination findings, and vital sign data will be 
presented.  Depending on the size and scope of changes in clinical laboratory, physical 
examination and vital sign data, the summaries of laboratory, physical examination, and vital sign 
data over time and/or changes from baseline over time may be provided.  Summaries over time 
and/or changes from baseline over time will be provided for all ECG parameters. 
The proportion of responding subjects in R/R AML, defined as any of the following:  CR, CRi, 
CRh, morphologic leukemia-free state, and PR with corresponding exact 80 CI, will be 
calculated using the Clopper-Person method (Clopper and Person, 1934) and tabulated for 
subjects treated at the estimated MTD.  For MRD AML, the MRD conversion rate will be 
presented with corresponding exact 80 CI and tabulated by group and for all subjects treated at 
the MTD.  Efficacy related endpoints (eg, duration of the response) will be presented per subject 
and Kaplan-Meier estimates may also be further presented if data allows.  For a full description of 
statistical analysis methods, please refer to Section 10.  
Sponsor:  Amgen Inc.


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 10 of 189 
CONFIDENTIAL 
 
Study Design and Treatment Schema 
Screening (14 days) 
Enrollment
DOSE ESCALATION (N = 110)
The initial cohorts are single subject cohorts. Multiple subject cohorts 
will be triggered by any observed pharmacologic activity. BLRM used 
for all subsequent cohorts. 
Number of cohorts, subjects per cohort, and actual doses dependent 
on observation of DLTs and Dose Level Review Team. 
(FIH: N = 90, MRD+: N = 10, eIV: N = 10)
DOSE EXPANSION 
(N = 90)
Will begin at or below the MTD or highest tested dose. 
(FIH: N = 40, MRD+: N = 50)
End of Treatment
Safety Follow-Up (SFU)
(4 weeks after last dose of AMG 427)
End of Study
Long Term Follow-Up (up to 2 years) 
Treatment
AMG 427 short infusions up to 12 treatment cycles with 2 to 6 infusions per cycle 
(D1/D5 or D1/D3/D5/D8; DLRT may recommend additional doses on D12, D19)
End of Treatment
Safety Follow-Up (SFU)
(4 weeks after last dose of AMG 427)
 


Product:  AMG 427 
Protocol Number:  20170528 
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Page 11 of 189 
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Study Glossary 
Abbreviation or Term Definition/Explanation 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APML 
acute promyelocytic leukemia 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AT III   
antithrombin III 
AUC 
area under the concentration-time curve 
AUC72h 
area under the concentration-time curve from time 0 to 72 hours 
AUC336h 
area under the concentration-time curve from time 0 to 336 hours 
BID 
twice a day 
BiTE 
bispecific T cell engager 
BiPAP 
bilevel positive airway pressure 
BLRM 
Bayesian logistic regression model 
BM 
bone marrow 
CAR-T 
chimeric antigen receptor T cell 
CD3 
cluster of differentiation 3 
CD19 
cluster of differentiation 19 
CD33 
cluster of differentiation 33 
CD135 
cluster of differentiation 135 
CI 
confidence interval 
cIV 
continuous intravenous 
CL 
systemic clearance 
CLD 
intercompartmental distribution 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CPAP 
continuous positive airway pressure 
CR 
complete response/remission (see Appendix E for details) 
CRF 
case report form 
CRi 
complete response/remission with incomplete recovery of peripheral 
blood counts (see Appendix E) 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 12 of 189 
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Abbreviation or Term Definition/Explanation 
CRh 
complete response/remission with partial hematologic recovery (see 
Appendix E for details) 
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CT (scan) 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentrations 
D1 
day 1 
D5 
day 5 
D8 
day 8 
D12 
day 12 
D19 
day 19 
DILI 
drug-induced liver injury 
DLRM 
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DLT 
dose-limiting toxicity  
EC50 
half maximal effective concentration: concentration of a drug, antibody or 
toxicant which induces a response halfway between the baseline and 
maximum 
EC90 
concentration of a drug, antibody or toxicant which induces a response 
that is 90 of the maximum response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
eGFR 
estimated glomerular filtration rate 
eIV 
extended intravenous 
End of Study 
(primary completion) 
Defined as when the last subject is assessed or receives an intervention 
for the purposes of final collection of data for the primary endpoint(s).   
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures/assessments 
are conducted for an individual subject. 
ELN 
EOI 
European Leukemia Network 
end of infusion 
EOL-1 
human acute myeloid (eosinophilic) leukemia cell line 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 13 of 189 
CONFIDENTIAL 
 
Abbreviation or Term Definition/Explanation 
EOS 
end of study - Defined as when the last subject is assessed or receives 
an intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts 
EOT 
end of treatment - defined as the last assessment for the protocol 
specified treatment phase of the study for an individual subject 
EpCAM 
epithelial cell adhesion molecule 
eSAE 
electronic serious adverse event (form) 
FAB 
French-American-British 
Fc 
fragment crystallizable  
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FLT3 
fms-like tyrosine kinase 3 
FLT3L 
FLT3 ligand 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice(s) 
Heart rate 
number of cardiac cycles per unit of time 
HepBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C virus antibody 
HiDAC 
high-dose cytarabine 
HIV 
human immunodeficiency virus 
HLE 
half-life extended 
HLH 
hemophagocytic lymphohistiocytosis 
HNSTD 
highest non-severely toxic dose 
HSCT 
hematopoietic stem cell transplant (or transplantation) 
IB 
investigator’s brochure 
ICANS 
immune effector cell-associated neurotoxicity syndrome 
ICE 
immune effector cell-associated encephalopathy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICP 
intracranial pressure 
IDH1 
isocitrate dehydrogenase 1 
IDH2 
isocitrate dehydrogenase 2 
IEC 
independent ethics committee 
IFN  
interferon gamma 
IgG 
immunoglobulin G 


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Abbreviation or Term Definition/Explanation 
IL-1Ra 
interleukin-1 receptor antagonist 
IL-2 
interleukin-2 
IL-6 
interleukin-6 
INR 
international normalized ratio 
IRB 
institutional review board 
ISDE 
intra-subject dose escalation 
ITD 
internal tandem duplication 
IUD 
intrauterine device 
IV 
intravenous 
IVSS 
intravenous solution stabilizer 
IWG 
International Working Group 
KDM 
kinase domain mutation(s) 
LAIP 
leukemia-associated immunophenotype 
LDH 
lactate dehydrogenase 
LTFU 
long-term follow-up 
MABEL 
minimum anticipated biological effect level 
MDS 
myelodysplastic syndrome 
MLFS 
Morphologic Leukemia Free State 
MOLM-13-luc 
human acute myeloid leukemia cell line genetically-engineered to 
express luciferase 
Morphologic 
leukemia-free state 
less than 5 blasts in bone marrow without recovery of peripheral blood 
counts (see Appendix E for details) 
MPN 
myeloproliferative neoplasm 
MRD 
minimal/measurable residual disease 
MRD- 
minimal/measurable residual disease-negative 
MRD 
minimal/measurable residual disease-positive 
MRI 
contrast-enhanced magnetic resonance imaging 
MTD 
maximum tolerated dose 
NGS 
next generation sequencing 
NOD/SCID 
non-obese diabetic/severe combined immunodeficiency disease 
NPM1 
Nucleophosmin 1 
PB 
peripheral blood 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 


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Abbreviation or Term Definition/Explanation 
PK 
pharmacokinetic(s) 
PG 
Pharmacogenetic(s) 
PPD 
purified protein derivative 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it takes 
for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle as measured by 
ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology 
RP2D 
recommended phase 2 dose 
R/R 
Relapsed/refractory 
RR interval 
The time elapsed between 2 consecutive R waves as measured by ECG 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
sc 
single chain 
sFLT3 
soluble FLT3 
SCR 
Screening 
SFU 
safety follow-up 
SOC 
System Organ Class 
Source Data 
Information from an original record or certified copy of the original record 
containing information for use in clinical research.  The information may 
include, but is not limited to, clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents (original 
records or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, and 
Stratification Value. 
study day 1 
defined as the first day that protocol specified investigational 
product(s)/protocol-required therapies is/are administered to the subject 
SVR24 
sustained virologic response 24 weeks after completion of 
anti-hepatitis C treatment 
t1/2 
terminal-phase elimination half-life 
TBIL 
total bilirubin 
TEAE 
treatment-emergent adverse event(s) 
TID 
3 times a day 
TK 
toxicokinetic(s) 


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Abbreviation or Term Definition/Explanation 
TKD 
tyrosine kinase domain 
TLS 
tumor lysis syndrome 
Tmax 
time of maximum concentration 
TNF 
tumor necrosis factor 
TPI 
toxicity probability interval 
TREA 
treatment-related adverse events(s) 
ULN 
upper limit of normal 
US 
United States 
Vc 
volume of distribution of central compartment 
Vp 
peripheral volume of distribution 
WBC 
white blood cell(s) 
WFI 
Water for Injection 
WHO 
World Health Organization 
 


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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema ........................................................................... 10 
Study Glossary .............................................................................................................. 11 
TABLE OF CONTENTS ................................................................................................ 17 
1. 
OBJECTIVES ....................................................................................................... 24 
1.1 
Primary ..................................................................................................... 24 
1.2 
Secondary ................................................................................................. 24 
1.3 
Exploratory ................................................................................................ 24 
2. 
BACKGROUND AND RATIONALE ...................................................................... 24 
2.1 
Disease ..................................................................................................... 24 
2.2 
Amgen Investigational Product Background .............................................. 26 
2.2.1 
Nonclinical Pharmacology ......................................................... 27 
2.2.2 
Nonclinical Pharmacokinetics .................................................... 28 
2.2.3 
Nonclinical Toxicology ............................................................... 28 
2.2.4 
Clinical Experience With AMG 427 ............................................ 29 
2.2.5 
Clinical Experience With Other BiTE Molecules ....................... 32 
2.3 
Risk Assessment ....................................................................................... 32 
2.4 
Rationale ................................................................................................... 34 
2.4.1 
Target Rationale ........................................................................ 34 
2.4.2 
Target Population Rationale ...................................................... 35 
2.4.3 
Dose Selection Rationale .......................................................... 35 
2.5 
Clinical Hypotheses ................................................................................... 38 
3. 
EXPERIMENTAL PLAN ........................................................................................ 39 
3.1 
Study Design ............................................................................................. 39 
3.1.1 
Dose Escalation ........................................................................ 40 
3.1.1.1 
FIH Group ............................................................... 42 
3.1.1.2 
eIV Infusion Group .................................................. 46 
3.1.1.3 
MRD Group ........................................................... 47 
3.1.2 
Determination of Maximum Tolerated Dose ............................... 47 
3.1.2.1 
Maximum Tolerated Dose 1 (MTD1) ....................... 48 
3.1.2.2 
Maximum Tolerated Dose 2 (MTD2) ....................... 49 
3.1.3 
Expansion Cohort ...................................................................... 51 
3.2 
Number of Sites ........................................................................................ 51 
3.3 
Number of Subjects ................................................................................... 52 
3.4 
Replacement of Subjects .......................................................................... 52 
3.5 
Estimated Study Duration .......................................................................... 52 
3.5.1 
Study Duration for Subjects ....................................................... 52 
3.5.2 
End of Study .............................................................................. 53 


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4. 
SUBJECT ELIGIBILITY ........................................................................................ 54 
4.1 
Inclusion Criteria ....................................................................................... 54 
4.2 
Exclusion Criteria ...................................................................................... 55 
5. 
SUBJECT ENROLLMENT .................................................................................... 57 
5.1 
Treatment Assignment .............................................................................. 58 
6. 
TREATMENT PROCEDURES .............................................................................. 59 
6.1 
Classification of Product ............................................................................ 59 
6.2 
Investigational Product .............................................................................. 59 
6.2.1 
Amgen Investigational Product AMG 427 .................................. 59 
6.2.1.1 
Dosage, Administration, and Schedule .................... 60 
6.2.1.2 
Overdose ................................................................ 63 
6.2.1.3 
Dose-cohort Study Escalation and 
Stopping Rules, Dose Limiting Toxicities 
(DLTs) ..................................................................... 63 
6.2.1.4 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 65 
6.3 
Other Protocol-required Therapies ............................................................ 68 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 69 
6.4.1 
Criteria for Permanent Withholding of AMG 427 due to 
Potential Hepatotoxicity ............................................................. 69 
6.4.2 
Criteria for Conditional Withholding of AMG 427 due to 
Potential Hepatotoxicity ............................................................. 70 
6.4.3 
Criteria for Rechallenge of AMG 427 After Potential 
Hepatotoxicity............................................................................ 71 
6.5 
Concomitant Therapy ................................................................................ 71 
6.5.1 
Vaccines .................................................................................... 71 
6.6 
Specific Recommendations for Cytokine Release Syndrome, 
Immune-effector Cell-associated Neurotoxicity Syndrome,Tumor 
Lysis Syndrome and Infection Prophylaxis ................................................ 74 
6.7 
Medical Devices ........................................................................................ 85 
6.8 
Product Complaints ................................................................................... 85 
6.9 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period .................................................................................. 86 
7. 
STUDY PROCEDURES ....................................................................................... 86 
7.1 
Schedule of Assessments ......................................................................... 86 
7.1.1 
Schedule of Assessments:  Schedule B 
(etanercept substudy – CLOSED) ........................................... 100 
7.2 
General Study Procedures ...................................................................... 115 
7.2.1 
Screening ................................................................................ 116 
7.2.2 
Treatment ................................................................................ 118 
7.2.3 
End of Treatment Visit ............................................................. 119 
7.2.4 
Safety Follow-up Visit .............................................................. 120 


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7.2.5 
Long-term Follow-up ................................................................ 121 
7.3 
Description of Study Procedures ............................................................. 121 
7.3.1 
Informed Consent .................................................................... 121 
7.3.2 
Demographic Data................................................................... 121 
7.3.3 
Medical History and Prior Therapy ........................................... 121 
7.3.4 
Concomitant Medications ........................................................ 121 
7.3.5 
Physical Examination .............................................................. 122 
7.3.6 
ECOG Performance Status ..................................................... 122 
7.3.7 
Height Measurements ............................................................. 122 
7.3.8 
Weight Measurements ............................................................. 122 
7.3.9 
Vital Signs ............................................................................... 122 
7.3.10 
Pulse Oximetry ........................................................................ 123 
7.3.11 
Electrocardiogram Performed in Triplicate ............................... 123 
7.3.12 
Clinical Laboratory Tests ......................................................... 123 
7.3.13 
Events ..................................................................................... 126 
7.3.14 
Head CT or Cranial MRI .......................................................... 126 
7.3.15 
Pharmacokinetic Blood Sampling ............................................ 126 
7.7 
Pharmacogenetic Studies ....................................................................... 133 
7.8 
Sample Storage and Destruction ............................................................. 133 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 134 
8.1 
Subjects’ Decision to Withdraw ............................................................... 134 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 135 
8.3 
Reasons for Removal From Treatment or Study ..................................... 135 
8.3.1 
Reasons for Removal From Treatment .................................... 135 
8.3.2 
Reasons for Removal From Study ........................................... 136 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 136 
9.1 
Definition of Safety Events ...................................................................... 136 
9.1.1 
Adverse Events ....................................................................... 136 
9.1.2 
Serious Adverse Events .......................................................... 137 
9.1.3 
Adverse Device Effect ............................................................. 137 


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9.2 
Safety Event Reporting Procedures ........................................................ 138 
9.2.1 
Adverse Events ....................................................................... 138 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .......................... 138 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ................................................................... 139 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................. 140 
9.2.1.4 
Adverse Device Effects ......................................... 141 
9.2.1.5 
Method of Detecting Adverse Events and 
Serious Adverse Events ........................................ 141 
9.2.1.6 
Regulatory Reporting Requirements for 
Serious Adverse Events ........................................ 141 
9.2.1.7 
Safety Monitoring Plan .......................................... 142 
9.3 
Pregnancy and Lactation Reporting ........................................................ 142 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 143 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 143 
10.1.1 
Study Endpoints ...................................................................... 143 
10.1.2 
Analysis Sets ........................................................................... 144 
10.1.3 
Covariates and Subgroups ...................................................... 144 
10.2 
Sample Size Considerations ................................................................... 144 
10.3 
Adaptive Design ...................................................................................... 145 
10.4 
Planned Analyses ................................................................................... 149 
10.4.1 
Interim Analyses and Early Stopping Guidelines ..................... 149 
10.4.2 
Dose Level Review Team (DLRT) ........................................... 149 
10.4.3 
Primary Analysis ...................................................................... 150 
10.4.4 
Final Analysis .......................................................................... 151 
10.5 
Planned Methods of Analysis .................................................................. 151 
10.5.1 
General Considerations ........................................................... 151 
10.5.2 
Primary Endpoint ..................................................................... 151 
10.5.3 
Secondary Endpoints .............................................................. 152 
10.5.3.1 
Pharmacokinetics Data Analysis ........................... 152 
10.5.3.2 
Efficacy Endpoint Analyses ................................... 152 
10.5.4 
Exploratory Endpoints ............................................................. 153 
11. 
REGULATORY OBLIGATIONS .......................................................................... 153 
11.1 
Informed Consent .................................................................................... 153 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 154 
11.3 
Subject Confidentiality ............................................................................. 155 
11.4 
Investigator Signatory Obligations ........................................................... 155 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 156 
12.1 
Protocol Amendments and Study Termination ........................................ 156 
12.2 
Study Documentation and Archive .......................................................... 156 


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12.3 
Study Monitoring and Data Collection ..................................................... 157 
12.4 
Investigator Responsibilities for Data Collection ...................................... 158 
12.5 
Language ................................................................................................ 158 
12.6 
Publication Policy .................................................................................... 158 
12.7 
Compensation ......................................................................................... 159 
13. 
REFERENCES ................................................................................................... 160 
14. 
APPENDICES .................................................................................................... 165 
List of Tables 
Table 1.  Important Identified Risks of AMG 427 ............................................................ 33 
Table 2.  Important Potential Risks of AMG 427 ............................................................ 33 
Table 5.  Management of COVID-19 ............................................................................. 72 
Table 6.  Cytokine Release Syndrome Grading (ASTCT; Lee et al, 2019) ..................... 76 
Table 7.  Management of Cytokine Release Syndrome ................................................. 77 
Table 8.  ASTCT Immune Cell-associated Neurotoxicity Syndrome (ICANS) 
Consensus Grading for Adults ................................................................ 82 
Table 9.  Assessment and Supporting Care Recommendations .................................... 83 
Table 10.  Schedule of Assessments: Schedule A Cycle 1 (Days 1 and 5) .................... 88 
Table 11.  Schedule of Assessments: Schedule A Cycle 2 (Days 1 and 5) .................... 90 
Table 12.  Schedule of Assessments: Schedule A Cycle 3 and Beyond (Days 
1 and 5) .................................................................................................. 92 
Table 13.  Schedule of Assessments: Schedule A Cycle 1 (Days 1, 5, 12 and 
19) .......................................................................................................... 94 
Table 14.  Schedule of Assessments: Schedule A Cycle 2 (Days 1, 5, 12 and 
19) .......................................................................................................... 96 
Table 15.  Schedule of Assessments: Schedule A Cycle 3 and beyond 
(Days 1, 5, 12, and 19) ........................................................................... 98 
Table 16.  Schedule of Assessments:  Schedule C Cycle 1 (Days 1, 3, 5, and 
8) .......................................................................................................... 101 
Table 17.  Schedule of Assessments:  Schedule C Cycle 2 (Days 1, 3, 5, and 
8) .......................................................................................................... 103 
Table 18.  Schedule of Assessments:  Schedule C Cycle  3 (Days 1, 3, 5, 
and 8) ................................................................................................... 105 
Table 19.  Schedule of Assessments:  Schedule C- Cycle 1 (Days 1, 3, 5, 8, 
12, and 19) ........................................................................................... 107 


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Table 20.  Schedule of Assessments:  Schedule C Cycle 2 (Days 1, 3, 5, 8, 
12, and 19) ........................................................................................... 109 
Table 21.  Schedule of Assessments:  Schedule C Cycle  3 (Days 1, 3, 5, 8, 
12, and 19) ........................................................................................... 111 
Table 22.  Schedule of Assessments:  MRD Group Only - Whole Blood 
MRD Collection (Days 1, 3, 5, and 8) .................................................... 113 
Table 23.  Schedule of Assessments:  MRD Group Only – Whole Blood 
MRD Collection (Days 1, 3, 5, 8, 12, and 19) ........................................ 114 
Table 24.  List of Analytes ........................................................................................... 125 
Table 25.  Bone Marrow Collections ............................................................................ 128 
Table 26.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 80 DLT Limit of 20 ...................................................................... 146 
Table 27.  Operating Characteristics With Batch Size of 6 Subjects ............................ 146 
Table 28.  Probability of Early Stopping and the Average Sample Size in 
Dose Expansion ................................................................................... 147 
Table 29.  Probability of Early Stopping and the Average Sample Size in 
Dose Expansion ................................................................................... 147 
Table 31.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD When the Target TPI is (0.20, 0.33) ...................... 182 
Table 36.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using a 33 Design .............................................. 187 
List of Figures 
Figure 1.  A Schematic Diagram of the FLT3 Receptor Tyrosine Kinase 
Showing the Location of the Membranous 
Immune-globulin-like Loops, Internal Tandem Duplication (ITD) 
of Genes Within the Juxtamembrane Domain and Point 
Mutations and Gene Insertion in the Second Kinase Domain ................. 35 
Figure 4.  Duration of Infusion-free Interval and Timing of Bone Marrow 
Assessments .......................................................................................... 61 


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List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 166 
Appendix B.  Sample Serious Adverse Event Form and eSerious Event 
Contingency Form ................................................................................ 168 
Appendix C.  Pregnancy and Lactation Notification Forms .......................................... 171 
Appendix D.  World Health Organization Classification for Acute Myeloid 
Leukemias ............................................................................................ 173 
Appendix E.  Revised International Working Group Response Criteria  ...................... 175 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ............................................................ 178 
Appendix G.  2017 ELN Risk Stratification by Genetics ............................................... 179 
Appendix H.  Two-Parameter BLRM Design ................................................................ 180 
Appendix I.  Protocol-specific Anticipated Serious Adverse Events ............................. 189 
 


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1. 
OBJECTIVES 
1.1 
Primary 
The primary objectives of this study are to: 
 
Evaluate the safety and tolerability of AMG 427 in adult subjects with 
relapsed/refractory (R/R) acute myeloid leukemia (AML) or minimal/measurable 
residual disease-positive (MRD) AML 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically optimal dose 
(eg, recommended phase 2 dose [RP2D]) 
 
Evaluate the safety and tolerability of extended intravenous (eIV) administration of 
AMG 427. 
1.2 
Secondary 
The secondary objectives of this study are to: 
 
Characterize the pharmacokinetics (PK) of AMG 427 
 
Evaluate the anti-leukemia activity of AMG 427  
1.3 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults in 
the United States (US), with a rising incidence possibly due to an aging population, 
increased environmental exposure (eg, ionizing radiation), and an increase in the 
population of cancer survivors previously exposed to chemotherapy and therapeutic 
radiation.  In 2020, an estimated 19 940 new cases of AML were expected in the US with 
approximately 11 180 deaths from this disease (American Cancer Society, 2020).   


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The general therapeutic strategy in patients with AML has not changed substantially in 
more than 30 years (Dohner et al, 2010) although 8 new drugs were approved by the US 
Food and Drug Administration (FDA) in 2017 and 2018 for various subsets of AML 
patients (Mylotarg USPI, Rydapt USPI, Idhifa USPI, Vyxeos USPI, Tibsovo USPI, 
Xospata UPSI, Daurismo USPI, Venclexta USPI).  These therapies have added to the 
therapeutic options for patients with AML, especially those bearing mutations that can be 
targeted with these novel agents (eg, FLT3 tyrosine kinase domain [TKD], isocitrate 
dehydrogenase 2 [IDH2] mutation); however, only a small subset of AML patients bear 
these mutations.  AML is cured only in 35 to 40 of adult patients who are 60 years of 
age or younger and in 5 to 15 of patients who are older than 60 years of age 
(Dohner et al, 2010).  Although the majority of patients with AML initially achieve 
complete remission (CR), over 60 will eventually relapse after a variable period of 
remission.  The relapse of AML, particularly early after a hematopoietic stem cell 
transplant (HSCT), is challenging to manage (de Lima et al, 2014).  Only 20 to 30 of 
patients can achieve durable remissions after reinduction in the relapsed setting and the 
rate of survival after relapse is poor (Dohner et al, 2015).  In addition, approximately 
one-third of patients younger than 60 years with newly diagnosed AML fail to achieve 
CR after induction therapy (Buchner et al, 2012).  For these resistant patients, 
chemotherapy alone does not offer any chance of cure (Estey, 2000).  For example, 
patients with AML refractory to 1 course of a high dose cytarabine (HiDAC) containing 
regimen have a median overall survival of only 3.8 months (Ravandi, 2013).  Patients 
whose initial CR duration is more than 1 year have been traditionally treated with 
HiDAC-containing salvage regimens but only a minority achieve a second CR and many 
are not candidates for a potentially curative allogeneic HSCT performed in second CR 
(Estey, 2000).  Apart from the duration of first CR, other predictors of outcome in first 
relapse include age, cytogenetics, and whether the patient received an allogeneic HSCT 
in the first CR (Breems et al, 2005).  However, in the study reported by 
Breems et al (2005), only a minority of patients with AML in first relapse had a 
successful long term outcome and the long term prognosis of the majority of patients 
with relapsed or refractory AML remains dismal. 
For patients with AML who achieve CR, relapsed disease remains the primary obstacle 
to long-term survival.  Consolidation therapy and allogeneic HSCT decrease the risk of 
relapse for many patients, but rates of relapse still remain high, and overall survival 
ranges from 2-15 for those with intermediate and adverse-risk genetics (Döhner et al, 


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2017).  Furthermore, due to patient performance status and comorbidities, many AML 
patients are not eligible for allogeneic HSCT, leaving a subset of patients with no further 
treatment options (Döhner et al, 2017).  
Minimal/measurable residual disease-positive is a proven risk factor for relapse and poor 
survival in patients with ALL (Richard-Carpentier et al, 2019), and this concept is quickly 
gaining wider acceptance in the AML community (Buccisano et al, 2018).  As 
minimal/measurable residual disease (MRD) methods and procedures become more 
harmonized, this post-treatment "biomarker" may lead to significantly more accurate 
prognostic assessment in AML (FDA Guidance, 2020), with greater predictive and 
prognostic power than currently available molecular genetic markers (Buccisano et al, 
2018).  As such, the National Comprehensive Cancer Network Guidelines recommend 
MRD testing after induction therapy 
(www.nccn.org/professionals/physician_gls/pdf/aml_blocks.pdf), and the European 
LeukemiaNet endorses the achievement of MRD-CR, noting the strong correlation 
between MRD negativity and increased survival (Schuurhuis et al, 2018). 
Unlike for ALL patients, where blinatumomab is effective at converting MRD status and 
prolonging survival (Jen et al, 2019), no approved MRD treatment options exist for AML 
patients.  When combined with the large proportion of AML patients who are 
HSCT-ineligible, a significant unmet medical need exists for this group.  For AML 
patients, several clinical trials are currently underway in order to determine additional 
frontline, MRD, and maintenance therapies, that will reduce relapse rates.  These 
include chimeric antigen receptor T-cell (CAR-T) and other cell-based therapies 
(NCT03190278), mutation-specific targeted small molecules (NCT03070093, 
NCT02927262, NCT03850535, NCT03515512, NCT03728335), other small molecules 
(NCT00387647, NCT02126553, NCT00350818), chemotherapy (NCT02349178), and an 
anti-CD33 antibody-drug conjugate (NCT03705858). 
2.2 
Amgen Investigational Product Background  
AMG 427, which targets FLT3 and engages host T cells via cluster of 
differentiation 3 (CD3) binding, is an FDA-designated FastTrack novel bispecific T cell 
engager (BiTE) molecule intended to treat patients with AML.  AMG 427 is a half-life 
extended (HLE) BiTE molecule combining the binding arms for FLT3 and CD3 
genetically fused to the N-terminus of a single chain (sc) immunoglobulin G (IgG) Fc 
(fragment crystallizable; scFc) region.  The anticipated terminal half-life of AMG 427 in 
humans is expected to be approximately 5 days.  This key HLE modification, designed to 


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maintain efficient FLT3 dependent target cell killing, should permit intermittent short IV 
infusions to be delivered over a course of several days up to 2 to 3 weeks. 
In addition to AMG 427, Amgen is developing other novel BiTE molecules that target 
different antigens for the treatment of patients with AML. 
Refer to the specific section of the AMG 427 investigator’s brochure (IB) for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulation(s). 
2.2.1 
Nonclinical Pharmacology 
In vitro Pharmacology: 
The activity of AMG 427 requires the simultaneous binding to FLT3 cells and T cells.  
The pharmacological effect of AMG 427 is mediated by specific redirection of cytotoxic 
CD8 or CD4 T lymphocytes to kill FLT3-expressing cells.  AMG 427 is a potent 
molecule showing half maximal-lysis (EC50) of FLT3-expressing tumor cell lines by 
human T cells in vitro over a range from 2.24 to 12.03 pM. 
As part of the T cell activation process, BiTE molecules, such as AMG 427, cause the 
formation of a cytolytic synapse between T cells and target cells, which has been 
exemplified for an EpCAM-specific BiTE molecule.  The subsequent release of the 
pore-forming protein perforin and the apoptosis-inducing proteolytic enzyme granzyme B 
by T cells results in the induction of apoptosis in the target cells (Offner et al, 2006). 
In serum of AML patients, elevated levels of soluble FLT3 (sFLT3) were observed 
(Ravandi et al, 2007).  Although maximal AMG 427-mediated redirected lysis was not 
affected in vitro, EC50 values of dose-response curves of cytotoxicity and T cell activation 
were higher in the presence of physiologically relevant sFLT3 concentrations.  In the 
absence of membrane bound FLT3, sole binding of sFLT3 to AMG 427 was not 
sufficient to induce T cell activation.  
In addition, FLT3 ligand (FLT3L) has been detected in serum of AML patients 
(Sato et al, 2011; Zwierzina et al, 1999).  In in vitro cytotoxicity assays, maximal target 
cell lysis was not affected by recombinant FLT3L, however, EC50 values calculated for 
AMG 427 dose-response curves of target cell lysis and T cell activation increased in the 
presence of recombinant FLT3L.   
The efficacy of AMG 427 was also evaluated in bone marrow aspirates obtained from an 
AML patient comprising FLT3 leukemic cells, but no autologous T cells.  


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AMG 427 induced a dose-dependent decrease of viable leukemic cells in co-cultures 
with allogeneic T cells isolated from a healthy donor.   
AMG 427-induced T cell activation not only caused redirected lysis of FLT3 cells, but 
also resulted in a transient production of inflammatory cytokines like tumor necrosis 
factor (TNF), interferon gamma (IFN ), interleukin-2 (IL-2), and interleukin-6 (IL-6) by 
T cells.  In addition, in vitro studies also demonstrated that cytokine release by 
AMG 427-activated T cells is attenuated by corticosteroids, which is accompanied by a 
slight reduction in cytotoxic potency. 
In vivo Pharmacology: 
Orthotopic mouse xenograft models using human MOLM-13-luc and EOL-1 AML tumor 
cell lines were used for the evaluation of the nonclinical in vivo efficacy of 
AMG 427 (Studies 124021 and 125009).  The AML cell lines were intravenously (IV) 
injected into the lateral tail vein of nonobese diabetic/severe combined 
immunodeficiency (NOD/SCID) mice.  Since AMG 427 does not recognize mouse CD3, 
the NOD/SCID mice were intraperitoneally injected with human T cells before treatment 
start.  AMG 427 monotherapy significantly prolonged of mice bearing established 
orthotopic MOLM 13-luc or EOL 1 tumors. 
2.2.2 
Nonclinical Pharmacokinetics 
The PK and toxicokinetics (TK) of AMG 427 were characterized in cynomolgus 
monkeys.  After intravenous (IV) bolus injection, serum concentrations of 
AMG 427 declined in a bi-phasic manner.  The maximum serum concentration (Cmax) 
and area under the concentration-time curve (AUC) were approximately dose 
proportional from 
 g/kg. 
The human PK parameters of AMG 427 were predicted using allometric scaling of PK 
parameters obtained from cynomolgus monkeys.  A 2‑compartment model with linear 
elimination was used to characterize the AMG 427 PK from the pooled data with doses 
ranging between 
 g/kg.  The model was parameterized using linear clearance 
(CL), volume of distribution of central compartment (VC), intercompartmental distribution 
rate (CLD), and peripheral volume of distribution (VP).   
2.2.3 
Nonclinical Toxicology 
The nonclinical safety assessment of AMG 427 was based on a 28-day cynomolgus 
monkey repeat dose IV injection study.  The cynomolgus monkey was selected as the 
toxicology species based on target binding affinity and bioactivity data similar to human.  


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Flat doses of 
 g/kg were administered on days 1, 5, and once weekly thereafter.  
Vehicle control or a step dose of 
 g/kg was administered on days 1 ( g/kg), 
5 (
 g/kg), 8 (
 g/kg), 12 (
 g/kg), and once weekly thereafter (
 g/kg).  
The flat dose regimen of  g/kg and the step dose regimen of 
 g/kg showed 
no adverse effects.  Results in these animals and in animals administered the flat dose 
of 
 g/kg that survived to the end of the study were consistent with expected 
AMG 427 pharmacology (cytotoxic T cell redirected lysis of FLT3-expressing bone 
marrow hematopoietic stem and progenitor cells).  AMG 427-related changes on 
days 1 and/or 2 were consistent with AMG 427-mediated T cell activation and included 
elevated heart rate, transient increases in cytokine levels, decreased circulating 
leukocytes, and clinical chemistry changes suggestive of an acute phase response.  At 
the end of the study, decreased bone marrow cellularity, decreased white blood cells, 
decreased neutrophils, decreased red blood cell mass associated with attenuated or 
decreased reticulocytes, and decreased platelets were observed.  Increased bone 
marrow cellularity and lymphoid germinal center cellularity in lymph nodes and/or spleen 
were attributed to a regenerative response following initial activity of 
 
  Administration of the flat dose regimen of 
 g/kg resulted in mortality in 
5 out of 10 animals on days 18 to 26.  
 
 
.  Decreased bone marrow cellularity was consistent with expected 
AMG 427 pharmacology (cytotoxic T cell redirected lysis of FLT3 expressing bone 
marrow hematopoietic stem and progenitor cells) and bacteremia was secondary to the 
decrease in myeloid cells and subsequent decreased innate immunity.
 
 
 
 
 
 
Thus, the highest non-severely toxic dose (HNSTD) for the flat dose regimen is  g/kg 
and the HNSTD for the step-dose regimen (
) is 
 g/kg.   
2.2.4 
Clinical Experience With AMG 427 
As of the 26 July 2021 data cutoff, a total of 54 subjects with R/R AML were 
enrolled in the first-in-human (FIH) Amgen Study 20170528.  Of the 54 subjects, 


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there were 53 subjects who received at least 1 dose of AMG 427 or etanercept 
(51 subjects received AMG 427 and 10 subjects received etanercept including 
2 subjects who received etanercept only).  One subject enrolled in cohort 
 was 
treated with AMG 427 but did not have exposure data entered into the database by 
the data cutoff date and was therefore not included in the Safety Analysis Set.  
Summary of Safety Findings:  Fifty-three subjects (100) who received at least 
1 dose of AMG 427 or etanercept had treatment-emergent adverse events.  
Adverse events by preferred term reported for  20.0 of subjects were cytokine 
release syndrome (42 subjects [79.2]); hypokalemia and pyrexia (13 subjects 
each [24.5]), febrile neutropenia (12 subjects [22.6]), and hypomagnesemia 
(11 subjects [20.8]).  Grade  3 treatment-emergent adverse events were 
reported for 46 subjects (86.8).  The grade  3 adverse events reported in 
 2 subjects included anemia (4 subjects [11.8]); febrile neutropenia (7 subjects 
[20.6]); white blood cell count decreased (4 subjects [11.8]); bacteremia, 
sepsis, sinusitis, hypophosphatemia (3 subjects [8.8] each); and leukocytosis, 
pancytopenia, cytokine release syndrome, pneumonia, alanine aminotransferase 
increased, lipase increased, white blood cell count increased, hypokalemia, acute 
myeloid leukemia, epistaxis, respiratory distress, and respiratory failure 
(2 subjects [5.9]).  Treatment-emergent serious adverse events were reported for 
34 subjects (64.2).  Preferred terms for these serious adverse events reported for 
 1 subjects were cytokine release syndrome (8 subjects [15.1]), acute myeloid 
leukemia and febrile neutropenia (5 subjects [9.4] each), pneumonia (3 subjects 
[5.7]), and sepsis, septic shock, sinusitis, leukocytosis, respiratory distress, 
decreased platelet count, and decreased white blood cell count (2 subjects [3.8] 
each).  Eleven subjects (20%) had treatment-emergent fatal adverse events of 
acute myeloid leukemia (2 subjects each), anemia, bacillus infection, cytokine 
release syndrome, fungal sinusitis hemophagocytic lymphohistiocytosis (HLH), 
intracranial hemorrhage, pneumonia, respiratory distress, and respiratory failure 
(1 subject each). 
Overall, 42 (79.2%) of the 53 subjects exposed to AMG 427 or etanercept reported 
1 or more adverse events of CRS.  No subjects enrolled in cohorts 
 
reported any adverse events of CRS, while at least 1 subject in each of the 
remaining cohorts (target and step dosing) reported 1 or more adverse events of 


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CRS.  Most subjects reported low grade (grade 1 or grade 2) CRS.  Subject 
incidence of grade 1 or grade 2 CRS was 6 (11.3%) and 31 (58.5%), respectively.  
Four (7.5%) subjects reported grade 3 CRS (1 subject in cohort  after receiving a 
day 1 dose of 
 µg, 1 subject in cohort 
 after receiving a day 1 dose of 
 µg, 
1 subject in cohort 
 after receiving a day 5 dose of 
 µg, and 1 subject in the 
etanercept substudy cohort ) and a single (1.9%) subject had a grade 5 (fatal) 
CRS event (1 subject in cohort 
 after receiving a day 5 dose of 
 µg).  
Eight (15.1%) events of CRS were considered serious adverse events.  Subject 
incidence of adverse events of CRS leading to hospitalization in the intensive care 
unit (ICU), interruption of AMG 427, or discontinuation of AMG 427 were 4 (7.5%), 
4 (7.5%), and 2 (3.8%) subjects, respectively.  Please refer to the AMG 427 
Investigator’s Brochure for additional details. 
A fatal case of ‘possible HLH’ was reported in the AMG 427 etanercept substudy.  
The fatal event was reported in a 
-year-old male with refractory AML.  No 
confirmatory bone marrow biopsy for HLH, or autopsy was performed.  The 
subject had multiple confounding factors for the diagnosis of HLH.  The subject’s 
ferritin was elevated (4902 µg/dL) 5 days prior to starting AMG 427, and 3 days 
prior to starting etanercept.  Hemophagocytic lymphohistiocytosis can also be 
caused by infection; the subject had worsening neutropenia, although no 
additional cultures were reported.  Hemophagocytic lymphohistiocytosis is known 
to occur in approximately 9% of patients with AML after intensive induction 
therapy (Delavigne et al, 2014).  There is a possible contributory role for 
etanercept and tocilizumab in this case.  Macrophage activation syndrome is 
listed as an adverse reaction for Enbrel (Enbrel® USPI, 2017 [Section 6.3 
Postmarketing Experience]) and events of macrophage activation syndrome 
occurred in patients treated with tocilizumab (Actemra® USPI, 2021 [Section 6.7 
Clinical Trials Experience]). 
Refer to the Investigator’s Brochure for additional detail on these safety findings.  
Summary of efficacy findings:  Best overall response observed to date included 
1 subject in cohort 
 µg) achieving CR, a second subject in 
cohort 
 µg) achieving CR with incomplete recovery of peripheral 
blood counts (CRi) with MRD negativity by flow cytometry, and 4 subjects 
achieving Morphologic Leukemia Free State (MLFS):  1 subject each in cohort  
 µg), cohort 
 µg), cohort 
 µg) and 


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cohort 
 µg).  Please refer to the Investigator’s Brochure for 
additional details. 
2.2.5 
Clinical Experience With Other BiTE Molecules 
BiTE molecules exert a unique but also uniform mechanism of action independent from 
their respective target.  Consequently, experiences with other BiTE molecules are 
regarded as being relevant for AMG 427.   
Most clinical experience exists with a BiTE molecule called blinatumomab (specificity 
for CD3 and cluster of differentiation 19 [CD19]) which has shown that administration of 
a BiTE by continuous IV (cIV) infusion can be performed with an acceptable safety 
profile and leads to improvement in overall survival in subjects with late-stage 
hematological malignancies (Kantarjian et al, 2017).  Blinatumomab is approved in the 
US under the tradename Blincyto for the treatment of relapsed or refractory B cell 
precursor acute lymphoblastic leukemia (ALL) and MRD-positive B-ALL (Blincyto USPI).  
The most common adverse reactions ( 20) are infections, pyrexia, headache, 
infusion- related reactions, anemia, febrile neutropenia, thrombocytopenia, and 
neutropenia.  In addition, Amgen is testing 2 BiTE molecules targeting cluster of 
differentiation 33 (CD33) in active clinical development in patients with AML. 
2.3 
Risk Assessment 
FLT3 is a transmembrane tyrosine kinase that stimulates survival and proliferation of 
blasts (Daver and Kantarjian, 2017).  AMG 427 targets FLT3 on AML cells and CD3 on 
host T cells.  
Based on the mode of action targeting membranous FLT3 and clinical observations with 
AMG 427 and other BiTE molecules developed in hematological malignancies, adverse 
events such as CRS, cytopenia, hemorrhage, tumor lysis syndrome (TLS), and infection 
are anticipated with the administration of AMG 427.  Neurotoxicity has been observed 
with the administration of blinatumomab (CD19 BiTE).  For a listing of important 
potential and identified risks for AMG 427 refer to Table 1 and Table 2 below.  See also 
Section 6.6 for specific recommendations for CRS grading and management, TLS, and 
infection prophylaxis.  
Please refer to the AMG 427 Investigator’s Brochure for further description of potential 
risks. 


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Table 1.  Important Identified Risks of AMG 427 
Risk 
Description 
Cytokine Release 
Syndrome 
(CRS)/Infusion 
Reactions 
Cytokine release is an anticipated consequence of T cell 
engagement induced by AMG 427.  Serious events of cytokine 
release syndrome, including a fatal event, have been reported in 
subjects receiving AMG 427.  Cytokine release syndrome is 
characterized by a massive release of cellular cytokines, which can 
have profound effects on blood pressure, vascular integrity, 
neurologic function, and heart, lung, liver, and kidney functions. 
Signs and Symptoms may include the following: 
 
constitutional - fever, rigors, fatigue, malaise 
 
neurologic - headache, mental status changes, dysphasia, 
tremors, dysmetria, gait abnormalities, seizure 
 
respiratory - dyspnea, tachypnea, hypoxemia 
 
cardiovascular - tachycardia, hypotension 
 
gastrointestinal - nausea, vomiting, transaminitis, 
hyperbilirubinemia 
 
hematology - bleeding, hypofibrinogenemia, elevated D-dimer 
 
skin – rash 
Potentially life-threatening complications of cytokine release 
syndrome include cardiac dysfunction, adult respiratory distress 
syndrome, neurologic toxicity, renal and/or hepatic failure, and 
disseminated intravascular coagulation (Lee et al, 2014). 
Infusion reactions may be clinically indistinguishable from manifestations 
of CRS 
Table 2.  Important Potential Risks of AMG 427 
Risk 
Description 
Cytopenia 
Transient myelosuppression including reductions in circulating 
neutrophils, platelets, and red cell mass  
Hemorrhage 
Bleeding complications, such as disseminated intravascular coagulation 
syndrome, are due to the massive intravascular activation of blood 
coagulation with consumption of clotting factors and platelets, leading to 
severe hemorrhages. 
Tumor lysis 
syndrome 
Complications caused by the breakdown products of dying cancer cells 
may include hyperkalemia, hyperphosphatemia, hyperuricemia, 
hyperuricosuria, and hypocalcemia, potentially causing lethal cardiac 
arrhythmias, seizures, and/or renal failure. 
Infections 
Immunocompromised patients are susceptible to both common 
community-acquired and opportunistic infections.  Subjects who have 
neutropenia for 7 days or more are at a high risk for infectious 
complications. 
Neurotoxicity 
A wide range of commonly observed neurological symptoms otherwise 
recognized as immune effector cell-associated neurotoxicity 
syndrome (ICANS) have been associated with the use of blinatumomab 
(anti-CD19 BiTE molecule) in patients with R/R ALL and included 
tremor, dizziness, encephalopathy, paresthesia, aphasia, and confusional 


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Risk 
Description 
state.  The majority of these events occurred during the first cycle.  In 
patients with AML, leptomeningeal involvement is expected to be much 
less frequently observed ( 3) than in patients with ALL. 
See also Section 2.2.3 for nonclinical safety observations.   
2.4 
Rationale 
2.4.1 
Target Rationale 
FMS-like tyrosine kinase 3 (FLT3)/cluster of differentiation 135 (CD135) is a member of 
the class III receptor tyrosine kinases and a type 1 transmembrane protein that plays an 
essential role in normal hematopoiesis.  An internal tandem duplication (ITD) of base 
pairs within the juxtamembrane coding portion or point mutations in the second kinase 
domain (KDM) result in constitutive activation of the gene in AML patients.  However, 
only about 1/3rd of AML patients harbor these mutations, which can be targeted by 
recently approved FLT3 inhibitor midostaurin (Figure 1).  In contrast, the immunoglobulin 
like loop expressed on the cell surface is expressed on more than 80 of leukemia 
isolates from patients with AML (Goldstein et al, 2017, Meshinchi et al, 2009, 
Rosnet et al, 1996), providing a useful target antigen for the treatment of patients with 
AML.  FLT3 transcripts are universally detectable in AML blasts with graded expression 
in distinct FAB (French-American-British) subtypes (Ozeki et al, 2004, 
Kuchenbauer et al, 2005).  Higher FLT3 transcript levels correlate with higher leukocyte 
counts and higher degrees of bone marrow infiltration by leukemic cells, independent 
from the presence of FLT3 mutations (Kindler et al, 2010).  FLT3 is also expressed on 
myeloid, lymphoid and dendritic cell progenitors and is considered an important growth 
and differentiation factor for several hematopoietic lineages (Tsapogas et al, 2017).  It is 
expressed by a fraction of the normal pluripotent hematopoietic stem cells  
(Rosnet et al, 1996).  Targeting membranous FLT3 via CAR-T cell therapy is currently 
being explored by several groups (Chen et al, 2017, Jetani et al, 2018).  


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Figure 1.  A Schematic Diagram of the FLT3 Receptor Tyrosine Kinase Showing 
the Location of the Membranous Immune-globulin-like Loops, Internal Tandem 
Duplication (ITD) of Genes Within the Juxtamembrane Domain and Point 
Mutations and Gene Insertion in the Second Kinase Domain 
 
2.4.2 
Target Population Rationale 
Target population rationale is described in the background (Section 2.1) and target 
rationale (Section 2.4.1) sections. 
2.4.3 
Dose Selection Rationale 
The planned doses of AMG 427 in this study are 
 
 g.  AMG 427 will be administered 
as single, short IV infusions (eIV infusion may apply) on D1/D5 or D1/D3/D5/D8 of a 
14-day treatment cycle, in which the second dose on day 3 or 5 may be the same or 
higher than the dose on day 1.  Based on observed safety and tolerability, the day 
1 dose may be established as a run-in dose (ie, MTD1), while day 3, 5, or 8 doses may 
be subsequently escalated.  Based on clinical experience from a CD33-targeting BiTE 
for R/R AML, the day 1 dose is unlikely to have anti-leukemic effect and will be used 
primarily to mitigate the risk of cytokine release syndrome following initiation of treatment 


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or exposure to higher concentrations of AMG 427 that are more likely to have anti-
leukemic activity.   
The proposed starting dose of AMG 427 in the FIH study is 
 g.  This was based on 
the predicted human dose necessary to provide a maximum serum concentration 
approximating 0.104 ng/mL, the mean in vitro EC50 of AMG 427-mediated 
CD69-upregulation, and is anticipated to have limited pharmacological activity.  
AMG 427 human PK profiles and exposures were predicted using a 2-compartment 
model with linear elimination from the central compartment.  Human PK parameters 
were scaled using allometry from estimated PK parameters in cynomolgus monkey 
studies described in Section 2.2.2.  Based on predicted AMG 427 PK, a starting dose of 
 g following a short IV infusion (approximately 30 minutes to 1 hour) is predicted to 
achieve maximum serum concentrations approximating the mean EC50 of 
AMG 427 mediated CD69-upregulation in MOLM-13 cells (MABEL; 0.104 ng/mL).  Of 
note, soluble FLT3 concentrations in the ranges observed in serum of AML patients 
(up to 140 ng/mL) did not have a significant effect on the predicted maximum serum 
concentrations of AMG 427 (within 2-fold) and were not used in the selection of the FIH 
starting dose.  The use of the EC50 as the MABEL and basis for the FIH starting dose is 
supported by the previous and safe implementation of this strategy to identify the 
maximum recommended starting doses of previous bi-specific CD3-targeting molecules 
in clinical development (Saber et al, 2017). 
Additionally, mean AUC from time zero to 72 hours (AUC72h) and Cmax exposures 
achieved at the HNSTD of the flat dose regimen of  μg/kg in the 28-day toxicology 
study in cynomolgus monkeys were approximately 47-fold and 119-fold greater than 
human AUC from time 0 to 336 hours (AUC336h) and Cmax exposures predicted at the 
 μg starting dose, respectively, after correction for a 10-fold lower potency in 
cynomolgus monkey effector cells.  Of note, relative to the step-dose regimen of  g/kg 
on day 1 followed by a step up to 
 g/kg on day 5, and another step up to 
 g/kg 
on day 8 and onwards (
 g/kg) also evaluated in the 28-day toxicology study, 
AUC72h and Cmax exposures were approximately 6950-fold and 6180-fold greater than 
human exposure predictions, after a 10-fold potency correction (Table 3). 
Subsequent planned escalations in AMG 427 dose up to 
 g are shown in Table 3.  
At the highest planned clinical dose of 
 g, the ratio of mean AUC72h and Cmax 
exposures achieved at the  g/kg HNSTD in the 28-day toxicology study in cynomolgus 


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monkeys and predicted human AUC336h and Cmax exposures were approximately 
, respectively, after a 10-fold potency difference in human and cynomolgus 
monkey effector cells (ratio of mean AUC72h and Cmax exposures achieved at the 
 g/kg HNSTD in the 28-day toxicology study were approximately 
 and 
 respectively, after potency correction). 
Minimally efficacious exposures of AMG 427 were estimated based on the in vitro 
assessments of AMG 427 activity.  Based on the assessment of individual 
dose-response curves of AMG 427-mediated cell cytotoxicity in 7 different 
FLT3-expressing AML cell lines, a median EC90 of 12.1 pM (1.3 ng/mL) was calculated.  


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An AMG 427 dose of 
 g is predicted to provide trough coverage of the EC90 following 
day 1 and day 5 administration and is expected to achieve anti-leukemic effect.  As FLT3 
expression is heterogenous between different AML patients, AMG 427-mediated 
cytotoxicity in the least sensitive cell line (KG-1 cells) was also used to establish a 
conservative prediction of efficacy.  Based on a mean EC90 of cell cytotoxicity in 
KG-1 cells (35.83 pM; 3.8 ng/mL), an AMG 427 dose of 
 g is predicted to be 
efficacious.  Collectively, minimally efficacious exposures of AMG 427 are predicted at 
doses of 
 g, following once weekly administration. 
As of 26 July 2021, 53 subjects have been treated, 51 at AMG 427 doses ranging from 
 g in the ongoing FIH study, and 2 subjects only receiving etanercept 
(Enbrel).  Clinical data show an acceptable safety profile up to doses of 
 g and 
preliminary PK analysis suggests dose-related increases in AMG 427 Cmax and AUC 
across the dose range evaluated.  The emerging clinical data from the ongoing FIH 
study support the exploration of additional dose levels and regimens to determine the 
MTD for AMG 427.  Additional doses and regimens of 
 
 g will be explored in the dose escalation part of the study. 
The eIV infusion group will enroll the first subjects, as eIV infusion is predicted to 
be the safest and most conservative dosing regimen (please see 
Section 3.1.1.2.1-Justification for eIV Investigational Product Dose).  Two to 
4 subjects will be initially enrolled for the 
 cohort.  Overall, the dosing regimen 
will be as follows: 
 
Day 1 and 2:  eIV infusion of 
 µg (over approximately 48 hours)  
 
Day 3:  eIV infusion of 
 µg (over approximately 24 hours)  
 
Day 5:  short IV infusion of 
 µg (over approximately 90 minutes) 
 
Day 8:  short IV infusion of 
 µg (over approximately 90 minutes) 
After Dose Level Review Team (DLRT) determines that the 
 µg target dose 
level and dosing route achieves an acceptable safety profile, then DLRT can 
recommend dose escalation and opening of additional experimental groups as 
described below. 
2.5 
Clinical Hypotheses 
AMG 427 will demonstrate evidence of anti-leukemic activity at a safe and well-tolerated 
dose in subjects with MRD or R/R AML. 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a FIH, open-label, phase 1 dose escalation study.  AMG 427 will be evaluated as 
a short-term IV infusion (eIV infusion may apply) in adult subjects with MRD or R/R 
AML.  The study will be conducted at approximately 15 sites in the US, Australia, 
Canada, Japan, South Korea, and Germany.  Additional countries or sites may be added 
later. 
The study will consist of up to a 14-day screening period, a treatment period, a safety 
follow-up period (SFU), and a long-term follow-up (LTFU) period (for subjects enrolled in 
the dose expansion phase only).   
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) of AMG 427 in subjects with MRD or R/R AML using a 
Bayesian logistic regression model (BLRM:  Neuenschwander et al, 2008).  Planned 
dose levels (dose per infusion) for the dose-escalation cohorts are as follows:  
 
 g 
(Table 4).  Additionally, an option for cohort escalation will be available for confirming the 
safety in Japanese population, at sponsor discretion, for up to a maximum of 6 subjects.  
The sponsor will notify Japanese sites, if applicable, when the extended slots for a 
cohort are open for enrollment (after the Dose Level Review Team [DLRT] has 
confirmed the dose level is safe).  The study will consist of 3 groups: 
 
FIH Group:  AMG 427 administered as short term IV infusions in R/R AML 
subjects.   
 
(CLOSED) Etanercept (Enbrel) substudy:  Etanercept will be administered for 
CRS prophylaxis 2 days prior to each cycle of AMG 427 short term IV infusions in 
R/R AML subjects in the US.  (Etanercept may be implemented to FIH expansion 
groups based on emerging data). 
 
eIV Infusion Group:  AMG 427 eIV infusions administered on days 1 and 2, and 3, 
with short term IV infusions on days 5 and 8 in R/R AML subjects.  (eIV infusion may 
be implemented to FIH expansion groups based on emerging data). 
 
MRD Group:  AMG 427 administered in short term IV infusions in MRD AML 
subjects. 


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At completion of the dose escalation cohorts, additional subjects (approximately 
90 subjects, with approximately 40 subjects in the FIH cohorts and 50 subjects in the 
MRD groups) will be enrolled in a dose expansion cohort to gain further clinical 
experience, safety, and efficacy data in subjects with AMG 427.  
3.1.1 
Dose Escalation 
The study will have 3 alternative dosing schedules:  
 
(CLOSED) Schedule A  
 
D1/D5 or D1/D5/D12/D19 (dexamethasone prophylaxis) 
 
(CLOSED) Schedule B:  Etanercept Substudy (R/R AML) 
 
D1/D5 or D1/D5/D12/D19 (etanercept 2 days prior to each cycle).   
The etanercept substudy used etanercept 2 days prior to infusion of each cycle 
D1, and if applicable, 2 days prior to infusion on D12.  
 
 
 
Schedule C (Table 16 through Table 21):  FIH, eIV (R/R AML); MRD Group 
(MRD AML) 
 
D1/D3/D5/D8 or D1/D3/D5/D8/D12/D19 (dexamethasone prophylaxis) 
Note: 
 
The MRD group will use Schedule C for all cycle collections and Table 22 for 
additional whole blood MRD collection, or Table 23, as applicable. 
The initial cohort will begin with Schedule A and will receive 2 doses (1 each on D1 and 
D5).  After reviewing the emerging PK, safety and efficacy data, the DLRT may 
recommend the administration of additional doses on D3 and D8, to comprise a 2-week 
cycle with doses on D1/D3/D5/D8 (Schedule C). 
Additionally, if the following conditions are met, the DLRT may recommend the 
administration of 2 additional doses (D12 and D19):  
 
the 2-4 dose regimen (D1/D5 and/or D1/D3/D5/D8) is deemed safe and tolerable 
 
it is determined from the observed AMG 427 exposures that AMG 427 is rapidly 
cleared and/or distributed (ie, its observed half-life is much shorter than its predicted 
half-life) 
 
efficacy (based on clinical data and pharmacodynamic markers eg, clearance of 
FLT3 blasts in the blood and/or bone marrow) is observed but is not sustained and 
addition of D12 and D19 doses may improve the duration or depth of response 
Once the DLRT recommends additional doses, all subsequent cohorts will be treated 
with a 4 or 6 dose regimen in each cycle.  The additional doses (if applicable), may be at 


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the same dose as the preceding dose or may be at higher doses (dose step).  A dose 
step is any dose that is higher for a given subject than the subject has previously 
received.  Dose steps may occur at D3, D5, D8, D12, or D19 infusions. 
Starting with an initial lower dose may improve tolerability of subsequently administered 
higher doses due to initial reduction of the bulk of blast cells, thereby improving efficacy.  
The DLRT will recommend an initial lower dose, which will not be higher than dose 
which triggered a DLT.  For a schematic overview of the different dose step options see 
Figure 2 below. 
Administration of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 hour 
prior to start of AMG 427 dose on days 1, 3, 5, and 8 and prior to each dose step of 
AMG 427, to mitigate CRS, is mandatory.  There is a  1-3 day window for dosing visits. 
Other dose level(s) of dexamethasone may be evaluated as necessary.   
All other dosing rules, including dose limiting toxicities and treatment interruption, 
withholding, rechallenge, and permanent discontinuation apply as stated in 
Sections 6.2-6.6. 
The estimate of the MTD(s), or the estimate of each MTD if step dosing is used, will use 
the BLRM design.  Dose escalation will proceed using 2 parts:  single subject cohorts 
and multiple subject cohorts. 


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3.1.1.1 
FIH Group 
The FIH group will evaluate AMG 427 administered as a short-term IV infusion in adult 
subjects with R/R AML.  In escalation, approximately 90 subjects with R/R AML will be a 
part of FIH cohorts 
 (Table 4).  Approximately 25 subjects with R/R AML will 
receive etanercept for CRS prophylaxis 2 days prior to their cycle and follow guidance 
below.  The option for group extension may be available, either at sponsor 
discretion or if recommended by the DLRT based on the review of the emerging 
safety data.  The sponsor will notify sites, if applicable, when the extended slots 
for a group are open for enrollment after DLRT has confirmed the dose level is 
safe.   


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3.1.1.2 
eIV Infusion Group 
The eIV group will evaluate AMG 427 administered as an eIV infusion in approximately 
10 subjects with R/R AML.  The study will be conducted in dose escalation, to explore 
and identify if alternative dosing of AMG 427 leads to an improved benefit/risk profile.  
The option for group extension may be available, either at sponsor discretion or if 
recommended by the DLRT based on the review of the emerging safety data.  The 
sponsor will notify sites, if applicable, when the extended slots for a group are open for 
enrollment after DLRT has confirmed the dose level is safe.  If improvement is seen in 
the benefit/risk profile for these subjects, eIV administration may be implemented in the 
ongoing FIH (short IV) dose escalation cohorts, as well as expansion cohorts. 
Utilizing Schedule C, the eIV study design will consist of eIV and short IV infusions of 
AMG 427 administered on days 1 and 2, 3, 5, and 8.   
 
Days 1 and 2 will consist of the D1 dose administered as an eIV infusion over 
48 hours (approximately 12-hour IV bag changes).   
 
Day 3 will consist of the D3 dose administered as an eIV infusion over 24 hours 
(approximately 12-hour IV bag changes).   
 
The remaining 2 doses (D5 and D8) will be regular short IV infusions 
(approximately 90 minutes) on day 5 and day 8. 
The first eIV group will start at a DLRT-approved dose level from the FIH group as 
described in Section 6.2.1.1. 
Subsequent eIV cohorts will use the same dose levels as the FIH (short IV) cohorts 
(Table 4).  Dose escalation may occur if the DLRT deems that the eIV cohorts 
demonstrate a better benefit/risk profile than the equivalent FIH (short IV) cohorts.  All 
other study processes remain unchanged.  Data will be continuously evaluated, and 
DLRT may recommend dose schedule/level changes based on emerging PK data. 
3.1.1.2.1 
Justification for eIV Investigational Product Dose 
Based on preliminary population pharmacokinetic analyses, AMG 427 Cmax is predicted 
to be approximately 40 lower with a delayed Tmax if infused over a 72 hour period, 
relative to the same total dose administered using a 1 hour infusion.  It is hypothesized 
that the use of eIV infusions over a 72 hour period may reduce the intensity and/or 
frequency of the symptoms associated with CRS, relative to the same total dose of 
AMG 427 infused over a 1 hour duration.  The DLRT may recommend modifying the 
dose or modifying the C1D1 eIV infusion time up to 7 days based on emerging safety 
and PK data. 


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3.1.1.3 
MRD Group  
The MRD group will evaluate AMG 427 administered as short IV infusions (90 minutes) 
in approximately 10 adult subjects with MRD AML.  The option for group extension 
may be available, either at sponsor discretion or if recommended by the DLRT 
based on the review of the emerging safety data.  The sponsor will notify sites, if 
applicable, when the extended slots for a group are open for enrollment after 
DLRT has confirmed the dose level is safe.   
In escalation, subjects will be enrolled and start at a dose level from the FIH group that 
has been cleared by the DLRT as safe and tolerable.  For example, if DLRT approves as 
safe and tolerable, the following dosing regimen for FIH short term IV:  day 1:  
 g, 
day 3:  
 g, day 5:  
 g, and day 8:  
 g, the first MRD+ group 1 will be: 
 
Day 1:  
 g  
 
Day 3:  
 g 
 
Day 5:  
 g 
 
Day 8:  
 g 
The escalation doses will follow Table 4 and all escalation rules and study procedures 
remain unchanged.  If an MTD/RP2D is not determined after approximately 10 subjects, 
DLRT may recommend additional subjects for dose escalation, which will follow the dose 
escalation in Table 4. 
3.1.2 
Determination of Maximum Tolerated Dose 
Dose escalation decisions will be made based on the recommendation of the BLRM 
model and the DLRT review after considering available safety, PK, PD, and efficacy 
data.  The estimate of MTD will use the BLRM design.  The model’s estimated MTD 
dose is the dose with the highest probability of the target toxicity probability interval 
(TPI), but with a less than 0.25 probability of an excessive or unacceptable TPI.  The 
target TPI is (0.20, 0.33), and TPIs of (0.33, 0.60) and (0.60, 1.00) are defined as 
excessive and unacceptable, respectively.  See Section 3.4 for replacement of subjects. 
Dose escalations will continue until either of the following occurs: 
 
No DLTs are observed on study and 
 
A minimum of 6 subjects are treated at the highest planned dose level. 
 
DLTs are observed on study and 
 
BLRM repeats the recommendation of a dose level (minimum of 6 treated subjects), 
or 


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 
A maximum of 90 subjects are enrolled.  If fewer than 6 subjects are treated at the 
MTD, additional subjects beyond 90 may be enrolled to confirm safety and 
tolerability. 
The MTD is defined as the highest dose level whose DLT rate has the highest probability 
of the target TPI, an excessive/unacceptable TPI of  0.25, and a minimum of 6 subjects 
have been treated at the MTD. 
Once the dose escalation phase has determined a final MTD or optimal RP2D, 
tocilizumab may be evaluated as an alternative prophylaxis to prevent/reduce the 
severity of CRS.  A cohort of 3 subjects may be treated with AMG 427 at the final MTD 
dose level and a single dose of 8 mg/kg IV tocilizumab will be administered prior to the 
dose of AMG 427 replacing pretreatment with dexamethasone.  If no DLTs are 
observed, 3 additional subjects will be included in this cohort.  The use of tocilizumab 
may be further explored based on observed tolerability and other clinical and 
pharmacological data.  
3.1.2.1 
Maximum Tolerated Dose 1 (MTD1) 
Dose escalation will proceed using 2 parts, single subject cohorts and multiple subject 
cohorts.  In the single subject cohorts, single subjects will be enrolled at initial dose 
levels.  When any pharmacologic activity (including, but not limited to, infusion reactions, 
cytokine release syndrome, decrease in peripheral blood blasts, or decrease in white 
blood cell count) is observed, the cohort size will be increased to multiple subject cohorts 
(N  2 to 4 subjects).  When the initial dose-limiting toxicity (DLT) is observed, the BLRM 
design will be used to guide dose level selection.  After each cohort, the model’s 
recommended MTD dose level for evaluation is the dose level with the highest 
probability of the target TPI, but with a less than 0.25 probability of an excessive or 
unacceptable TPI.  The actual dose selected at each dose decision may be at or below 
the model’s recommended dose as recommended by the DLRT after considering all 
information.  
The dose escalation will be stopped when any of the following occurs: 
 
A minimum of 6 subjects have been treated at the MTD1 level 
 
When the sample size reaches 120 subjects 
 
Or as recommended by the DLRT after considering available safety, PK, PD, and 
efficacy data 


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3.1.2.2 
Maximum Tolerated Dose 2 (MTD2) 
Dose escalation for the MTD2 following the initial dosing (MTD1) will proceed after 
MTD1 is determined and implements a dose step.  The cohort for which a dose step will 
be implemented will start treatment for the first dose at the MTD1 assessed in the dose 
escalation for the first MTD.  After this run-in dose, there may be a dose increase to the 
next higher dose as per the dosing schedule shown in Table 3 of the protocol.  If this 
treatment schedule is tolerated, the following dose cohorts will continue to receive the 
run in (initial) dose at MTD1 to assess the MTD2.  The target (second) dose will be 
increased until an MTD2 is reached.  Testing of an MTD3 will be guided in the same way 
by the BLRM and the DLRT review after considering all information. 
Subjects who complete the DLT period (see Section 6.2.1.4) may proceed to a higher 
dose level for the following treatment cycle once the next dose cohort has been deemed 
safe by the DLRT, after consultation with the sponsor, if the subject has:  
 
No DLT reported during or after the completion of the DLT period 
See Section 7.2.2 for details on assessments applicable in case of intra-subject dose 
escalation.  Dose limiting toxicities experienced by subjects after completing the DLT 
period will be considered in the BLRM design to account for any late onset toxicity.   


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Single Subject Cohorts 
In the initial dose escalation cohorts, a single subject will be enrolled until any 
pharmacologic activity (including but not limited to infusion reaction, CRS, drop in white 
count) is noted.  Evidence of pharmacologic activity will trigger multiple subject 
enrollment in the same and all subsequent cohorts.  The initial dose levels are 
anticipated to be lower than the dose levels at which any clinical activity related to 
AMG 427 may be observed. 
Multiple Subject Cohorts  
Once multiple subject cohorts are triggered as described above, the same and 
subsequent cohorts will enroll 2 to 4 evaluable subjects based on BLRM output.   
Time interval between Enrollment of Subjects in Each Cohort 
There will be at least a 7-day (168-hour) interval between the start of treatment of the 
first and second subject in each cohort (ie, at the same dose and schedule).  On day 7 of 
this interval, the site investigator will evaluate all available safety and laboratory data for 
the treated subject and confirm the occurrence/non-occurrence of a DLT to the sponsor.  
The sponsor will only be able to open enrollment for the next subject in the cohort after 
receipt of this confirmation.  If deemed necessary, the 7-day interval may be extended 
until sufficient data are available to allow an assessment of the feasibility of treatment 
start of the next subject.  In addition, there will be at least a 96-hour interval between the 
start of treatment of the second subject and all subsequent subjects in each cohort.  
Hence, no more than 3 subjects will be enrolled in 2 weeks.  
Intra-subject dose escalation (ISDE)  
A subject may receive a dose higher than what they received in the first cycle if: 
 
the next dose cohort has been deemed safe by the DLRT 
 
after consultation with the sponsor 
 
no DLT is reported during or after completion of the DLT period for that subject 


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 
Subjects receiving low, subtherapeutic doses of AMG 427, such as subjects in the 
etanercept (Enbrel) substudy, may intra-subject dose escalate to a Dose Level 
Review Meeting (DLRM) approved dose immediately after cycle 1 if they have not 
experienced a DLT; the DLT window will remain 28 days (21 days if the subject 
shows disease progression) 
3.1.3 
Expansion Cohort 
At completion of the dose escalation cohorts, approximately 90 additional subjects 
(approximately 40 R/R AML subjects in the FIH cohorts and 50 MRD AML subjects in 
the MRD cohorts) will be enrolled in dose expansion cohorts to gain further clinical 
experience, safety, and efficacy data in subjects with AMG 427.  The dose to be 
evaluated will be at or below the MTD estimated in the dose escalation cohorts.  Once 
the preliminary MTD and R2PD are established, the FDA will be provided with brief 
interim results of the dose escalation phase. 
In the expansion phase, all available study data will be reviewed (with recruitment 
ongoing) by the DLRT once every 6th subject has at least completed their first treatment 
cycle plus 2 weeks or dropped out of treatment/study, whichever occurs earlier.  The 
MTD will be further evaluated by applying BLRM using all available data, including data 
from subjects in the expansion phase.  Ad hoc meetings may be convened any time in 
case of important safety events (see also Section 6.2.1.3). 
Based on emerging safety data, the planned dose level and dose schedule may be 
modified during the conduct of the expansion phase.  Additionally, enrollment to dose 
expansion will be paused and possibly terminated if safety stopping rules and/or efficacy 
futility rules are met (see Section 10.3 for details). 
A final estimate of the MTD and RP2D using BLRM will be evaluated and confirmed 
utilizing all DLT-evaluable subjects from the dose escalation and the dose expansion 
cohorts.  For definition of DLT-evaluable, see Section 6.2.1.3.  Additional expansion 
cohorts testing alternative dose levels or biologic subsets may be considered by 
amendment.   
The overall study design is described by a Study Design and Treatment Schema at the 
end of the protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
This study will be conducted at approximately 15 sites in the US, Australia, Canada, 
Japan, South Korea, and Germany.  Additional countries or sites may be added if 
necessary.   


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Sites that do not enroll subjects into an open cohort within 6 months of site initiation may 
be closed or replaced.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.” 
It is anticipated that approximately 200 subjects will be enrolled in this study, with 
approximately 110 subjects enrolled in the dose escalation cohorts and 90 subjects in 
the dose expansion cohorts:   
Dose escalation cohorts: 
 
FIH (R/R AML):  approximately 90 subjects 
 
(CLOSED) etanercept substudy (R/R AML):  approximately 25 subjects  
 
eIV (R/R AML):  approximately 10 subjects 
 
MRD Group (MRD):  approximately 10 subjects  
Dose expansion cohorts: 
 
FIH (R/R AML):  approximately 40 subjects 
 
MRD Group (MRD):  approximately 50 subjects  
For ethical and operational reasons subjects who already are in the screening phase at 
the time of enrollment stop (end of expansion phase) will still be allowed to be treated.  
Therefore, an over running of subject recruitment might be possible. 
Based on emerging data, additional subjects may be enrolled. 
The rationale for the number of subjects is provided in Section 10.2. 
3.4 
Replacement of Subjects 
Ineligible subjects (eg, subjects who were exposed to investigational product but post 
hoc were found to be ineligible) may be replaced.  During dose escalation, subjects that 
are not DLT-evaluable will be replaced.  See Section 6.2.1.3 for definition of 
DLT-evaluable subjects.  
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Dose escalation phase 
It is anticipated that an individual subject enrolled in the dose escalation phase will 
participate in the study for up to 14 months.  This includes a screening period lasting up 
to 14 days, a treatment period lasting approximately 10 to 12 months, and an SFU 
period lasting approximately 4 weeks after the last dose.  


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Dose expansion phase 
Individual subjects enrolled in the dose expansion phase will participate in the study for 
up to about 2 years.  This includes a screening period lasting up to 14 days, a treatment 
period lasting approximately 10 to 12 months, an SFU period lasting approximately 
4 weeks after the last dose, and an LTFU period lasting up to 2 years after the first dose 
of AMG 427 (for subjects enrolled in the expansion phase only). 
The actual duration for individual subjects will vary depending upon tolerability of 
AMG 427, evidence of clinical progression, and willingness to participate in the study. 
After completion of a first cycle without a DLT, up to 11 additional treatment cycles can 
be administered as long as, in the judgment of the investigator, the subject is deriving 
benefit. 
3.5.2 
End of Study 
End of Study (Primary Completion):  The primary completion date is defined as the 
date when the last subject is assessed or receives an intervention for the purposes of 
final collection of data for the primary endpoint(s), for the purposes of conducting the 
primary analysis, whether the study concluded as planned in the protocol or was 
terminated early.  
The primary completion date is the date when the last subject either had the opportunity 
to receive up to 12 cycles of treatment or terminated the study early. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study (For an Individual Subject):   
An individual subject is considered to have completed the study if he/she has completed 
SFU visit for subjects enrolled in the dose escalation phase, or LTFU visit for subjects 
enrolled in the dose expansion phase as shown in the Schedule of Assessments 
(Section 7.1).  The SFU visit should occur approximately 4 weeks (or up to 7 days 
thereafter) after the last dose of AMG 427 or prior to the initiation of other AML therapy, 
whichever occurs earlier.   
End of study (EOS) for an individual subject is defined as the last day that 
protocol-specified procedures/assessments are conducted for the individual subject.  


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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101. 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102. 
Subjects  18 years of age at the time of signing consent 
103. 
For R/R AML subjects only, AML as defined by the WHO Classification 
(Appendix D) as persisting or recurring following 1 or more treatment courses 
(exceptions noted in exclusion criteria).  Subjects must have failed treatment 
with, be intolerant to, or must not be candidates for available therapies for the 
treatment of R/R AML (not applicable to MRD subjects) 
104. 
For R/R AML subjects only, myeloblasts  5 in bone marrow, as confirmed by 
immunophenotype by flow cytometry (not applicable to MRD subjects) 
105. 
Eastern Cooperative Oncology Group (ECOG, Appendix F) Performance Status 
of  2 
106. 
Renal function as follows:  
 
serum creatinine  2.0 mg/dL (176.84 mol/L)  
 
estimated glomerular filtration rate (eGFR)  30 mL/min/1.73 m2 
107. 
Hepatic function as follows: 
 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 3.0 x upper limit of normal (ULN) 
 
bilirubin  1.5 x ULN (unless considered due to Gilbert's syndrome or 
hemolysis) 
108. 
(CLOSED) Etanercept (Enbrel) substudy only: 
No active tuberculosis in the setting of anti-TNF therapy 
National guidelines should be followed for appropriate tuberculosis screening in 
the setting of anti-TNF therapy, including a minimum of: 
 
Subject has a negative test for tuberculosis during screening defined as 
either: 
 
Negative purified protein derivative (PPD) ( 5 mm induration at 48 to 
72 hours after test is placed) OR 
 
Negative Quantiferon test 


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Subjects with positive PPD and a history of bacillus Calmette-Guérin vaccination 
are allowed with a negative Quantiferon test. 
Subjects with a positive PPD test (without a history of bacillus Calmette-Guérin 
vaccination) or subjects with a positive or indeterminate Quantiferon test are 
allowed if they have all of the following: 
 
no symptoms, per tuberculosis worksheet provided by Amgen 
 
documented history of a completed course of adequate treatment or 
prophylaxis (per local standard of care) prior to the start of investigational 
product 
 
no known exposure to a case of active tuberculosis after most recent 
prophylaxis 
 
no evidence of active tuberculosis on chest radiograph within 3 months 
prior to the first dose of investigational product  
109. 
For the MRD Group, AML subjects in any CR/CRh/CRi: 
 
with detectable measurable/MRD as assessed by local institution 
 
The MRD assessment must have been performed within 3 months of 
enrollment. 
 
not eligible for allogenic HSCT per investigator assessment, lacking a donor, 
or declining the procedure 
Subject may have received any induction and consolidation/maintenance 
regimens, including cytotoxic agents, hypomethylating agents, transplant, or 
other therapeutics, to achieve CR/CRh/CRi, prior to screening. 
4.2 
Exclusion Criteria 
201. 
Patients with acute promyelocytic leukemia (APML) 
202. 
Active extramedullary AML in the central nervous system (CNS) 
203. 
Known hypersensitivity to immunoglobulins 
204. 
White blood cells (WBC)  15,000 cells/mcL (15 cells x 10^9/L) at screening 
(hydroxyurea is permitted to enable eligibility)   
205. 
Subjects with a prior or concurrent malignancy whose natural history or treatment 
is anticipated to interfere with the safety or efficacy assessment of the 
investigational regimen.  
Exception:  Subjects with prior or concurrent malignancy not anticipated to 
interfere with the safety or efficacy assessment of the investigational regimen 
may be included only after discussion with the Amgen Medical Monitor. 
206. 
For R/R AML subjects only, autologous HSCT within 6 weeks prior to start of 
AMG 427 treatment (MRD subjects may be enrolled only after discussion with 
sponsor) 


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207. 
For R/R AML subjects only, allogeneic HSCT within 3 months prior to start of 
AMG 427 treatment (MRD subjects may be enrolled only after discussion with 
sponsor) 
208. 
Any graft-versus-host disease requiring systemic therapy with 
immunomodulators 
209. 
History or evidence of significant cardiovascular risk including any of the 
following: symptomatic congestive heart failure, unstable angina, clinically 
significant arrhythmias (eg, ventricular fibrillation, ventricular tachycardia etc.), 
recent coronary angioplasty, intra-cardiac defibrillators or any clinically relevant 
concurrent disorder that may pose a risk to subject safety or interfere with study 
evaluation, procedures, or completion  
210. 
History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
3 months 
211. 
Active infection requiring intravenous antibiotics within 1 week of study 
enrollment (day 1).  Antibiotics may be administered for prophylaxis as per 
institutional standards up to and after enrollment.  
212. 
Known positive test for human immunodeficiency virus (HIV) 
213. 
Positive for hepatitis B surface antigen (HepBsAg) 
214. 
Positive for hepatitis C or chronic hepatitis C 
Possible exceptions:  acute hepatitis C and completely cleared of the virus 
(demonstrated by negative viral load), chronic hepatitis C with undetectable viral 
load defined by sustained virologic response 24 weeks (SVR24) after completion 
of anti-hepatitis C treatment. 
215. 
Live vaccination(s) within 4 weeks before the start of AMG 427 treatment on 
day 1, during treatment, and until the end of the last study dose  
216. 
Unresolved toxicities from prior antitumor therapy, defined as not having resolved 
to Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0 grade 1 (with the exception of myelosuppression, eg, neutropenia, 
anemia, thrombocytopenia), or to levels dictated in the eligibility criteria with the 
exception of alopecia or toxicities from prior antitumor therapy that are 
considered irreversible (defined as having been present and stable for 
 2 months) which may be allowed if they are not otherwise described in the 
exclusion criteria AND there is agreement to allow by both the investigator and 
sponsor 
217. 
Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy 
such as FLT3 inhibitors, or investigational agent) within 14 days of day 1   
 
Exception:  hydroxyurea to control peripheral blood leukemic cell counts 
is allowed until start of investigational product treatment 
 
Exception:  antitumor therapies with short half-lives only require passing 
of 5 half-lives from last dose, and after discussion with sponsor 
218. 
Treatment with systemic immune modulators including, but not limited to,  
non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks 
before enrollment (day 1)  


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 
Exception: physiologic replacement steroids or steroids for treatment of 
transfusion/hypersensitivity reactions 
219. 
Prior treatment with a FLT3 targeting CAR-T  
220. 
Major surgery within 28 days of study day 1 with the exception of biopsy and 
insertion of central venous catheter 
221. 
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the investigator or Amgen medical monitor would 
pose a risk to subject safety or interfere with the study evaluation, procedures or 
completion 
222. 
Males and females of reproductive potential who are unwilling to practice a highly 
effective method(s) of birth control while on study through 4 weeks after receiving 
the last dose of study drug.  Acceptable methods of highly effective birth control 
include sexual abstinence (males, females); vasectomy; bilateral tubal 
ligation/occlusion; or a condom with spermicide (men) in combination with 
hormonal birth control or intrauterine device (IUD) (women) 
223. 
Females who are lactating/breastfeeding or who plan to breastfeed while on 
study through 4 weeks after receiving the last dose of study drug 
224. 
Females with a positive pregnancy test 
225. 
Females planning to become pregnant while on study through 4 weeks after 
receiving the last dose of study drug 
226. 
Subjects likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject’s and investigator’s knowledge 
227. 
History of multiple sclerosis or any other demyelinating disease 
228. 
Active hepatitis secondary to alcoholic hepatitis or nonalcoholic steatohepatitis  
229. 
History or evidence of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection unless agreed upon with Medical Monitor and 
meeting the following criteria: 
 
Negative test for SARS-CoV-2 RNA by reverse 
transcriptase-polymerase chain reaction (RT-PCR) within 72 hours of 
first dose of investigational product 
 
No acute symptoms of coronavirus disease 2019 (COVID-19) disease 
within 10 days prior to first dose of investigational product (counted 
from day of positive test for asymptomatic subjects) 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the ICF before commencement of study-specific 


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activities/procedures.  A subject is considered enrolled when they have met all the 
eligibility criteria.  The Investigator is to document the enrollment decision and date in 
the subject’s medical record.   
Each subject who enters the screening period for the study (defined as the point at 
which the subject signs the informed consent) receives a unique subject identification 
number before any study procedures are performed.  The subject identification number 
will be assigned manually.  This number will be used to identify the subject throughout 
the clinical study and must be used on all study documentation related to that subject.   
The unique subject identification number will consist of 11 digits.  The first 3 digits will 
represent the last 3 digits of the protocol number (ie, 528).  The next 5 digits will 
represent the country code and site number (eg, 66001) and will be identical for all 
subjects at the site.  The next 3 digits will be assigned in sequential order as subjects 
are screened (eg, 001, 002, or 003).  For example, the first subject to enter screening at 
site 66001 will receive the number 
, and the second subject at the same 
site will receive the number 
   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
Subjects who do not meet the eligibility criteria within the 14-day screening period will 
not be eligible for enrollment.  Subjects may be re-screened up to 3 times at the 
discretion of the investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside the 14-day screening period.  With the exception of hepatitis 
serology and bone marrow assessments, re-screened subjects who are re-consented 
will repeat all screening procedures.  See Section 7.2.1 for assessments during 
re-screening.  Subjects who are deemed ineligible will be documented as screen 
failures. 
Subjects may be eligible to begin treatment once all screening tests and procedures are 
completed and results indicate that all eligibility criteria are met.  A site representative 
will complete and send the enrollment eligibility worksheet to the sponsor or designee.   
5.1 
Treatment Assignment 
An Amgen representative will notify the site(s) in writing when a cohort is open to screen 
new subjects.  In the initial dose escalation cohorts, only a single subject will be enrolled 
to a cohort because the dose level is not anticipated to be clinically active.  Evidence of 


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pharmacologic activity will trigger multiple subject enrollment in the same and all 
subsequent cohorts.  Enrollment will be performed according to the BLRM design 
(see Section 3.1 for details) from the first multiple subject cohort onwards.  Each multiple 
subject cohort will enroll up to 4 evaluable subjects. 
At completion of the dose escalation cohorts, additional subjects, approximately 
90 (FIH:  N  40, MRD:  N  50) will be enrolled in a dose expansion cohorts to gain 
further clinical experience, safety and efficacy data in subjects with AMG 427.  The dose 
to be evaluated will be at or below the MTD estimated in the dose escalation cohorts. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
The Amgen investigational product used in this study is AMG 427.   
In this study (starting with the etanercept (Enbrel) substudy 
 
), etanercept (Enbrel [investigational use of a marketed product]) will be used 
(US only) prophylactically to mitigate signs, symptoms, and severity of CRS.  Etanercept 
is not FDA-approved for the disease/condition being studied.  Etanercept will be 
manufactured and packaged by Amgen Inc. and distributed using Amgen clinical study 
drug distribution procedures.   
6.2 
Investigational Product 
The investigational product will be administered at the research facility by a qualified 
staff member.  
A physician or nurse trained in emergency procedures must be available when the 
infusion of investigational product is started for immediate intervention in case of 
complications.  
6.2.1 
Amgen Investigational Product AMG 427 
AMG 427 will be manufactured and packaged by Amgen Inc., or its agents, and 
distributed using Amgen or its agents’ clinical study drug distribution procedures.   
AMG 427 is supplied as a sterile, preservative-free lyophilized powder for 
IV administration after reconstitution with sterile Water for Injection (WFI).  After 
reconstitution with 1.2 mL of sterile WFI, the 1 mg/mL AMG 427 drug product is 


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formulated with 
mM glutamic acid,  (w/v) sucrose, and 
 (w/v) polysorbate 80, 
pH 
  The final container is a single-use, 6R glass vial and contains a target 
extractable amount of 1 mg AMG 427.   
The intravenous solution stabilizer (IVSS) is intended for pre-treatment of IV bags prior 
to dilution of AMG 427 drug product.  The IVSS is supplied as a sterile solution in a 
10-cc glass vial containing 10 mL deliverable product.  The IVSS does not contain an 
active pharmaceutical ingredient and is a buffered, preservative-free solution (
 mM 
citric acid, 
M lysine hydrochloride, 
 (w/v) polysorbate 80, pH 
).   
6.2.1.1 
Dosage, Administration, and Schedule 
AMG 427 may be administered as short-term IV infusions, delivered using infusion 
pumps (for the higher doses) and syringe pumps (for the lower doses), respectively, 
which are both approved for use by the appropriate regulatory authority for the country in 
which the subject is undergoing treatment.   
AMG 427 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines.  An IV flush bag will be connected to the IV infusion line after 
AMG 427 dose infusion is completed to administer a controlled rate post-infusion flush.  
The drug will be administered as short-term IV infusions (approximately 90 minutes) on 
D1, D3 (if applicable), D5, and D8 (if applicable) of each treatment cycle followed by an 
infusion-free interval prior to the start of the following treatment cycle.  AMG 427 solution 
will be prepared in bags for short or eIV infusion and delivered through infusion lines.  
The first eIV group will start at a DLRT-approved dose level from the FIH group, eg, if 
DLRT approves as safe and tolerable, the following dosing regimen will be administered: 
 
Days 1 and 2:  eIV of 
 g (over approximately 48 hours, with approximately 
12-hour bag changes) 
 
Day 3:  eIV of 
 g (over approximately 24 hours, with approximately 12-hour bag 
changes) 
 
Day 5:  short IV of 
 g (over approximately 90 minutes) 
 
Day 8:  short IV of 
 g (over approximately 90 minutes) 
Subsequent eIV cohorts will use the same dose levels as the FIH (short IV) cohorts 
(Table 4).    
Two additional infusions, on D12 and D19 of each cycle, may be implemented by DLRM 
recommendation.  The infusion-free interval will have a duration of 1 to 5 weeks 
(depending on treatment response), but may be extended to up to 7 weeks in case of 


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prolonged marrow aplasia and aleukemic cytopenias after consultation with the sponsor.  
It may also be extended for up to 3 days from the planned duration if necessary for 
logistical reasons.  For further details on planned dosing and infusion details can be 
provided if needed, please also see Section 3.1. 
The planned dose levels for the dose escalation cohorts are: 
 
 g.  The MTD or highest 
tested dose (or doses, in case of dose step) will be administered in the dose-expansion 
cohort. 
After completion of a first cycle without DLT, up to 11 additional treatment cycles can be 
administered as long as in the judgment of the investigator the subject is deriving 
benefit.   
The duration of the infusion-free interval between the last infusion of a treatment cycle 
and the D1 infusion of the subsequent cycle is dependent on treatment response and 
recovery of blood counts (see below and Figure 4 for details).  It may also be extended 
for up to 3 days from the planned duration, if necessary, for logistical reasons.  The 
DLRT may recommend on changes of the duration of the infusion-free interval for future 
cohorts after evaluation of PK data. 
Figure 4.  Duration of Infusion-free Interval and Timing of Bone Marrow 
Assessments 
BM assessment at D14
(Cohorts receiving D1/5 
OR 
Day 1/3/5/8 doses only)
BM assessment at D28
(Cohorts receiving D1/5/12/19 
OR 
Day 1/3/5/8/12/19 doses only)
Start next 
cycle on 
D21
Start next 
cycle on 
D15
Start next 
cycle on 
D29
Start next 
cycle on 
D35
The infusion-free interval may be extended up to a maximum of 7 weeks in case of 
insufficient recovery of peripheral blood counts in the absence of active AML 
(neutrophils > 500/µL, platelets > 20 000/µL)
AML = acute myeloid leukemia; BM = bone marrow; D = day
* Myeloblasts must be confirmed by flow-cytometry based immunophenotype
< 5% blasts*
< 5% blasts*
≥ 5% blasts*
≥ 5% blasts*
The infusion-free interval may be extended up to a maximum of 7 weeks in case of 
insufficient recovery of peripheral blood counts back to baseline or neutrophils  500/L, 


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platelets  20 000/L without transfusion in the absence of active AML, after consultation 
with the sponsor.  In case the infusion--free interval is extended to 7 weeks, a bone 
marrow assessment is recommended 5 weeks after the last infusion of a cycle.  In case 
this assessment shows leukemic infiltration of the bone marrow ( 5 blasts), treatment 
should be resumed immediately even if peripheral blood counts have not yet recovered 
at this time point. 
Hospitalization 
Subjects will be hospitalized for a minimum of 8 or 11 days from the start of the first dose 
in cycle 1 (ie, until at least 72 hours after D5 or D8, depending on schedule) and for a 
minimum of 72 hours following D12 and D19 doses in cycle 1.  If the subject receives a 
second subsequent cycle of AMG 427 at the same dose, hospitalization will be for a 
minimum of 8 or 11 days from start of the day 1 dose (ie, at least 72 hours after D5 or 
D8, depending on schedule).  Hospitalization following D12 and D19 doses in cycle 
2 and onwards will be at the discretion of the treating physician.  For subjects receiving 
 2 cycles, hospitalization for cycle 3 onwards for all doses will be at the treating 
physician’s discretion. 
Additionally, subjects will be hospitalized for a minimum of 72 hours under the following 
circumstances:  
 
after each new dose step, if applicable 
 
after dose increase in case of intra-subject dose escalation 
 
after re-start of treatment after an interruption due to adverse event 
Subjects can be hospitalized for a longer time period at the discretion of the investigator.  
Hospitalization requirements may be reduced for subjects enrolled in the dose 
expansion phase based on cumulative safety and tolerability data from the dose 
escalation phase, by DLRT recommendation.  
A nurse trained in emergency procedures or a physician must be available when the 
dose of AMG 427 is started for immediate intervention in case of complications.  The 
hospitalization period may be extended at the discretion of the investigator.  During 
hospitalization periods, an immediately accessible emergency room with resuscitation 
equipment must be available.  
Prior to hospital discharge, vital signs will be measured in order to detect possible signs 
and symptoms of CRS.  If required for logistical reasons (eg, long travel times), subjects 
may be hospitalized the day before start of dosing (eg, day -1).  


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The start time of dose should be chosen carefully so as to avoid any interference or 
inconvenience with time points of safety assessments or PK/PD measurements.  The 
site should record any unscheduled interruption of a dose on the electronic case report 
form (eCRF), and provide the start and stop date/time of the infusion. 
AMG 427 should be administered through a central venous access at a constant flow 
rate.  The drug should not be administered as a bolus.  In the event that administration 
through a central venous access is not possible, AMG 427 may be administered through 
a peripheral venous line.  
The concentration, quantity administered, start date/time, stop date/time, and lot number 
of investigational product are to be recorded on each subject’s eCRF.  
6.2.1.2 
Overdose 
The effects of overdose of this product are not known.  The administered AMG 427 dose 
may be up to 10 lower or higher than specified in the protocol due to pump variation 
and will not be considered an overdose.  A dose of up to 10 higher than the intended 
dose may not require specific intervention. 
In any case of overdose, consultation with the Amgen medical monitor is strongly 
recommended for prompt reporting of clinically apparent or laboratory adverse events 
possibly related to overdosage.  Consultation with the Amgen medical monitor is also 
strongly recommended even if there are no adverse events, in order to discuss further 
management of the subject.  If the overdose results in clinically apparent or symptomatic 
adverse events, the subject should be followed carefully until all signs of toxicity are 
resolved and the adverse event(s) should be recorded/reported per Section 9.2.1.2.   
A dose of  10 higher than the intended AMG 427 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 9.2.1.2. 
6.2.1.3 
Dose-cohort Study Escalation and Stopping Rules, Dose Limiting 
Toxicities (DLTs) 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT window.  The DLT window will start on D1 (start of the administration of the first 
dose) and last for 28 days for all cohorts.  Any adverse event occurring outside the DLT 
window that is determined by the investigator to be possibly related to the investigational 
product, which is seen more frequently or is more severe than expected or is persistent 
despite appropriate management, can be determined to be a DLT upon unanimous 


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recommendation by the DLRT after review of the adverse event and all available safety 
data.   
DLT Evaluation 
A subject will be DLT-evaluable if the subject has received the doses planned for the 
respective cohort, and completed the DLT window of 28 days for all cohorts.  The DLT 
window may also be extended to assess events starting within the window in case the 
DLT definition is time dependent (eg, in case of neutropenia).   
A subject is not DLT-evaluable if he/she drops out before completion of the DLT window 
for reasons other than a DLT; exception: if a subject has received the planned doses in 
cycle 1 and drops out within 1 week of the completion of the DLT period due to 
progressive disease, 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 DLRM recommendations.  A DLT will be defined as any of 
the events described below occurring in a subject during the DLT window unless clearly 
attributable to causes other than AMG 427 treatment.  The CTCAE version 4.0 (see 
Appendix A) will be used to assess toxicities/adverse events with the exception of CRS 
(see Table 6 for grading criteria of CRS) and immune-effector associated 
neurotoxicity syndrome (ICANS) (see Table 8 for grading criteria of ICANS).  
Events to be considered as DLTs and exceptions are listed below: 
 
Cases of drug-induced liver injury confirmed by Hy’s Law criteria 
 
Any treatment-related death 
 
Grade 2 or 3 CRS meeting any of the criteria listed below: 
 
Grade 2 CRS that does not resolve, with or without intervention, to 
 grade 1 within 7 days will be considered a DLT 
 
Grade 3 CRS that does not resolve, with or without intervention, to 
 grade 2 within 5 days, or  grade 1 within 7 days, will be considered a DLT 
 
Grade 3 CRS reported at the initial run-in dose (ie, at MTD1; applicable only after 
MTD1 has been defined) will be considered a DLT  
 
Two separate events of grade 3 CRS 
 
Grade 4 CRS/infusion reactions occurring during AMG 427 treatment, immediately 
stop the infusion.  Permanently discontinue AMG 427 therapy.  
 
Grade 3−5 non-hematologic toxicity not clearly resulting from the underlying 
leukemia EXCEPT: 
 
alopecia 
 
grade 3 rash 
 
grade 3 fatigue, asthenia, fever, anorexia, or constipation 


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 
grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral 
nutrition, or requiring or prolonging hospitalization 
 
infection, bleeding, or other expected direct complication of cytopenias due to 
active underlying leukemia 
 
grade 3 infusion reaction including CRS, if successfully managed and which 
resolves within 12 hours 
 
grade 3 TLS if it is successfully managed clinically and resolves within 7 days 
without end-organ damage. 
 
Grade 4 neutropenia that persists beyond 42 days in the absence of leukemia 
 
Laboratory parameters  grade 3, not considered clinically relevant, and improved to 
 grade 2 within 72 hours, will not be considered DLT’s.  Laboratory parameters with 
long half-lives, ie, ALT, GGT, ALP, and lipase, will likewise not be considered DLT’s 
if they are not considered clinically relevant, and improve to grade  2 within 7 days. 
 
Grade 3 transaminitis (per CTCAE criteria) reported for subjects with grade 2 CRS 
(per Lee et al, 2019 criteria) will not be reported as a DLT if there is improvement to 
CRS  grade 1 within 7 days. 
The dosing schedule is described by a schema in Figure 2. 
See Section 3.1 for description of dose escalation and stopping rules and Section 3.4 for 
description of replacement of subjects. 
Subjects who have experienced a DLT at a certain dose level may continue to receive 
AMG427 at a lower dose, if AMG 427 has shown a potential for benefit in the specified 
subject, the subject’s adverse events have reduced to grade 2 or lower, and after 
discussion with the Amgen Medical Monitor. 
6.2.1.4 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Treatment Interruption 
Significant events attributed to the drug or infusion may require treatment interruption.  
Note: The definition of treatment interruption may include interruption of infusion or delay 
of the subsequent dose.  
Events leading to treatment interruption may include:  
 
The subject experiences a grade  3 adverse event related to the infusion/drug 
 
Technical problem with the syringe/infusion pump/syringe pump 
 
The investigational product is incorrectly prepared or administered (eg, overdose) 


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Treatment Interruption and Re-Start in Case of Adverse Events During the Infusion 
Treatment must be modified for any clinically relevant (as determined by investigator) 
adverse events that occur during the infusion and are related to investigational product, 
as follows: 
 
grade 2 adverse event:  Prior to next dose, adverse event must resolve to 
grade 1 or less for at least 24 hours, including isolated lab abnormalities and 
organ toxicity labs  
 
grade 3 adverse event:  Interrupt the infusion until the adverse event is grade 1 for 
at least 24 hours prior to the next dose of AMG 427.  Restart at the same dose if 
interruption is 72 hours.  If interruption is 72 hours, restart at a lower dose (last 
safe dose as recommended by DLRT or a lower dose).  If the adverse event is a 
DLT, follow Section 6.2.1.3 for management of DLT. 
 
Subjects who experience CRS grade 3 should have next dose delayed until 
CRS resolves to grade ≤ 1 for at least 24 hours prior to the next dose of 
AMG 427 (including isolated lab abnormalities and organ toxicity labs, 
except for liver function tests, which must resolve to grade 2 or less), and 
should have next dose(s) reduced by one-half or more, if given on 
scheduled day (please consult with the study medical monitor). 
 
grade 4 adverse events during the infusion: Permanently discontinue the 
investigational product 
The Amgen medical monitor has to be consulted prior to a planned re-start.  
In case of a dose reduction, re-escalation to the target dose can be considered for the 
next infusion if treatment at the lower dose has been well tolerated.  An intermediate 
dose level may be administered prior to stepping up to the target dose after consultation 
with the Amgen medical monitor.  
The subject should be hospitalized for at least 72 hours after re-start of the infusion.   
If possible, the number of infusions at the target dose in a cycle should sum up to the 
planned number of infusions.  In this case, the cycle would still be DLT-evaluable.  
Permanent Discontinuation 
A subject will permanently discontinue treatment with investigational product in the event 
of:  
 
dose-limiting or other unmanageable toxicity 
 
except subjects who have experienced a DLT at a certain dose level may 
continue to receive AMG427 at a lower dose, if AMG 427 has shown efficacy in 
the specified subject, and the subject’s adverse events have reduced to 
grade 2 or lower, and after discussion with the Amgen Medical Monitor. 
 
grade 4 CRS 
 
grade 2 or 3 CRS meeting any of the criteria listed below: 


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 
grade 2 or 3 CRS that does not improve to  grade 1 within 7 days  
 
grade 3 CRS that does not improve to  grade 2 within 5 days 
 
grade 3 CRS at the initial run-in dose for a cycle (ie, at the MTD1) (for cohorts 
with dose step only) 
 
If a subject experiences 2 separate grade 3 CRS events 
 
disease progression as defined by revised IWG response criteria (Appendix E) 
 
withdrawal of subject’s consent to treatment 
 
subject or investigator not compliant with the study protocol 
 
occurrence or progression of a medical condition, which in the opinion of the 
investigator, should preclude further participation of the subject in the study 
 
a treatment interruption of more than 21 days due to an adverse event not clearly 
related to the underlying disease (except neutropenia) 
 
occurrence of a CNS-related adverse event considered related to AMG 427 by the 
investigator and meeting 1 or more of the following criteria: 
 
more than 1 seizure 
 
a CNS-related adverse event grade 4 
 
a CNS-related adverse event leading to treatment interruption that needed more 
than 1 week to resolve to grade  1 
 
graft-versus-host disease  
 
investigator’s decision that a change of therapy (including immediate HSCT) is in the 
subject’s best interest 
Females who become pregnant while on study through 4 weeks after receiving the last 
dose of study drug will not receive subsequent scheduled doses and will be followed for 
safety until the end of study visit. 
Males on study through 4 weeks after receiving the last dose of study drug must practice 
sexual abstinence or use a condom while on study through 4 weeks after receiving the 
last dose of study drug.   
All reasons for treatment discontinuation should be clearly and concisely documented in 
the eCRF.  If a subject has not continued to present for study visits, the investigator 
should determine the reason and circumstances as completely and accurately as 
possible. 
In any case of premature treatment discontinuation, the investigator should make every 
effort to perform all examinations scheduled for the end of treatment (EOT) and 
SFU visits.  These data should be recorded, as they comprise an essential evaluation 
that should be performed prior to discharging any subject from the study and to allow for 
the evaluation of the study endpoints. 


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6.3 
Other Protocol-required Therapies  
All other protocol-required and recommended therapies, including corticosteroids, that 
are commercially available are not provided or reimbursed by Amgen (except if required 
by local regulation).  The investigator will be responsible for obtaining supplies of these 
therapies.   
Oxygen:  Oxygen administration as a supportive measure is permitted during study 
treatment.   
Hydroxyurea:  Hydroxyurea may be permitted according to standard practice prior to 
the first cycle of investigational product treatment for subjects with high WBC 
( 15,000 cells/L or 15 cells x 109/L).  Administration of hydroxyurea after the start of 
AMG 427 may be permitted after discussion with the Amgen medical monitor.  
Dexamethasone:  Premedication with dexamethasone is required for every cycle before 
infusion of AMG 427 dosing and prior to each dose step of AMG 427 to mitigate the risk 
of CRS.  When dosed, dexamethasone should be administered as a single IV dose 
(8 mg) within 1 hour of start of infusion.  
Methylprednisolone:  may also be utilized as per Table 6 to treat CRS, per 
institutional practice.  
Tocilizumab:  Tocilizumab will be used to treat cytokine release syndrome 
(Actemra® USPI, 2021), as described in Table 6.  In addition, use of prophylactic 
tocilizumab to mitigate CRS will be tested in a cohort of subjects once final MTD has 
been established, as described in Section 3.1.2.  For administration of dexamethasone 
and tocilizumab after occurrence of CRS, follow guidance in Section 6.6.  Additional 
details regarding these protocol-required therapies are provided.  Sites are required to 
have tocilizumab or siltuximab (if tocilizumab not available) on site for potential 
treatment of CRS (Sylvant™ USPI, 2015).  If tocilizumab is not available, siltuximab 
(an anti-IL-6 monoclonal antibody) may be used in the management of cytokine 
release syndrome, following the criteria outlined in Table 7.  The recommended 
dose of siltuximab is 11 mg/kg administered over 1 hour as an intravenous 
infusion, consistent with the prescribing information for the treatment of 
multicentric Castleman’s disease (Sylvant™ USPI, 2015), and the CARTOX 
Working Group Guidelines for CRS management (Neelapu et al, 2018).  Siltuximab 
may be repeated if needed, in the event that CRS recurs after a subsequent 
infusion of AMG 427.  Siltuximab may not be repeated in an individual subject that 
develops anaphylaxis to siltuximab, or gastrointestinal perforation after 


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siltuximab.  A subgroup analysis for those treated with siltuximab will be 
evaluated, including CRS outcomes, safety, and PK data. 
Anakinra:  The interleukin-1 receptor (IL-1R) blocker/inhibitor will be used for 
symptoms of CRS-related ICANS as per Table 8.  In preclinical models, Anakinra 
has shown to abolish both CRS and neurotoxicity, resulting in substantially 
extended leukemia-free survival (Norelli et al, 2018).  Interleukin-1 receptor 
inhibitor has been found to be useful in managing CRS related acute respiratory 
distress syndrome and ICANS/neurotoxicity (Morris et al, 2021).  
(CLOSED) Etanercept:  Etanercept will be used prophylactically to mitigate 
signs/symptoms/severity of cytokine release syndrome.  
 
. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBIL]) or international normalized ratio [INR]) or signs/symptoms of 
hepatitis may meet the criteria for withholding of investigational product.  Withholding is 
either permanent or conditional depending upon the clinical circumstances discussed 
below (as specified in the FDA Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009).  
6.4.1 
Criteria for Permanent Withholding of AMG 427 due to Potential 
Hepatotoxicity 
Investigational product should be discontinued permanently and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met: 
 
Increased AST or ALT from the relevant baseline value as specified below:   
Baseline AST or ALT value 
AST or ALT elevation 
 ULN 
 3x ULN 
AND  
 
TBIL  2x upper limit of normal (ULN) or INR  1.5  
AND  
 
No significant elevation of ALP ( 2x ULN) 


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 
No other cause for the combination of the above laboratory abnormalities is 
immediately apparent including pre-existing or acute liver disease.  Important 
alternative causes for elevated AST/ALT and/or elevated TBIL values include, but 
are not limited to:  
 
hepatobiliary tract disease  
 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus)  
 
right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia   
 
exposure to hepatotoxic agents/drugs including herbal and dietary supplements, 
plants, and mushrooms   
 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir)   
 
alpha-1 antitrypsin deficiency  
 
alcoholic hepatitis  
 
autoimmune hepatitis  
 
Wilson’s disease and hemochromatosis  
 
nonalcoholic fatty liver disease including steatohepatitis (NASH)  
 
non-hepatic causes (eg, rhabdomyolysis, hemolysis)  
6.4.2 
Criteria for Conditional Withholding of AMG 427 due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of 
AMG 427 outlined above and have no underlying liver disease and eligibility criteria 
requiring normal transaminases and TBIL at baseline or subjects with underlying liver 
disease and baseline abnormal transaminases, the following rules are recommended for 
withholding of Amgen investigational product and other protocol-required therapies:   
 
Elevation of either AST or ALT according to the following schedule:  
 
Any AST or ALT elevation:   8 x ULN at any time 
 
Any AST or ALT elevation:   5 x ULN but  8 x ULN for  2 weeks 
 
Any AST or ALT elevation:   5 x ULN but  8 x ULN and unable to adhere to 
enhanced monitoring schedule 
 
Any AST or ALT elevation:   3 x ULN with clinical signs or symptoms which are 
consistent with hepatitis (such as right upper quadrant pain/tenderness, fever, 
nausea, vomiting, or jaundice).   
 
OR:  TBIL  3 x ULN at any time 
 
OR:  ALP  8 x ULN at any time 


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AMG 427 should be withheld pending investigation into alternative causes of the 
laboratory elevations.  If the investigational product is withheld, the subject is to be 
followed according to recommendations in Appendix A for possible DILI.  Rechallenge 
may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) 
and/or elevated TBIL level is discovered and the laboratory abnormalities resolve to 
normal or baseline (Section 6.4.3). 
Discontinuation of the product should be considered and the decision to re-challenge 
should be discussed with the Amgen medical monitor before re-initiating treatment with 
investigational product. 
6.4.3 
Criteria for Rechallenge of AMG 427 After Potential Hepatotoxicity 
If signs or symptoms recur with rechallenge, then the investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.4.1) should not be rechallenged.  
6.5 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9.  COVID-19 vaccine administration (if applicable) should be 
captured in the concomitant medications. 
Concomitant therapies are to be collected from informed consent, through the SFU or 
LTFU, as applicable.  For all concomitant therapies including vaccines, collect therapy 
name, indication, dose, unit, frequency, route, start date, and stop date. 
6.5.1 
Vaccines 
Every effort should be made to fully vaccinate subjects prior to 14 days from first 
dose of AMG 427.  The use of vaccines except live vaccines will be allowed during 
therapy per regional and institutional standard of care.  However, SARS-CoV-2 
vaccinations should be avoided during screening (within a minimum of 14 days 
from first dose of AMG 427) and should be also avoided in the first treatment cycle 
for better assessment of safety parameters.  Throughout the trial, SARS-CoV-2 
vaccination should be avoided within 3 days after the administration of AMG 427.  
In the event where a subject requires steroids for treatment of adverse events, 
vaccination should be avoided while on steroids.


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Table 5.  Management of COVID-19 
Grade 
Interruption/Delay 
Specific 
Management 
Re-start guidance 
Permanent Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Asymptomatic 
Interruption 
required until at 
least 10 days 
since positive 
SARS-CoV-2 test 
UNLESS patient 
previously fully 
vaccinated 
against 
SARS-CoV-2.  If 
patient previously 
vaccinated and 
tests positive, 
then discuss with 
Medical Monitor. 
Follow local 
guidelines and 
standard of care 
for COVID-19 
treatment and 
isolation 
Contact Amgen 
Medical Monitor 
within 1 business 
day to ensure 
appropriate 
documentation & 
management of 
study activities 
 
Re-start possible upon agreement between 
Investigator and Amgen Medical Monitor provided: 
o 
There are no new findings on physical exam 
related to SARS-CoV-2, AND 
o 
Subject tests negative for SARS-CoV-2 by 
RT-PCR,  
OR 
o 
If subject continues to test positive for 
SARS-CoV-2 more than 10 days after initial 
positive test, or If subject initially tests 
positive in the setting of prior COVID 
vaccination, resume investigational product 
only after discussion with patient and 
reassessment of individual risk/benefit 
 
Consider chest imaging, EKG, ECHO, and cardiology 
assessment 
 
Consider hospitalization for re-start of investigational 
product based on length of treatment interruption, 
risk of CRS at restart, and amount of time since 
patient was last treated 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
 
Premedication and assessments:  follow guidance in 
schedule of assessment tables 
Immediately stop the infusion (if 
applicable) and permanently 
discontinue investigational product 
therapy IF: 
Subject required treatment 
interruption greater than 28 days 
and upon discussion with Amgen 
Medical Monitor the decision is 
made to permanently discontinue 
treatment 
OR 
Initial benefit/risk assessment for 
individual patient is not maintained 
any longer 
Page 1 of 2 
Footnotes defined on next page of the table 
 


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Table 5.  Management of COVID-19 
Grade 
Interruption/Delay 
Specific 
Management 
Re-start guidance 
Permanent Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Symptomatic 
Interruption 
required until at 
least 10 days 
since complete 
resolution of 
acute symptoms 
Interruption 
required until at 
least 10 days 
since complete 
resolution of 
acute symptoms 
 
Re-start possible upon agreement between 
Investigator and Amgen Medical Monitor provided: 
o 
There are no new findings on physical exam 
and chest imaging, related to SARS-CoV-2, 
o 
Subject tests negative for SARS-CoV-2 by 
RT-PCR,  
OR 
o 
If subject continues to test positive for 
SARS-CoV-2 more than 10 days after initial 
positive test, resume investigational product 
only after discussion with patient and 
reassessment of individual risk/benefit 
 
Consider chest imaging, EKG, ECHO, and cardiology 
assessment 
 
Consider hospitalization for re-start of investigational 
product based on length of treatment interruption, 
risk of CRS at restart, and amount of time since 
patient was last treated 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
 
Premedication and assessments:  follow guidance in 
schedule of assessment tables 
Immediately stop the infusion (if 
applicable) and permanently 
discontinue investigational product 
therapy IF 
Subject required treatment 
interruption greater than 28 days 
due to severe or life-threatening 
COVID-19 
OR 
Initial benefit/risk assessment for 
individual patient is not maintained 
any longer 
Page 2 of 2 
COVID-19 = coronavirus-19; CRS = cytokine release syndrome; ECHO = echocardiography; EKG = electrocardiogram; RT-PCR = reverse transcriptase-
polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 
 


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6.6 
Specific Recommendations for Cytokine Release Syndrome, 
Immune-effector Cell-associated Neurotoxicity Syndrome,Tumor 
Lysis Syndrome and Infection Prophylaxis 
Cytokine Release Syndrome 
Cytokine release syndrome is clinically defined and may have various manifestations.  
There are no established diagnostic criteria.  Signs and symptoms of CRS may include:   
 
Constitutional – fever, rigors, fatigue, malaise 
 
Neurologic – headache, mental status changes, dysphasia, tremors, dysmetria, gait 
abnormalities, seizure 
 
Respiratory – dyspnea, tachypnea, hypoxemia 
 
Cardiovascular – tachycardia, hypotension 
 
Gastrointestinal – nausea, vomiting, transaminitis, hyperbilirubinemia 
 
Hematology – bleeding, hypofibrinogenemia, elevated D-dimer 
 
Skin – rash 
Cytokine release is an anticipated consequence of T cell engagement induced by 
AMG 427.  Cytokine release syndrome, including serious events and a fatal event, has 
been reported in subjects receiving AMG 427 in the clinical trial.  Subjects may be at an 
increased risk for CRS during the first few days following the initial dose of AMG 427 and 
after a dose step.  More severe cases of CRS and/or ICANS have also been 
associated with higher tumor burden in multiple malignancies including leukemia, 
lymphoma, and multiple myeloma, which is likely to be associated with greater 
expansion of T cell populations and synchronous activation with BiTEs.  Please 
refer to the Investigator’s Brochure for additional information. 
Infusion reactions may be clinically indistinguishable from manifestations of CRS.  
Throughout the infusion with AMG 427 and at least 12 hours after the start of infusion, 
monitor subjects intensively for clinical signs (eg, fever, hypotension, tachycardia, 
dyspnea, tremors) and laboratory changes (eg, increase in transaminases, C-reactive 
protein [CRP], lactate dehydrogenase [LDH], ferritin, D-dimer, and erythrocyte 
sedimentation rate [ESR]) which may be related to CRS.  Cytokine release syndrome 
may be clinically associated with the development of fever, nausea, chills, hypotension, 
tachycardia, asthenia, headache, rash, scratchy throat, dyspnea, and 
ICANS/neurotoxicity as a consequence of systemic release of cellular cytokines such 
as TNF, IL-1Ra, IL-2, IL-3, IL-4, and IL-6 (Morris et al, 2021; Winkler et al, 1999).  
Potentially life-threatening complications of CRS include cardiac dysfunction, adult 
respiratory distress syndrome, renal and/or hepatic failure, and disseminated 


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intravascular coagulation (Lee et al, 2014) and ICANS/neurotoxicity which may occur 
concurrently or immediately following CRS. 
Grading of CRS should be performed according to the guidelines provided in 
Table 6 and management of CRS should be performed according to the guidelines 
provided in Table 7 (based on the adopted grading system referenced in 
Lee et al, 2019). 


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Table 6.  Cytokine Release Syndrome Grading (ASTCT; Lee et al, 2019) 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature  38°C 
Temperature  38°C 
Temperature  38°C 
Temperature  38°C 
 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a single vasopressor (not 
including vasopressin) 
Requiring multiple vasopressors 
(not including vasopressin) 
 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
( 6 L/minute) nasal 
cannula or blow-by 
Requiring high-flow nasal cannula 
( 6 L/min), facemask, non-rebreather 
mask, or Venturi mask 
Requiring positive pressure (eg, 
CPAP, BiPAP, intubation and 
mechanical ventilation) 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway 
pressure; CRS = cytokine release syndrome 
Organ toxicities associated with CRS may be graded according to CTCAE v4.0 but they do not influence CRS grading. 
aFever is defined as temperature  38°C not attributable to any other cause.  In subjects who have CRS then receive antipyretic or anticytokine therapy 
such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.  In this case, CRS grading is driven by hypotension and/or 
hypoxia. 
bCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause.  For example, a subject with temperature 
of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 


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Table 7.  Management of Cytokine Release Syndrome  
Description of CRS Severitya 
Minimum Expected Intervention 
Instructions for Interruption of 
AMG 427 
Fever (temperature  38C) without 
hypotension and hypoxia 
 Administer symptomatic treatment (eg, paracetamol/acetaminophen 
for fever). 
 Administer tocilizumabb 4 to 8 mg/kg IV over 1 hour (not to 
exceed 800 mg).  If no clinical improvement in signs and 
symptoms of CRS after the first dose, repeat tocilizumab every 
8 hours (maximum of 3 doses in a 24-hour period; maximum 
total of 4 doses).  If improving discontinue tocilizumab. 
Monitor for CRS symptoms including vital signs and pulse oximetry at 
least Q2 hours for 12 hours or until resolution, whichever is earlier. 
If symptoms of grade 1 CRS do not improve after 24 hours 
consider managing as grade 2. 
 
Page 1 of 4 
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Table 7.  Management of Cytokine Release Syndrome  
Description of CRS Severitya 
Minimum Expected Intervention 
Instructions for Interruption of 
AMG 427 
Fever (temperature  38C) with: 
 
Hypotension not requiring 
vasopressor AND/OR 
 
Hypoxia requiring low-flow 
 6 L/min nasal cannula or blow-by 
Administer:  
 
Symptomatic treatment (eg, paracetamol/ acetaminophen for fever) 
 
Tocilizumabb 8 mg/kg IV over 1 hour (not to exceed 800 mg).  If 
no clinical improvement in signs and symptoms of CRS after 
the first dose, repeat tocilizumab every 8 hours (maximum 
3 doses in a 24-hour period; maximum total of 4 doses).  If 
improving discontinue tocilizumab. 
 
Dexamethasone 10 mg IV up to 3 times a day.  Continue 
corticosteroids until the severity is grade 1 or less.  If not 
improving manage as grade 3 below. 
 
Supplemental oxygen when oxygen saturation is  90 on room air 
 
Intravenous fluids or low dose vasopressor for hypotension when 
systolic blood pressure is  100 mmHg.  Persistent tachycardia (eg, 
 120 bpm) may also indicate the need for intervention for 
hypotension. 
Monitor for CRS symptoms including vital signs and pulse oximetry at 
least Q2 hours for 12 hours or until resolution to CRS grade  1 for at 
least 24 hours prior to the next dose of AMG 427. 
For subjects with extensive co-morbidities or poor performance status, 
manage per CRS guidance below. 
If hypotension worsens or persists 
2 hours after adequate medical 
management, interrupt AMG 427 until 
CRS is grade  1 for at least 24 hours 
prior to the next dose of AMG 427.  
Refer to re-start criteria below for CRS 
grade 3.  If symptoms progress to 
grade 3 criteria, see row below.  
Permanently discontinue AMG 427 if 
there is no improvement to CRS 
 grade 1 within 7 days. 
Page 2 of 4 
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Table 7.  Management of Cytokine Release Syndrome 
Description of CRS Severitya 
Minimum Expected Intervention 
Instructions for Interruption of 
AMG 427 
Fever (temperature  38C) with: 
 Hypotension requiring a single 
vasopressor (not including 
vasopressin) AND/OR 
 Hypoxia requiring high-flow ( 6 L/min) 
nasal cannula, facemask, 
nonrebreather mask, or Venturi mask 
Admit to intensive care unit (ICU) for close clinical and vital sign 
monitoring per institutional guidelines. 
 
Tocilizumabb 8 mg/kg IV over 1 hour (not to exceed 800 mg).  If 
no clinical improvement in signs and symptoms of CRS after 
the first dose, repeat tocilizumab every 8 hours (maximum 3 
doses in a 24-hour period).  If improving discontinue 
tocilizumab. 
Administer dexamethasone 10-20 mg up to three times a day.  If 
improving manage as appropriate grade above and continue 
corticosteroids until severity is grade 1 or less, then taper as 
clinically appropriate. 
Consider methylprednisolone up to 1000 mg or as per institutional 
practice. 
Subjects who experience CRS grade 
3 should have next dose delayed 
until CRS resolves to grade ≤ 1 for at 
least 24 hours prior to the next dose 
of AMG 427 (including isolated lab 
abnormalities and organ toxicity 
labs, except for LFTs, which must 
resolve to grade 2 or less), and 
should have next dose(s) reduced 
by one-half or more, if given on 
scheduled day (please consult with 
the study medical monitor). 
Permanently discontinue AMG 427 if 
there is no improvement to CRS 
 grade 2 within 5 days or CRS  grade 
1 within 7 days. 
Permanently discontinue AMG 427 if 
CRS grade 3 occurs at the initial run in 
dose (ie, at MTD1). 
Page 3 of 4 
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Table 7.  Management of Cytokine Release Syndrome 
Description of CRS Severitya 
Minimum Expected Intervention 
Instructions for Interruption of 
AMG 427 
 Fever (temperature  38C) with: 
 Hypotension requiring multiple 
vasopressors (excluding vasopressin) 
AND/OR 
 Hypoxia requiring positive pressure 
(eg, CPAP, BiPAP, intubation and 
mechanical ventilation) 
Admit to ICU for close clinical and vital sign monitoring per institutional 
guidelines. 
 
Tocilizumabb 8 mg/kg IV over 1 hour (not to exceed 800 mg).  If 
no clinical improvement in signs and symptoms of CRS after 
the first dose, repeat tocilizumab every 8 hours (maximum 
3 doses in a 24-hour period).  If improving discontinue 
tocilizumab. 
Administer methylprednisolone up to 1000 mg once per day for 
3 days.  If improving manage as appropriate grade above and 
continue corticosteroids until severity is grade 1 or less then taper 
as clinically appropriate. 
If not improving consider methyl prednisolone 1000 mg two to 
three times a day or alternate therapy. 
Immediately stop the infusion and 
permanently discontinue 
AMG 427 therapy.  
Page 4 of 4 
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS  Cytokine Release Syndrome; ICU = intensive care unit; 
IL-6 = interleukin 6; IL-6R = interleukin 6 receptor; IV  Intravenous; LFT(s) = liver function test(s); MTD  maximum-tolerated dose 
a Grading system for CRS (Lee et al, 2019) 
b If tocilizumab is not available, another IL-6/IL-6R inhibitor eg, siltuximab may be used per institutional practice for CRS.


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Re-start of treatment after CRS: 
Please refer to the general guidance for re-start of treatment after adverse events in 
Section 6.2.1.4 
For grade 3 and 4 CRS, please see Section 6.2.1.3 for DLT considerations. 
Immune-effector Cell-associated Neurotoxicity Syndrome (ICANS): 
Immune-effector cell-associated neurotoxicity syndrome (ICANS) typically 
manifests as a toxic encephalopathy and starts with word-finding difficulty, 
confusion, dysphasia, aphasia, impaired fine motor skills, and somnolence.  In 
more severe cases, seizures, motor weakness, cerebral edema and coma have 
been noted.  The majority of patients who develop clinical features of ICANS will 
have had preceding CRS.  Cytokine release syndrome can, therefore, be 
considered an ‘initiating event’ or cofactor for ICANS.  Neurotoxicity generally 
occurs after the symptoms of CRS have subsided, although, less frequently, 
concurrent presentation of CRS and ICANS can occur.  Similar to CRS, ICANS is 
reversible in most patients with no permanent neurological deficits (Schuster et 
al, 2019; Neelapu et al, 2018; Santomasso et al, 2018; Gust et al, 2017). 
For this trial, ICANS will be managed using the criteria referenced in the American 
Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
Criteria for ICANS associated with immune effector cells (Lee et al, 2019).  While 
the grading system has been developed in large part from CAR-T therapies, 
symptoms of ICANS may be shared among immune effector-cell associated 
therapies such as BiTE molecules.  Although there may be a wide range of 
symptoms associated with ICANS, subjects may have a stereotypic course of a 
specific set of symptoms.  The earliest manifestations of ICANS are tremor, 
dysgraphia, mild difficulty with expressive speech (especially in naming objects), 
impaired attention, apraxia, and mild lethargy. 
ICANS grade is determined by the most severe event (eg, depressed level of 
consciousness, seizure, motor findings, raised intracranial pressure [ICP]/cerebral 
edema) not attributable to any other cause.  Refer to the immune effector 
cell-associated encephalopathy (ICE) score below for grading of ICANS. 
ICE Assessment Tool 
 Orientation:  Orientation to year, month, city, hospital:  4 points  
 Naming:  ability to name 3 objects (eg, point to clock, pen, button):  3 points 


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 Following commands:  ability to follow simple commands (eg, “Show me 
2 fingers” or “Close your eyes and stick out your tongue”):  1 point 
 Writing:  ability to write a standard sentence (eg, “Our national bird is the 
bald eagle”):  1 point 
 Attention:  ability to count backwards from 100 by 10:  1 point 
ICE scoring 
 
7-9, grade 1 
 
3-6, grade 2 
 
0-2, grade 3 
 
0 due to subject unarousable and unable to perform ICE assessment, 
grade 4 
Table 8.  ASTCT Immune Cell-associated Neurotoxicity Syndrome (ICANS) 
Consensus Grading for Adults 
Neurotoxicity 
Domaina 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scoreb 
7-9 
3-6 
0-2 
0 (subject is 
unarousable and unable 
and unable to perform 
ICE) 
Depression 
level of 
consiousnessc 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to 
tactile stimulus 
Subject is unarousable 
or requires vigorous or 
repetitive tactile stimuli 
to arouse. 
Stupor or coma  
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves 
rapidly or 
nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or repetitive 
clinical or electrical 
seizures without return 
to baseline in between 
Motor findings 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema 
on neuroimagingd 
Diffuse cerebral edema 
on neuroimaging; 
Decerebrate or 
decorticate posturing; or 
Cranial nerve VI palsy; 
or Papilledema; or 
Cushing’s triad 


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ASTCT = American Society for Transplantation and Cellular Therapy; CTCAE = Common 
Terminology Criteria for Adverse Events; EEG = electroencephalogram; ICANS = immune-effector 
cell-associated neurotoxicity syndrome; ICE = immune effector cell-associated encephalopathy; 
ICP = intracranial pressure; N/A = not applicable. 
a Other signs and symptoms such as headache, tremor, myoclonus, asterixis, and hallucinations 
may occur and could be attributable to immune effector-cell engaging therapies.  Although they 
are not included in this grading scale, careful attention and directed therapy may be warranted.  
b A subject with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, 
but a subject with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
c Depressed level of consciousness should be attributable to no other cause (eg, no sedating 
medication).  
d Intracranial haemorrhage with or without associated edema is not considered a neurotoxicity 
feature and is excluded from ICANS grading.  It may be graded according to CTCAE v4.0. 
Source:  Lee et al, 2019 
Assessment and Supportive Care Recommendations (all grades) 
 
Neurologic assessment and grading at least twice a day to include cognitive 
assessment and motor weakness 
 
Magnetic resonance imaging (MRI) of the brain with and without contrast (or 
brain computed tomography [CT] if MRI is not feasible) for ≥ grade 2 
neurotoxicity 
 
Neurology consultation at first sign of neurotoxicity 
 
Conduct electroencephalogram (EEG) for seizure activity for ≥ grade 2 
neurotoxicity 
 
Aspiration precautions; IV hydration 
 
Use caution when prescribing medications that can cause CNS depression 
(aside from those needed for seizure prophylaxis/treatment) 
Table 9.  Assessment and Supporting Care Recommendations 
Treatment 
by Grade 
No Concurrent CRS 
Additional Therapy if 
Concurrent CRS 
Grade 1 
 
Supportive care 
 
If neurotoxicity is observed within 
6 hours of dosing, consider 
anakinra 100 mg subcutaneously 
every 12 hours for up to 7 days (or 
another IL-1 receptor inhibitor per 
institutional practice). 
In the setting of grade ≥ 3 CRS 
with hypotension, tocilizumab 
8 mg/kg IV over 1 h (not to 
exceed 800 mg/dose) 
 
If neurotoxicity is observed 
within 6 hours of dosing, 
consider anakinra 100 mg 
subcutaneously every 12 hours 
for up to 7 days (or another IL-1 
receptor inhibitor per 
institutional practice). 
Grade 2c 
 
Supportive care 
 
Dexamethasone 10 mg IV x 1.  Can 
repeat every 6 hours or 
methylprednisolone 1 mg/kg IV 
every 12 h if symptoms worsen. 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours for 
up to 7 days (or another IL-1 
receptor inhibitor per institutional 
Anti-IL-6 therapy as per grade 1 
 
Consider transferring subject to 
ICU if neurotoxicity associated 
with grade ≥ 2 CRS 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours 
for up to 7 days (or another IL-1 
receptor inhibitor per 


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Treatment 
by Grade 
No Concurrent CRS 
Additional Therapy if 
Concurrent CRS 
practice) if neurotoxicity is 
observed within 6 hours of dosing. 
institutional practice) if 
neurotoxicity is observed within 
6 hours of dosing. 
Grade 3c 
 
Supportive care 
 
Dexamethasone 10 mg IV every 6 h 
or methylprednisolone, 1 mg/kg IV 
every 12 ha 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours for 
up to 7 days if neurotoxicity is 
observed within 6 hours of dosing. 
 
Consider repeat neuroimaging (CT 
or MRI) every 2-3 days if subject had 
persistent grade ≥ 3 neurotoxicity. 
Anti-IL-6 therapy as per grade 1 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours 
for up to 7 days if neurotoxicity 
is observed within 6 hours of 
dosing 
Grade 4c 
 
ICU care, consider mechanical 
ventilation for airway protection. 
 
High-dose corticosteroidsa,b 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours for 
up to 7 days (or another IL-1 
receptor inhibitor per institutional 
practice) if neurotoxicity is 
observed within 6 hours of dosing 
 
Consider repeat neuroimaging (CT 
or MRI) every 2-3 days if subject has 
persistent grade ≥ 3 neurotoxicity. 
 
Treat convulsive status epilepticus 
per institutional guidelines. 
Anti-IL-6 therapy as per grade 1 
 
Consider Anakinra 100 mg 
subcutaneously every 12 hours 
for up to 7 days (or another IL-1 
receptor inhibitor per 
institutional practice) if 
neurotoxicity is observed within 
6 hours of dosing. 
CRS = cytokine release syndrome; CT = computed tomography; ICU = intensive care unit; 
IL-1 = interleukin 1; IL-6 = interleukin 6; IV = intravenous; MRI = magnetic resonance imaging. 
a Antifungal prophylaxis should be strongly considered in subjects receiving steroids for the 
treatment of CRS and/or neurotoxicity. 
b For example, methylprednisolone IV 1000 mg/day for 3 days, followed by rapid taper at 250 mg 
every 12 hours for 2 days, and 60 mg every 12 hours for 2 days. 
c Diagnostic lumbar puncture for grade 3-4 neurotoxicity; consider for grade 2. 
d Repeat tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing 
supplemental oxygen.  Limit to a maximum of 3 doses in a 24-hour period; maximum total of 
4 doses 
Tumor Lysis Syndrome 
Subjects with AML and WBC  10 000/mcL (or 10 cells x 109/L) are considered to be at 
low risk for tumor lysis syndrome.  White blood cells (WBC)  10 000/mcL and 
 50 000/mcL are considered to be at intermediate risk, and subjects with 
WBC  50 000/mcL are considered at high risk.  This protocol requires that subjects 
have a maximum WBC count of 15 000/mcL or 15 cells x 109/L.  


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Additional high risk features include baseline uric acid  450 mol/L (7.5 mg/dL), serum 
creatinine  1.4 mg/dL, and lactate dehydrogenase (LDH) greater than the ULN. 
Subjects with intermediate risk WBC count and elevated baseline uric acid 
( 450 mol /L), serum creatinine  1.4 mg/dL, or LDH greater than ULN will be 
recommended to receive allopurinol prophylaxis.  Typical dosing is 600 - 800 mg/day 
administered twice a day (BID) or 3 times a day (TID) and should begin 3 days before 
the first dose of study drug.  Subjects should be well hydrated and supplemented with 
intravenous fluid as clinically indicated. 
For grade 3 and 4 TLS, please see Section 6.2.1.3 for DLT considerations. 
Infection Prophylaxis 
Subjects who may experience neutropenia for 7 days or longer are at a high risk for 
infectious complications.  As appropriate, these subjects should be administered 
prophylactic antibacterial (eg, fluoroquinolones), antifungal, and antiviral medications.  
These subjects should be monitored for early signs of breakthrough infections after the 
initiation of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. 
6.7 
Medical Devices 
Depending on the dose, the investigational product must be administered using syringe 
pumps (for IV lower doses) or infusion pumps (for higher IV doses) approved for use by 
the appropriate regulatory authorities for the country in which the subject is undergoing 
treatment.  Investigational product infusion for solution will be prepared in syringes or 
bags for IV infusion and delivered through infusion lines.   
Other non-investigational medical devices may be used in the conduct of this 
stuady as part of standard of care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that 
are commercially available are not usually provided or reimbursed by Amgen (except, 
for example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or by (2) distributors and partners for 


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whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any drug(s), device(s), or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided. 
6.9 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period  
Any anti-tumor therapy other than the investigational product, including cytotoxic and/or 
cytostatic drugs, hormonal therapy, immunotherapy or any biological response modifiers, 
any other investigational agent, chronic systemic corticosteroid therapy, other 
immunosuppressive therapies, or stem-cell transplantation is not allowed.   
Exception:  Hydroxyurea is allowed to control WBCs as described in Section 6.3. 
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the Amgen medical monitor first.  Investigators should ensure that the need for 
radiation does not indicate progressive disease and that for subjects with measurable 
disease, radiation is not to the sole site of measurable disease.   
Live vaccines are prohibited during treatment with AMG 427. 
The following procedures should also not be undertaken within the time frames specified 
prior to enrollment and during the study:  
 
Participation in an investigational study (drug or device) within 14 days of study day 1 
 
Major surgery within 28 days of study day 1 (with the exception of biopsy or insertion 
of central venous catheter) 
 
Enrollment into another investigational drug or device study 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
Summary of Schedule of Assessments: 
Schedule 
Dosing Schedule 
Cycle/Assessment 
Table Number 
Schedule A 
(CLOSED) 
Days 1 and 5 
Cycle 1 
Table 10 
Cycle 2 
Table 11 


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Cycle  3 
Table 12 
Days 1, 5, 12, and 19 
Cycle 1 
Table 13 
Cycle 2 
Table 14 
Cycle  3 
Table 15 
Schedule B 
(CLOSED) 
Etanercept substudy 
Section 7.1.1 
Schedule C 
Days 1, 3, 5, and 8 
Cycle 1 
Table 16 
Cycle 2 
Table 17 
Cycle  3 
Table 18 
MRD Group Only 
Whole Blood MRD 
collection 
Table 22 
Days 1, 3, 5, 8, 12, 
and 19 
Cycle 1 
Table 19 
Cycle 2 
Table 20 
Cycle  3 
Table 21 
MRD Group Only 
Whole Blood MRD 
collection 
Table 23 
 


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Table 10.  Schedule of Assessments: Schedule A Cycle 1 (Days 1 and 5)  
 
Footnotes defined on next page 


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ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; eGFR  estimated glomerular filtration rate; IV  intravenous; PK  pharmacokinetic; 
SCR  Screening; 
 
a The Dose Level Review Team may recommend to change timing of D5 within a window of  1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly.  
b Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject’s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e Schedule for triplicate ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle. 
f Two (2) sets of triplicate ECGs collected at Screening. 
g Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
h The estimated glomerular filtration rate (eGFR) will be calculated based on institutional standards. 
i Premedication should be administered 1 hour before the start of infusion and prior to each step-up dose of AMG 427 infusion to mitigate the risk for the prevention of 
CRS. 
k Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 


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Table 11.  Schedule of Assessments: Schedule A Cycle 2 (Days 1 and 5) 
 
Footnotes defined on next page 


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ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; IV  intravenous; PK  pharmacokinetic;
a The Dose Level Review Team may recommend to change timing of D5 within a window of 1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly. 
b Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.  
e Premedication should be administered  1 hour before the start of infusion and prior to each step-up dose of AMG 427 infusion to mitigate the risk for the prevention of 
CRS. 
f Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 


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Table 12.  Schedule of Assessments: Schedule A Cycle 3 and Beyond (Days 1 and 5)  
 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EOT  End of Treatment; IV  intravenous; LTFU  long term follow-up; 
PK  pharmacokinetic; SFU  safety follow-up  


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a The safety follow-up (SFU) visit occurs 4 weeks (1 week) after the last infusion of AMG 427.  For subjects enrolled in the escalation phase, this visit may also be the 
end of study (EOS) visit.  
b The long term follow-up (LTFU) period may consist of a telephone call performed every 8 weeks ( 2 weeks) after the SFU visit, to assess survival, disease status 
and anti-AML therapy(ies).  LTFU applies only to subjects enrolled in the dose expansion phase.  The last contact with a subject may also signify EOS.  During the 
long-term follow-up phase serious adverse events suspected to be related to investigational product that the investigator becomes aware of will be 
reported to Amgen. 
c The Dose Level Review Team may recommend to change timing of D5 within a window of  1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly.   
d Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   
e See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
f Collect anti-AML treatments only. 
g Vital signs/pulse oximetry will also be assessed prior when the subject leaves the clinic in order to detect possible signs and symptoms of infusion reactions. 
h Time points for vital sign and pulse oximetry measurements after the end of infusion time point apply only if the subject is still at the clinic at the time. 
i Premedication should be administered 1 hour before the start of infusion and prior to each step-up dose of AMG 427 infusion to mitigate the risk for the prevention of 
CRS.  
j Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is not 
logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 
k Beginning with cycle 4, only predose PK samples are collected (predose:  D1, D5), EOT, and SFU for cycles 4 through 12.  Day 8 PK collection will not be collected 
C4 and beyond. 
o If applicable, urine pregnancy test required 4 weeks after the last dose of AMG 427. 


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Table 13.  Schedule of Assessments: Schedule A Cycle 1 (Days 1, 5, 12 and 19) 
Footnotes defined on next page 


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ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; eGFR  estimated glomerular filtration rate; IV  intravenous; PK  pharmacokinetic; 
SCR  Screening; 
a The Dose Level Review Team may recommend to change timing of dose within a window of  1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly.  
b Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e Schedule for triplicate ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle. 
f Two (2) sets of triplicate ECGs collected at Screening. 
g Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
h The estimated glomerular filtration rate (eGFR) will be calculated based on institutional standards.  
j Whole blood for peripheral blood mononuclear cells (PBMCs) collected prior to the infusion on cycle 1 day 1 only if subject provides consent for collection of the 
pharmacogenetic (PG) sample. 
k Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 


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Table 14.  Schedule of Assessments: Schedule A Cycle 2 (Days 1, 5, 12 and 19) 
 
Footnotes defined on next page 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; IV  intravenous; PK  pharmacokinetic; 
a The Dose Level Review Team may recommend to change timing of dose within a window of 1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly 
b Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   


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c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital or leaves the clinic in order to detect possible signs and symptoms of 
infusion reactions.  
e Time points for vital sign and pulse oximetry measurements after the end of infusion time point apply only if the subject is still at the clinic at the time. 
f Premedication should be administered 1 hour before the start of infusion and prior to each step-up dose of AMG 427 infusion to mitigate the risk for the prevention of 
CRS. 
g Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 


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Table 15.  Schedule of Assessments: Schedule A Cycle 3 and beyond (Days 1, 5, 12, and 19) 
 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EOT  End of Treatment; IV  intravenous; LTFU  long term follow-up; 
PK  pharmacokinetic; SFU  safety follow-up  
a The safety follow-up (SFU) visit occurs 4 weeks (1 week) after the last infusion of AMG 427.  For subjects enrolled in the escalation phase, this visit may also be the 
end of study (EOS) visit. 


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b The long term follow-up (LTFU) period may consist of a telephone call performed every 8 weeks ( 2 weeks) after the SFU visit to assess survival, disease status, 
and anti-AML therapy(ies).  LTFU applies only to subjects enrolled in the dose expansion phase.  The last contact with a subject may also signify EOS.  During the 
long-term follow-up phase serious adverse events suspected to be related to investigational product that the investigator becomes aware of will be 
reported to Amgen. 
c The Dose Level Review Team may recommend to change timing of dose within a window of  1-3 days.  In this case, timing of the following visits would be adjusted 
accordingly.   
d Collect assessments at the end of infusion (EOI).  End of infusion time is defined as the time at which the total infusion is complete (end of investigational product 
AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, 90 minutes).   
e See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of infusion for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be 
related to cytokine release syndrome (CRS). 
f Collect anti-AML treatments only. 
g Vital signs/pulse oximetry will also be assessed prior when the subject leaves the clinic in order to detect possible signs and symptoms of infusion reactions. 
h Time points for vital sign and pulse oximetry measurements after the end of infusion time point apply only if the subject is still at the clinic at the time. 
i Premedication should be administered 1 hour before the start of infusion and prior to each step-up dose of AMG 427 infusion to mitigate the risk for the prevention of 
CRS.  
j Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is not 
logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 
k Beginning with cycle 4, ONLY predose PK samples are collected (Predose: D1, D5, D12, D19), EOT and SFU for cycles 4 through 12.  Day 28 PK collection will not 
be collected C4 and beyond. 
o If applicable, urine pregnancy test required 4 weeks after the last dose of AMG 427. 
 


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7.1.1 
Schedule of Assessments:  Schedule B (etanercept substudy –
 CLOSED) 
 
Only for the etanercept (Enbrel) substudy (
 
): 
 
Schedule A  etanercept to be administered subcutaneously (50 mg SC) on 
day - 2 (minus 2) prior to each cycle 
All other study measures and schedules remain unchanged.  Please refer to 
Schedule A (Table 10 - Table 15) for daily visits and sample collections for 
etanercept subjects. 
 
Schedule C may also be considered with sponsor approval (Table 16 - Table 21). 
 
The MRD Group will use Schedule C for all cycle collections and Table 22 or 
Table 23 for additional whole blood MRD collections, as applicable.   
 


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Table 16.  Schedule of Assessments:  Schedule C Cycle 1 (Days 1, 3, 5, and 8) 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; eIV = extended IV; IV = intravenous; 
PK = pharmacokinetic; SCR = Screening 
a The Dose Level Review Team may recommend to change timing of D3, D5, D8 within a window of  1-3 days.  In this case, timing of the following visits would be 
adjusted accordingly. 
b Collect assessments at the end of infusion (EOI).  For the First-in-Human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours).   
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e Schedule for triplicate ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle. 
f Two (2) sets of triplicate ECGs collected at Screening. 


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g Serum pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal. 
h The estimated glomerular filtration rate (eGFR) will be calculated based on institutional standards 
i Premedication should be administered within 1 hour before the start of AMG 427 dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the 
prevention of CRS. 
 Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory. 
o Of note, for the eIV cohorts, please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (90 minutes each). 


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Table 17.  Schedule of Assessments:  Schedule C Cycle 2 (Days 1, 3, 5, and 8) 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eIV = extended IV; IV = intravenous; PK = pharmacokinetic 
a The Dose Level Review Team may recommend to change timing of D3, D5, D8 within a window of 1-3 days.  In this case, timing of the following visits would be 
adjusted accordingly 
b Collect assessments at the end of infusion (EOI).  For the First-in-human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours).  
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e Premedication should be administered within 1 hour before the start of AMG 427 dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the 
prevention of CRS. 


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f Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory.  
i Of note, for the eIV cohorts, please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (0 minutes each). 


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Table 18.  Schedule of Assessments:  Schedule C Cycle  3 (Days 1, 3, 5, and 8) 
 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EOT  End of Treatment; eIV  extended IV; IV  intravenous; LTFU  long term follow-up;  
PK  pharmacokinetic; SFU  safety follow-up 
a The safety follow-up (SFU) visit occurs 4 weeks (1 week) after the last dose of AMG 427.  For subjects enrolled in the escalation phase, this visit may also be the 
end of study (EOS) visit. 
b The long term follow-up (LTFU) period may consist of a telephone call performed every 8 weeks ( 2 weeks) to assess disease status and anti-AML therapy(ies).  
LTFU applies only to subjects enrolled in the dose expansion phase.  The last contact with a subject may also signify EOS.  During the long-term follow-up phase 
serious adverse events suspected to be related to investigational product that the investigator becomes aware of will be reported to Amgen. 
c The Dose Level Review Team may recommend to change timing of D3, D5, D8 within a window of  1-3 days.  In this case, timing of the following visits would be 
adjusted accordingly.  
d Collect assessments at the end of infusion (EOI).  For the First-in-Human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours).   


Product:  AMG 427 
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e See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
f Collect anti-AML treatments only. 
g Vital signs/pulse oximetry will also be assessed prior when the subject leaves the clinic in order to detect possible signs and symptoms of infusion reactions. 
h Time points for vital sign and pulse oximetry measurements after the end of dose time point apply only if the subject is still at the clinic at the time. 
i Premedication should be administered within 1 hour before the start of dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the prevention of 
CRS. 
j Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is not 
logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory.   
k For cycles 4 through 12, only predose PK samples are collected (Predose:  D1, D3, D5, D8), EOT and SFU for cycles 4 through 12.  Day 8 PK collection will not 
collected C4 and beyond. 
o If applicable, urine pregnancy test required 4 weeks after the last dose of AMG 427.  
q Of note, for the eIV cohorts, please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (90 minutes each). 


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Table 19.  Schedule of Assessments:  Schedule C- Cycle 1 (Days 1, 3, 5, 8, 12, and 19) 
 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; eGFR  estimated glomerular filtration rate; eIV  extended IV; IV  intravenous; 
PK  pharmacokinetic; SCR  Screening 
a The Dose Level Review Team may recommend to change timing of D3/D5/D8//D12/D19 within a window of  1-3 days.  In this case, timing of the following visits 
would be adjusted accordingly. 
b Collect assessments at the end of infusion (EOI).  For the First-in-Human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours). 
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e Schedule for triplicate ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle. 
f Two (2) sets of triplicate ECGs collected at Screening. 


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g Serum pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal. 
h The estimated glomerular filtration rate (eGFR) will be calculated based on institutional standards 
i Premedication should be administered within 1 hour before the start of dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the prevention of 
CRS. 
j Whole blood for peripheral blood mononuclear cells (PBMCs) collected prior to the dose on cycle 1 day 1 only if subject provides consent for collection of the 
pharmacogenetic (PG) sample. 
k Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory.   
o Of note, for the eIV cohorts please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (90 minutes each). 


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Table 20.  Schedule of Assessments:  Schedule C Cycle 2 (Days 1, 3, 5, 8, 12, and 19) 
 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eIV = extended IV; IV = intravenous; PK = pharmacokinetic 
a The Dose Level Review Team may recommend to change timing of D3/D5/D8/D12/D19 within a window of 1-3 days.  In this case, timing of the following visits 
would be adjusted accordingly 
b Collect assessments at the end of infusion (EOI).  For the First-in-Human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours). 
c See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
d Vital signs/pulse oximetry will also be assessed prior to subject`s discharge from hospital or leaves the clinic in order to detect possible signs and symptoms of 
infusion reactions. 
e Time points for vital sign and pulse oximetry measurements after the end of dose time point apply only if the subject is still at the clinic at the time. 
f Premedication should be administered within 1 hour before the start of dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the prevention of 
CRS. 
g Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory.   


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m Of note, for the eIV cohorts please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (90 minutes each). 
 


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Table 21.  Schedule of Assessments:  Schedule C Cycle  3 (Days 1, 3, 5, 8, 12, and 19) 
 
ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; eIV  extended IV; EOT  End of Treatment; IV  intravenous; LTFU  long term follow-up;  
PK  pharmacokinetic; SFU  safety follow-up; 
a The safety follow-up (SFU) visit occurs 4 weeks (1 week) after the last infusion of AMG 427.  For subjects enrolled in the escalation phase, this visit may also be the 
end of study (EOS) visit. 
b The long term follow-up (LTFU) period may consist of a telephone call performed every 8 weeks ( 2 weeks) to assess disease status and anti-AML therapy(ies).  
LTFU applies only to subjects enrolled in the dose expansion phase.  The last contact with a subject may also signify EOS.  During the long-term follow-up phase 
serious adverse events suspected to be related to investigational product that the investigator becomes aware of will be reported to Amgen. 
c The Dose Level Review Team may recommend to change timing of D3/D5/D8/D12/D19 within a window of  1-3 days.  In this case, timing of the following visits 
would be adjusted accordingly. 
d Collect assessments at the end of infusion (EOI).  For the First-in-Human cohorts:  End of infusion time is defined as the time at which the total infusion is complete 
(end of investigational product AMG 427 and flush infusion).  Collect assessments after total infusion time is complete (ie, short IV 90 minutes, eIV 24 hours).  


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e See protocol Section 6.2.1.1 for details on hospitalization requirements and in case of dose step.  Subjects should be monitored intensively for at least 4 hours after 
the start of dose for clinical signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) which may be related 
to cytokine release syndrome (CRS). 
f Collect anti-AML treatments only. 
g Vital signs/pulse oximetry will also be assessed prior when the subject leaves the clinic in order to detect possible signs and symptoms of infusion reactions. 
h Time points for vital sign and pulse oximetry measurements after the end of dose time point apply only if the subject is still at the clinic at the time. 
i Premedication should be administered within 1 hour before the start of dose and prior to each step-up dose of AMG 427 dose to mitigate the risk for the prevention of 
CRS. 
j Blood must not be drawn from the port catheter during investigational product infusion and for 5 minutes after the end of infusion.  If sample processing/shipment is 
not logistically feasible for a certain time point (eg, in case it coincides with the weekend) this sample time point is not mandatory.   
k For cycles 4 through cycle 12:  ONLY predose PK samples are collected (predose:  D1, D3, D5, D8, D12, D19).  EOT and SFU also to be collected cycles 4 through 
12.   
o If applicable, urine pregnancy test required 4 weeks after the last dose of AMG 427. 
q Of note, for the eIV cohorts please reference protocol details for dosing.  Day 1 eIV will be over day 1 and 2 (eg, 
 g dose will be infused over days 1 and 
2 [48 hours]), day 3 eIV infusion will be over day 3 only (eg, 
 g over 24 hours), day 5 and day 8 will be short term IV infusions (90 minutes each). 
 


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Table 22.  Schedule of Assessments:  MRD Group Only - Whole Blood MRD Collection (Days 1, 3, 5, and 8) 
 
 
EOT  End of Treatment; MRD  minimal/measurable residual disease; MRD  minimal/measurable residual disease-positive  
a MRD groups will follow all Schedule C (Table 16 through Table 21) for all collections.  Additionally, MRD cohorts will collect whole blood MRD at the following 
timepoints for all cycles. 


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Table 23.  Schedule of Assessments:  MRD Group Only – Whole Blood MRD Collection (Days 1, 3, 5, 8, 12, and 19) 
 
 
EOT  End of Treatment; MRD  minimal/measurable residual disease; MRD  minimal/measurable residual disease-positive  
a MRD cohorts will follow all Schedule C (Table 16 through Table 21) for all collections.  Additionally, MRD cohorts will collect whole blood MRD at the following 
timepoints for all cycles.


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7.2 
General Study Procedures 
A signed and dated IRB/IEC approved ICF must be obtained prior to performing any 
study-specific procedures including discontinuing standard therapy for observing a study 
washout period.  
During the study, every effort should be made to perform the study procedures as 
indicated on the Schedules of Assessments (Table 10 to Table 23).  Every effort should 
be taken to collect all biomarker and PK samples as described in the schedule of 
assessments.  However, if sample processing/shipment on a weekend/holiday is not 
logistically feasible for a site, this needs to be documented and will not be considered a 
deviation from the protocol. 
Subjects will be seen in the clinic for study evaluations.  When electrocardiograms 
(ECGs), vital signs, blood sample collections, biomarker sample collections, and 
aspirate/biopsy sample collections occur on the same visit, ECGs and vital signs should 
be performed before samples (blood, biopsy/aspirate) are collected.  Blood samples 
must not be taken/drawn from the catheter port used for AMG 427 infusion.  If a 
permanent central line with more than 1 lumen is used, blood draws can be done via the 
lumen that is not used for drug administration (see also Section 7.3.15).  The time of 
blood sample collection must be recorded with the exact time of collection (do not use 
the time that the samples were frozen or any other time point).   
The study specific manuals provide additional details regarding the requirements for 
these procedures. 
Acceptable deviation windows are as follows: 
 
Infusion duration 10 minute window.  
 
ECGs, biomarker blood draws (cycles 1 – 3), vital signs (including pulse 
oximetry):   
o  15 minute window if collected within the first 24 hours (excluding the 
24 hour sample) after the start of any dose 
o  2 hour window if collected between 24 hours and 3 days after the start 
of any dose   
o Assessments after day 3 but within 7 days post infusion start should be 
performed on the indicated study day, but are not required at a certain 
hour of the day   
o Assessments after day 7 have a  1 day window 
 
For R/R AML subjects, bone marrow assessments post treatment start:   3 days 


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 
For MRD subjects, bone marrow assessments do not need to be repeated if 
done within 3 months prior to start of treatment with AMG 427.  If more than 
3 months have passed, discuss with medical monitor prior to performing. 
 
PK blood draws in cycles 1 - 3:  
o within 2 hours prior to infusion start 
o  15 minute window for samples taken after the end of each dose 
o Blood must not be drawn from the port catheter during infusion and for 
5 minutes after the end of infusion.  End of infusion (EOI) is defined as 
end of total infusion time (after investigational product and IV flush 
infusion).   
For dosing visits a  1 - 3 day time window applies. 
Local laboratories should be used for the following assessments: hematology, 
hematological bone marrow assessments, clinical chemistry, coagulation, urinalysis, 
hepatitis serology, and serum pregnancy tests.  The following collections will be shipped 
to a central laboratory for analysis: blood samples for determination of serum 
concentrations of AMG 427 and presence of 
 
.  
Refer to the laboratory manual for detailed collection, processing, and shipping 
procedures. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion.  
7.2.1 
Screening  
After written informed consent has been obtained, subjects will be screened in order to 
assess eligibility for study participation.  All screening procedures must be performed 
within 14 days prior to start of investigational product administration, unless otherwise 
noted.  The ICF may be signed earlier than 14 days prior to start of investigational 
product in case of washout times that have to be observed to meet eligibility criteria.  
Re-consent is necessary if the date of consent is longer than 14 days prior to the start of 
the first dose of AMG 427. 
Subjects who meet the inclusion and exclusion criteria will be eligible to be enrolled in 
the study.  Subjects who do not meet the eligibility criteria within the 14-day screening 
period will not be eligible for enrollment.  Subjects who are deemed ineligible will be 
documented as screen failures. 
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation (up to a total of 2 times during the 14-day screening period) if necessary 


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before the subject is considered a screen failure.  If any assessments are repeated 
during the screening period, the value that is closest to the enrollment date will apply for 
the determination of eligibility.   
The following procedures are to be completed during the screening period at the time 
points designated in the Schedules of Assessments (Table 10 to Table 23).  
Assessments that were performed as standard of care prior to signature of informed 
consent but within 14 days prior to start of treatment with AMG 427 can be used as 
screening assessments and do not need to be repeated to confirm subject eligibility.  
Hepatitis serology does not need to be repeated to determine eligibility if it was 
performed within 6 weeks prior to start of treatment with AMG 427.  
 
Confirmation that the ICF has been signed  
 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety 
 
Clinical evaluation 
 
Physical examination as per standard of care (including medical/surgical 
history).  Physical examination findings should be recorded on the appropriate 
eCRF.   
 
ECOG performance status 
 
Height and weight 
 
Vital signs (ie, blood pressure, heart rate, respiratory rate, temperature) 
 
Pulse oximetry 
 
ECG triplicate measurements (2 sets of triplicates) 
 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test (females only), and hepatitis serology 
 
Estimated glomerular filtration rate (eGFR) 
 
Bone marrow assessments 
 
Serious adverse event reporting 
 
Documentation of concomitant and rescue medications. 
Re-screening: 
A subject may be rescreened up to 3 additional times during the study at the discretion 
of the investigator.  The subject must be re-consented if a re-screening attempt occurs 
outside the 14-day screening period.  
Re-screened subjects must be documented as screen failed in the subject’s medical 
record and subsequently documented as re-screened.  Subjects will retain the same 
subject identification number assigned at the time of initial screening.  Once the subject 


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is recorded as re-screened, a new 14-day screening window will begin.  The following 
assessments do not have to be repeated during re-screening if they were performed as 
standard of care or during the initial screening attempt within the time frames specified 
below:  
 
Hepatitis serology does not need to be repeated if it was performed within 6 weeks 
prior to start of treatment with AMG 427   
 
Bone marrow assessments (except molecular panel, see last bullet) do not need to 
repeated if done within 4 weeks prior to start of treatment with AMG 427 as long as 
subject did not receive any anti-leukemic therapy in the interim 
 
Molecular panel on bone marrow does not need to be repeated if done within 
3 months of starting AMG 427 therapy  
7.2.2 
Treatment 
Treatment begins on day 1 (cycle 1 day 1) when the first dose of investigational product 
is administered to a subject. 
After the mandatory hospitalization period (see Section 6.2.1.1), clinic visits may be 
conducted per institutional standard of care  
The following procedures will be completed during the treatment period at the times 
designated in the Schedules of Assessments (Table 10 to Table 23).   
Laboratory assessments that were done within 24 hours prior to treatment start do not 
need to be repeated at D1 prior to dose. 
 
Hospitalization (see Section 6.2.1.1 for minimum required hospitalization times) 
 
Investigational product doses (See Section 6.2.1.1 for details) 
 
Physical examination as per standard of care.  Abnormal findings from the physical 
examination findings should be recorded in the events form.   
 
ECOG performance status 
 
Weight  
 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature)  
 
Pulse oximetry 
 
ECG triplicate measurement (1 set) 
 
Laboratory assessments:  hematology, chemistry, coagulation, and urinalysis 
 
Biomarker assessments:   


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 
AMG 427 PK sample collection 
 
 
Bone marrow assessments  
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Documentation of concomitant medications 
 
Contrast enhanced MRI or computed tomography (CT) scan (to be considered in 
case of CNS adverse event of grade  3 only, particularly in cases of confusion, 
disorientation or seizures) 
 
Receipt of protocol-required therapies (may include premedication) 
 
Pharmacogenetics sample (optional) collected pre-dose cycle 1 day 1 
 
For subjects to whom intra-subject dose escalation (see Section 7.2.2) applies: 
 
ECG assessments should be performed as in cycle 1, regardless of actual study 
cycle 
 
PK samples should be taken as in cycles 1 and 2, respectively, regardless of 
actual study cycle 
 
All other assessments should be performed as per the schedule of assessments 
for the actual cycle.   
7.2.3 
End of Treatment Visit 
The EOT visit will occur at the end of the last treatment cycle.  For subjects who 
prematurely discontinue investigational product treatment, the EOT visit should occur as 
soon as possible after the last dose of investigational product was administered.  The 
following procedures will be completed during the EOT visit as designated in the 
Schedules of Assessments (Table 10 to Table 23): 
 
Physical examination as per standard of care.  Physical examination findings should 
be recorded on the appropriate eCRF.   
 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature) 
 
Pulse oximetry 
 
ECG triplicate measurement (1 set) 
 
Laboratory assessments: hematology, chemistry, coagulation, and urinalysis 
 
Biomarker assessments:   
 
AMG 427 PK sample collection 


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 
Serious adverse event reporting 
 
Adverse event reporting 
 
Documentation of concomitant medications   
7.2.4 
Safety Follow-up Visit 
The safety follow-up (SFU) visit is to be performed at least 4 weeks (or up to 7 days 
thereafter) after the last dose of AMG 427 or prior to the initiation of other AML therapy, 
whichever occurs earlier.  The safety follow-up period minimum is 30 days post last 
dose of investigational product.  All efforts should be made to conduct this visit 
including subjects who withdraw from treatment early.  If it is not possible to conduct the 
SFU visit, documentation of the efforts to complete the visit should be provided in the 
source documents and noted as not done in the eCRF.  
Subjects enrolled in the dose escalation phase who complete the safety follow-up visit 
will be considered to have completed the study.  
The following procedures will be completed at the SFU visit as designated in the 
Schedules of Assessments (Table 10 to Table 23).   
 
Physical examination as per standard of care.  Physical examination findings should 
be recorded on the appropriate eCRF. 
 
ECOG Performance Status 
 
Weight 
 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature) 
 
Pulse oximetry 
 
ECG triplicate measurement (1 set) 
 
Laboratory assessments: hematology, chemistry, and coagulation 
 
Biomarker assessments:   
 
AMG 427 PK sample collection 
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Documentation of concomitant medications 
 
Bone Marrow/MRD assessment 


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7.2.5 
Long-term Follow-up 
After the safety follow-up visit all subjects in the expansion phase only will enter the 
long-term follow-up (LTFU).  Subjects will be contacted by telephone to assess survival, 
disease status, and anti-AML therapy following the end of AMG 427 treatment.  On-site 
visits are not required by all subjects.  Contact for all subjects will be attempted every 
8 weeks ( 2 weeks) following the safety follow-up visit, as applicable, until death, 
subject withdraws full consent, or up to a maximum of 2 years from the first dose of 
AMG 427, whichever occurs first. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures listed in 
Section 7.2. 
7.3.1 
Informed Consent 
A signed ICF must be obtained from each subject prior to any study-mandated 
procedures.   
7.3.2 
Demographic Data 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.   
Additionally, demographic data will be used to study the impact of the protocol-required 
therapy on biomarker variability and PK.   
7.3.3 
Medical History and Prior Therapy 
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening up until the time of consent.  Medical history will 
include information on the subject’s concurrent medical conditions.  Record all findings 
on the medical history eCRF. 
Relevant medical history, including antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, bleeding, and infection (resolved and ongoing) will 
be collected.  AML history must date back to the initial diagnosis and any response 
duration must be recorded.  The current toxicity grade will be collected for each condition 
that has not resolved.  All prior cancer treatment therapies will be collected.  
7.3.4 
Concomitant Medications 
Concomitant therapies (including vaccines) are to be collected from informed consent 
through the EOS.  In case the screening period is shorter than 2 weeks (ie, informed 
consent is obtained less than 2 weeks prior to start of study treatment), concomitant 


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medications for which washout periods have to be observed (refer to Section 4.2, 
Section 6.3, and Section 6.9) are to be collected starting 2 weeks prior to start of study 
treatment.  Collect therapy name, indication, dose, unit, frequency, route, start date, and 
stop date. 
7.3.5 
Physical Examination 
A complete physical examination as per standard of care (rectal and vaginal examination 
not required) will be performed by the investigator or designee at screening and at the 
time points specified in the Schedules of Assessments (Table 10 to Table 23).  The 
physical examination will include general appearance, including examination of the skin, 
spleen, and signs of extramedullary leukemia and respiratory, cardiovascular, 
musculoskeletal, and neurological systems. 
The individual performing the physical examination will characterize their findings as 
either normal or abnormal.  Abnormal physical examination findings found during 
screening should be reported on the Medical History eCRF.  Abnormal physical 
examination findings found after the subject has provided consent will be reported on the 
Event eCRF. 
7.3.6 
ECOG Performance Status 
Subjects will be graded according to the ECOG Performance Status (see Appendix F).   
7.3.7 
Height Measurements 
Height in centimeters should be measured without shoes at screening. 
7.3.8 
Weight Measurements 
Weight in kilograms should be measured without shoes. 
7.3.9 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Record all measurements on the vital signs 
eCRF. 
The subject must be in a supine position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted.  If the subject is unable to be in the 
supine position, the subject should be in most recumbent position as possible.  The 
position selected for a subject should be the same that is used throughout the study and 
documented on the vital signs eCRF. 


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The location for temperature measurement selected for a subject should be the same 
that is used throughout the study and documented on the vital signs eCRF. 
7.3.10 
Pulse Oximetry 
Oxygen saturation will be measured using a standard pulse oximeter.  The subject must 
be in a rested and calm state for at least 5 minutes before pulse oximetry assessments 
are completed. 
7.3.11 
Electrocardiogram Performed in Triplicate 
The subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. 
ECGs should be performed in a standardized method, in triplicate, (ie, 
approximately 30 seconds apart), prior to blood draws or other invasive procedures.  
Each ECG must include the following measurements: QRS, QT, QTc, RR, and PR 
intervals. 
Electrocardiograms will be performed as follows: 
 
Baseline ECGs will be collected  30 minutes apart, with each baseline ECG in 
triplicate (ie, triplicate must be done approximately 30 seconds apart) 
 
2 sets collected at screening, and 
 
1 set collected pre-dose on cycle 1 day 1 [ie, total  9 ECGs]) 
 
Triplicate ECGs at time points after dosing. 
The investigator or designated site physician will review all ECGs.  Electrocardiograms 
will be transferred electronically to an ECG central reader for processing per Amgen 
instructions.  Once signed, the original ECG tracing will be retained with the subject’s 
source documents.  At the request of the sponsor, a copy of the original ECG will be 
made available to Amgen. 
Standard ECG machines should be used for all study-related ECG requirements. 
7.3.12 
Clinical Laboratory Tests 
The tests listed below in Table 24 will be conducted on samples collected and analyzed 
by standard laboratory procedures at the time points specified in the Schedule of 
Assessments (Table 10 to Table 23).  The test results are to be recorded on the eCRFs.  
Missed test(s) that are not done must be reported as such on the eCRFs. 


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Additional procedures (eg, collection of an unscheduled blood sample to measure 
cytokine levels) deemed necessary as part of standard of care or as required by local 
laws and regulations may be performed at the investigator’s discretion.   
A serum pregnancy test will be performed locally at each site at the screening visit on all 
females unless they are surgically sterile or  2 years postmenopausal.   
 


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Table 24.  List of Analytes 
Local Laboratory 
Central Laboratory 
Chemistry 
Hematology 
Urinalysis 
Coagulation 
Other Labs 
 
Sodium 
Potassium 
Bicarbonate or Total 
CO2  
Chloride 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
AST 
ALT 
Amylase 
Lipase 
CRP 
LDH 
Uric Acid 
eGFR (per institutional 
formula) 
Hemoglobin 
Hematocrit 
Platelets 
White Blood Cells  
Total Neutrophils  
Segmented Neutrophils  
Lymphocytes 
Monocytes  
Bands/Stabs 
Eosinophils 
Basophils 
Blasts 
Absolute neutrophil count 
Myeloblasts 
Erythrocyte 
sedimentation rate (ESR) 
Ferritin 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
Ketones 
Microscopic 
exam 
(performed at 
the discretion of 
the investigator) 
PT 
aPTT 
INR 
Fibrinogen 
D-Dimer 
Antithrombin 
Pregnancy testa 
Serology (HepB and HepC)b 
Bone marrow 
assessmentsc,d 
 
morphology 
 
immunophenotype 
 
cytogenetics 
 
molecular panel 
 
MRD  
 
 
AMG 427 PK samples 
Pharmacogenetics sample 
Biomarkers 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; aPTT  activated partial thromboplastin time; AST  aspartate aminotransferase;; CRP  C-reactive 
protein; HepB  hepatitis B; HepC  hepatitis C;
 INR  international normalize ratio; LDH  lactate dehydrogenase;
; MRD  Minimal/Measurable Residual Disease; PK  pharmacokinetic; PT  prothrombin time;
a Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal.  Urine pregnancy test will be performed 4 weeks after 
the last dose of AMG 427 (if applicable). 
b Serology may include: HepBsAg (hepatitis B surface antigen) and HepCAb (hepatitis C antibody). 
c A screening molecular panel on bone marrow is required (NPM1, FLT3 ITD/TKD, IDH1/2, CEBPA, etc.).  Molecular panel done within 3 months of study day 1 is 
acceptable. 
d Post-treatment bone marrow assessment is optional if the absolute peripheral blood blast count is  20 (screening bone marrow is still required). 


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7.3.13 
Events 
Adverse event and serious adverse event assessments will be made throughout the 
study and will be evaluated and recorded in the source documents and on the eCRF as 
specified in Sections 9.2 and 9.1.1, respectively.  The severity of all events will be 
graded according to CTCAE, version 4.0 (Appendix A) unless specified otherwise.  
Exception:  CRS will be graded according to the adopted grading system referenced in 
Lee et al, 2019 (see Table 6) and ICANS will be graded according to the criteria 
referenced in the publication by Lee et al, 2019 (see Table 8).  
7.3.14 
Head CT or Cranial MRI 
A contrast-enhanced MRI or CT scan of the head should be considered for subjects who 
experienced a CNS event grade 2 or higher, particularly in cases of confusion, 
disorientation or seizures. 
7.3.15 
Pharmacokinetic Blood Sampling 
Blood samples will be obtained for determination of serum concentrations of AMG 427 at 
the time points specified in the Schedules of Assessments (Table 10 to Table 23).  Blood 
must not be drawn from the port catheter during investigational product infusion and for 
at least 5 minutes after the end of infusion.  End of infusion is defined as end of total 
infusion time (after investigational product and IV flush infusions).  If a permanent central 
line with more than 1 lumen is used, blood draws can be done via the lumen that is not 
used for drug administration.  However, the preference is for PK samples to be drawn 
peripherally during infusion.  Sample collection, processing, storage, and shipping 
instructions are provided in a separate laboratory manual. 


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Table 25.  Bone Marrow Collections 
Test 
Time point 
Screening 
D14 (for cohorts 
receiving D1, D3 & 
5 doses)/D28 (for 
cohorts receiving 
D1, D3, 5, 8, 12, 
19 doses) for all 
cycles 
Unscheduled 
Bone marrow 
aspirate 
Required 
Required (unless 
peripheral blood 
absolute blast count 
20, in which case 
bone marrow 
assessments are 
optional). 
As needed (eg, if 
infusion-free period is 
prolonged beyond 
4 weeks for cytopenia, 
bone marrow aspirate 
must be performed 
before starting next 
cycle of AMG 427 
Bone marrow biopsy 
Required if aspirate 
is inadequate (eg, no 
spicules seen); 
optional if aspirate is 
adequate 
Optional 
Optional  
Conventional 
cytogenetics 
Required 
Optional 
Optional 
Immunophenotype 
(including 
FLT3/CD135)a 
Required on BM 
aspirate 
Required on BM 
aspirate/peripheral 
blood blasts 
Required on BM 
aspirates/peripheral 
blood blasts 
Molecular panel 
(NPM1, FLT3 
ITD/TKD, IDH1/2, 
CEBPA etc.) 
Required on BM 
aspirate, within 
3 months of day 1 is 
acceptable 
Optional 
Optional 
Minimal/Measurable 
residual disease 
assessment  
Required for MRD 
AML subjects, only if 
not done within 
3 months of 
enrollment (at local 
and central 
laboratory). 
Required on BM 
aspirates only for 
subjects in CR 
Required on BM 
aspirates only for 
subjects in CR 
AML  Acute Myeloid Leukemia; BM  bone marrow; C  cycle; CR  complete response; 
MRD  minimal/measurable residual disease; MRD  minimal/measurable residual disease-positive; 
R/R  relapsed/refractory; SOA  schedule of assessments 
a All disease/blast assessments must be confirmed by flow-cytometry based immunophenotype (a complete 
“AML flow panel” per institutional practices must be performed).  This assessment may include FLT3 
(CD135) expression ( and mean fluorescent intensity) on the myeloblasts. 


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Bone marrow assessments will be performed for the following: 
 
Morphology and immunophenotype to confirm eligibility at screening and response to 
treatment   
 
Standard cytogenetics – mandatory at screening only  
 
Immunological phenotyping to verify myeloid leukemia and assessments of MRD (if 
applicable) and 
 
 
See Section 7.2.1 for guidelines for re-screening. 
Additional bone marrow sampling may occur at other time points at the investigator’s 
discretion as clinically indicated.  Unscheduled bone marrow aspirate and biopsy results 
will be captured in the respective eCRFs. 
7.5.2 
Assessment of MRD 
The term MRD refers to the ‘occult’ low amount of leukemia that may persist during 
remission in the absence of clinical or hematological evidence of disease.  Recently, the 
level of MRD was established as a prognostic factor that predicts relapse.  MRD 
detection in AML using polymerase chain reaction (PCR) based techniques for 
molecular markers is applicable only in a minority of cases.  Immunophenotypical 
detection of MRD is analyzed in 1 of 2 ways:  (a) leukemia-associated 
immunophenotype (LAIP) or (b) deviation from normal maturation.  The first is based 
upon the presence of so called LAIPs, which are unusual or aberrant 
immunophenotypes that distinguish leukemic cells from normal hematopoietic cells.  The 
second, deviation from normal maturation, relies upon immunophenotypic deviation 
relative to normal bone marrow maturation.  In this study, we will utilize the deviation 
from normal maturation method of MRD detection, as determined by a board-certified 
hematopathologist.  This method relies upon cross-lineage antigen expression (eg, the 
expression of lymphoid markers on myeloid cells), asynchronous antigen expression 
(eg, the coexpression of early markers with mature myeloid markers), overexpression of 
antigens (eg, relatively high expression levels of particular myeloid or lymphoid 
markers), and/or ectopic expression (eg, the expression of particular antigens that 
normally are not expressed on hematopoietic cells).  At diagnosis, the 
immunophenotypic deviation relative to normal bone marrow maturation is identified, and 
this diagnostic immunophenotype is used as a starting point to follow the discrete 
population having an immunophenotype different from normal bone marrow.  Deviation 


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from normal maturation has an advantage over the LAIP method of MRD detection in 
that it has improved sensitivity through population identification and it is less sensitive to 
immunophenotypic instability. 
The method of MRD detection is quite easy to perform and is sensitive, with a detection 
ability of 1 malignant cell among 1,000 to 10,000 normal cells, but it requires detailed 
immunophenotypical knowledge of normal bone marrow cell differentiation.  Bone 
marrow after different courses of therapy, stem cell transplants, and sequential follow-up 
bone marrow sampling have been used for MRD assessment.  
In this study, MRD assessments will be utilized as both an eligibility/inclusion criteria in 
the MRD cohort, as well as an additional efficacy endpoint for all cohorts.  
 
 
.  For 
subjects enrolling in MRD group, bone marrow sample for MRD assessment is required 
for both local and central testing (except at screening visit for subjects with historical test 
result available  3 months from start of treatment). 
7.5.2.1 
MRD Testing for Screening/Eligibility for MRD Group 
For subjects to be eligible for study participation in MRD groups, bone marrow MRD 
assessment is required prior to enrollment to establish MRD status; local testing is 
sufficient for enrollment.  Collection of bone marrow aspirate following local standard of 
care procedure for MRD testing is not expected to present any additional risk to the 
health, safety, and welfare of the subject.  Screening for MRD will be conducted using an 
investigational diagnostic or validated local test/assay at a CLIA certified laboratory (for 
US only) agreed upon by the Sponsor; local testing is sufficient for the enrollment 
decision if the test result is from  3 months from the start of treatment.  If new local 
testing is performed during screening, additional bone marrow aspirate from the same 
bone marrow pull is required to be sent for exploratory testing at central lab for these 
subjects. 


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7.7 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of AML and/or to identify 
subjects who may have positive or negative response to AMG 427.  For subjects who 
consent to this/these analysis/analyses, DNA may be extracted.  
7.8 
Sample Storage and Destruction 
Any blood, biomarker, PK, cytogenetic, and bone marrow aspirate and biopsy samples 
collected according to the Schedule of Assessments (Table 10 to Table 23) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand AML, 
the dose response and/or prediction of response to AMG 427, characterize antibody 
response, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained, but are 


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not necessarily reported as part of this study.  Samples can be retained for up to 
20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker, biomarker development, or 
other exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, biomarker, PK, cytogenetic, and bone marrow aspirate and biopsy samples and 
any other components from the cells can be located and destroyed.  Samples will be 
destroyed once all protocol-defined procedures are completed.  However, information 
collected from samples prior to the request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 


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(Table 10 to Table 23) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other treating 
physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events, and device related events.  Subjects who have discontinued 
investigational product and/or protocol required therapies or procedures should not be 
automatically removed from the study.  Whenever safe and feasible it is imperative that 
subjects remain on-study to ensure safety surveillance and/or collection of outcome 
data.  The investigator must document the level of follow-up that is agreed to by the 
subject.    
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, medical device(s), and/or other protocol required therapies, protocol 
procedures, or the study as a whole at any time prior to study completion.  
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
subject request   
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 


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 
Confirmed disease progression as defined by revised IWG response criteria 
(Appendix E) or disease progression accompanied by worsening of symptoms or 
deterioration of the subject’s general condition 
 
Protocol specified criteria: 
 
Proceeding to HSCT 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study, or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
Every increase in severity of an adverse event needs to be recorded.  Decrease in 
severity only has to be recorded for DLTs and adverse events that lead to interruption of 
treatment/delay of a subsequent dose.   
For situations when an adverse event or serious adverse event is due to AML, report all 
known signs and symptoms.  Death due to disease progression in the absence of signs 
and symptoms should be reported as the primary tumor type (eg, metastatic pancreatic 
cancer).  
Note:  The term “disease progression” should not be used to describe the adverse event.   


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The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria): 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization,” if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event.”  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
9.1.3 
Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 6.7 for the list of Amgen medical devices). 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include, but are not limited to, 
adverse events resulting from insufficient or inadequate instructions for use, adverse 
events resulting from any malfunction of the device, or adverse events resulting from use 
error or from intentional misuse of the device. 


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A combination product is a product composed of any combination of a drug, a 
device, and a biological product.  Each drug, device, and biological product 
included in a combination product is referred to as a “constituent part” of the 
combination product. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from the time of consent through 
30 days after the last day of the dosing interval of investigational product/safety 
follow-up visit (whichever occurs later), are reported using the Events CRF.  Adverse 
events will be collected up to the safety follow up visit. 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Assessment of seriousness, 
 
Severity (and/or toxicity per protocol), 
 
Assessment of relatedness to investigational products or study 
procedure/activity, and 
 
Action taken. 
The adverse event grading scale used will be the CTCAE, version 4.0.  The grading 
scale used in this study is described in Appendix A.  Exception:  CRS will be graded 
according to the guidelines provided in Table 6 (based on the adopted grading system 
referenced in Lee et al, 2019) and ICANS will be graded according to the guidelines 
provided in Table 8 (based on the grading system referenced in the publication by 
Lee et al, 2019). 
The investigator must assess whether the adverse event is possibly related to the 
investigational product.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational product, and/ or study procedure/activity?   
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 


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findings without clinical significance (based on the Investigator’s judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval of investigational 
product/safety follow-up visit, whichever occurs later, are recorded in the subject’s 
medical record and are submitted to Amgen.  All serious adverse events must be 
submitted to Amgen within 24 hours following the investigator’s awareness of the event 
via the Events CRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report form within 24 hours of the 
investigator’s awareness of the event.  See Appendix B for a sample of the serious 
adverse event worksheet/electronic Serious Adverse Event Contingency Report form.  
For EDC studies where the first notification of a serious adverse event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product or study procedure.  This relationship is indicated by a “yes” 
or “no” response to the question: Is there a reasonable possibility that the event may 
have been caused by the investigational product and/or study procedure?  Relatedness 
means that there are facts or reasons to support a relationship between investigational 
product/study procedure/activity and the event.  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 


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Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
During the Long Term Follow-up period, if the investigator becomes aware of 
serious adverse events suspected to be related to investigational product after the 
protocol-required reporting period (as defined in Section 9.2.1.2) is complete, then 
these serious adverse events will be reported to Amgen within 24 hours following 
the investigator’s awareness of the event on the Events CRF.   
After End of Study, there is no requirement to actively monitor study subjects 
after the study has ended with regards to study subjects treated by the 
investigator.  However, if the investigator becomes aware of serious adverse 
events suspected to be related to investigational product, then these serious 
adverse events will be reported to Amgen within 24 hours following the 
investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period 
will be captured within the safety database as clinical trial cases and handled 
accordingly based on relationship to investigational product.  If further safety 
related data is needed to fulfill any regulatory reporting requirements for a 
reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 


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9.2.1.4 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
Any adverse event resulting from an adverse device effect that occur during the study 
will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event case report form (CRF) page. 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident. 
9.2.1.5 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.1.6 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 


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Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy, and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.1.7 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking AMG 427 report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 4 weeks after the last dose of AMG 427.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s awareness of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Form (Appendix C).  Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, 
or neonatal death or there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a serious adverse event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur through 30 days after the last dose of protocol-required 
therapies.  


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Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s awareness of event.  Report a lactation case on the Lactation 
Notification Form (Appendix C).  Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint:   
Safety:  
 
Dose limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and 
treatment-related adverse events (TRAEs) 
Secondary Endpoints:   
 
AMG 427 PK parameters including, but not limited to, maximum serum concentration 
(Cmax), minimum serum concentration (Cmin), area under the concentration-time curve 
(AUC), and if feasible, half-life (t½) of AMG 427 
 
Efficacy parameters for R/R AML:  subject response to treatment with 
AMG 427 (response defined as complete response/remission [CR]/ complete 
response/remission with incomplete recovery of peripheral blood counts [CRi], 
morphologic leukemia-free state, partial remission [per modified IWG criteria]), 
complete response/remission with partial hematologic recovery (CRh), and duration 
of response (duration of response will only be measured for subjects treated with the 
dose and schedule of the expansion cohort) 
 
Efficacy parameters for MRD AML:  subject response to treatment with 
AMG 427 (response refers to conversion from MRD status to MRD- status), relapse 
free survival and overall survival (relapse free survival, and overall survival will only 
be measured for subjects in expansion cohort) 
Exploratory Endpoints:   


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10.1.2 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 427. 
The analysis of DLT will be restricted to DLT-evaluable subjects (see Section 6.2.1.3 for 
definition).  The analysis of DLT will be restricted to DLT-evaluable subjects (see 
Section 6.2.1.3 for definition).   
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and 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.   
10.1.3 
Covariates and Subgroups 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
Subgroup analysis for those treated with siltuximab will be evaluated, including 
CRS outcomes, safety, and PK data. 
10.2 
Sample Size Considerations 
It is anticipated that approximately 200 subjects will be enrolled in this study.  
Approximately 110 subjects will be enrolled in the dose escalation cohorts (FIH:  N  90, 
Etanercept substudy (CLOSED):  N  25, MRD:  N  10, eIV:  N  10) and 90 subjects 
will be enrolled in the dose expansion cohorts (FIH:  N  40, MRD AML:  N  50).  
The sample size in the dose escalation is based on practical considerations and it is 
consistent with conventional oncology studies with the objective to estimate the MTD.  
With 2 subjects per cohort, there is a 19 to 55 probability of observing at least 1 DLT.  
With 3 subjects per cohort, there is a 27-70 probability of observing at least 1 DLT if 
the true DLT rate is 10-33 and with 4 subjects per cohort, there is a 34-80 probability. 


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In the dose expansion cohort, a subject number of 40 will provide an 87 probability of 
observing at least 1 adverse event with 5 incidence rate and 99 probability of 
observing at least 1 adverse event with 10 incidence rate.  A subject number of 50 will 
provide a 92.3 probability of observing at least 1 adverse event with 5 incidence rate 
and 99.5 probability of observing at least 1 adverse event with 10 incidence rate.  
These probabilities will be 64 and 88 respectively with a subject number of 20.  An 
exact 80 binomial confidence interval (CI) will be provided for response rate.  With the 
20 subjects and 20 response rate, the expected 80 CI would be 9 to 36.  With 
40 subjects and 20 response rate, the expected 80 CI would be 12 and 30.  With 
50 subjects and 40 response rate, the expected 80 CI would be 30.6 and 50.1. 
10.3 
Adaptive Design 
During dose expansion, Amgen will conduct evaluations of the ongoing DLT event rate 
and the ongoing overall response rate.  
Safety Stopping Rules during Dose Expansion: 
During dose expansion, Amgen will conduct evaluations of the ongoing DLT event rate 
to assess if the threshold for pausing enrollment has been reached.  If these stopping 
rules are met, then enrollment to the dose expansion will be paused pending a review of 
safety data and available pharmacokinetic, pharmacodynamics, and efficacy data by the 
DLRT.  This review may result in early termination of the study, notification to Health 
Authorities, or may result in re-initiation of enrollment.  The DLRT may implement 
additional measures, as appropriate, to reduce the risk of toxicity or to adapt and 
manage the toxicity.  The stopping rules to pause enrollment use a Bayesian approach 
proposed by Thall, et al (1995); enrollment to dose expansion will be halted if the 
posterior probability that the DLT rate is greater than 20 is  80.  The stopping 
boundaries assuming a prior distribution of Beta (0.40, 1.60) are presented in Table 26 
and the operating characteristics with pre-specified batch size of 6 new subjects per 
batch are presented in Table 35.  The evaluations could occur more frequently if 
necessary to address emerging safety concerns.  


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Table 26.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80 DLT Limit of 20 
Number of subjects 
Pause study enrollment if observing the number of these many DLT 
events 
6 
 3 
12 
 4 
18 
 6 
24 
 7 
30 
 9 
36 
 10 
40 
R/R AML expansion cohort completes 
42 
 11 
48 
 13 
50 
MRD+ AML expansion cohort completes 
AML  acute myeloid leukemia, MRD  minimal/measurable residual disease-positive, 
R/R  relapsed/refractory. 
Table 27.  Operating Characteristics With Batch Size of 6 Subjects 
 
R/R AML 
MRD AML 
True DLT 
rate 
Probability of 
early stopping 
of dose 
expansion 
Average 
dose 
expansion 
sample 
size* 
Probability of 
early stopping 
of dose 
expansion 
Average dose expansion 
sample size* 
0.10 
3.8 
38.9 
3.9 
48.5 
0.20 
34.0 
31.5 
37.8 
37.8 
0.25 
58.2 
25.6 
64.9 
29.4 
0.30 
78.9 
19.9 
85.5 
21.6 
0.35 
91.6 
15.4 
95.7 
16.0 
0.40 
97.4 
12.2 
99.1 
12.3 
0.50 
99.9 
8.7 
100 
8.7 
AML  acute myeloid leukemia, MRD  minimal/measurable residual disease-positive, 
R/R  relapsed/refractory. 
* The average dose expansion sample size assumes early termination of the study whenever the rules to 
pause study enrollment are met. 
Efficacy Futility Rules during Dose Expansion: 
During dose expansion, Amgen will conduct evaluations of the ongoing overall response 
rate to assess if the threshold for early trial termination for futility has been reached.  For 
R/R AML, a response consists of any of the following efficacious outcomes:  CR, 
CR with incomplete recovery of peripheral blood counts (CRi), morphologic 
leukemia-free state, partial remission and complete response/remission with partial 
hematologic recovery (CRh).  An overall response rate less than 15 is considered 


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insufficient efficacy.  Amgen proposes stopping enrollment to the dose expansion 
cohorts early if any of the following occurs. 
 
None of the initial 12 subjects treated experience a response 
 
2 or fewer of the initial 18 subjects treated experience a response 
 
3 or fewer of the initial 24 subjects treated experience a response 
Using these futility stopping rules, Table 28 shows the probability of early stopping and 
the average sample size in dose expansion. 
Table 28.  Probability of Early Stopping and the Average Sample Size in Dose 
Expansion 
True overall 
response rate 
Probability of early 
stopping after 
12 or fewer 
subjects 
Probability of early 
stopping after 
18 or fewer 
subjects 
Probability of early 
stopping after 
24 or fewer 
subjects 
Average 
sample size 
0.05 
0.54 
0.94 
0.98 
15.5 
0.10 
0.28 
0.74 
0.82 
20.7 
0.15 
0.14 
0.49 
0.58 
27.0 
0.20 
0.07 
0.28 
0.34 
32.5 
0.30 
0.01 
0.06 
0.07 
38.3 
  A conversion rate 
from MRD to MRD-  25 is considered insufficient efficacy.  Amgen proposes 
stopping enrollment to the dose expansion cohorts early if any of the following occurs: 
 
2 or fewer of the initial 12 subjects treated experience a response 
 
4 or fewer of the initial 18 subjects treated experience a response 
 
5 or fewer of the initial 24 subjects treated experience a response 
Using these futility stopping rules, Table 29 shows the probability of early stopping and 
the average sample size in dose expansion. 
Table 29.  Probability of Early Stopping and the Average Sample Size in Dose 
Expansion 
True overall 
response rate 
Probability of early 
stopping after 
12 or fewer 
subjects 
Probability of early 
stopping after 
18 or fewer 
subjects 
Probability of early 
stopping after 
24 or fewer 
subjects 
Average 
sample size 
0.05 
0.98 
1.00 
1.00 
12.1 


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0.15 
0.74 
0.90 
0.92 
16.2 
0.25 
0.39 
0.56 
0.60 
28.7 
0.35 
0.15 
0.23 
0.24 
41.4 
0.45 
0.04 
0.06 
0.06 
47.7 
Siltuximab Safety Stopping Rules: 
Amgen will conduct evaluations of the treatment and outcome of the CRS events 
treated with siltuximab on an ongoing basis to assess if the threshold for pausing 
siltuximab treatment has been reached as outlined in the table below.  If these 
stopping rules are met, an adhoc DLRM will be triggered to review safety data and 
available pharmacokinetic, pharmacodynamics, and efficacy data.  If 
recommended by DLRT, the use of siltuximab will resume.  The stopping rules to 
trigger an adhoc DLRM to review siltuximab treatment use a Bayesian approach 
proposed by Thall et al (1995); an adhoc DLRM will be triggered if the posterior 
probability that the CRS progression to grade 3 rate is greater than 20% is > 80% 
or the posterior probability that the CRS progression to grade 4 rate is greater 
than 7.5% is > 80%; or observation of any grade 5 CRS after the event has been 
treated with siltuximab.  The stopping boundaries presented below assume a prior 
distribution of Beta (0.4, 1.6) for progression to grade 3 CRS and a prior 
distribution of Beta (0.15, 1.85) for progression to grade 4 CRS.  The evaluations 
could occur more frequently if necessary to address emerging safety concerns.  If 
the triggered ad hoc DLRM coincide with regular DLRM, they may be combined. 
Number of Subjects 
Treated with Siltuximab 
Trigger DLRM if severity of any CRS event treated with 
siltuximab progresses to Grade 5  
Or this number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab 
Or this number of 
subjects with severity 
of CRS progressed to 
Grade 4 after being 
treated with siltuximab 
5 
≥ 3 
≥ 2 
10 
≥ 4 
≥ 2 
15 
≥ 5 
≥ 3 
20 
≥ 6 
≥ 3 
25 
≥ 7 
≥ 4 
30 
≥ 9 
≥ 4 
35 
≥ 10 
≥ 5 
40 
≥ 11 
≥ 5 
CRS = cytokine release syndrome; DLRM = dose level review meeting 


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10.4 
Planned Analyses 
The following data analyses are planned:  (1) the primary analysis after all 
dose-escalation and dose-expansion subjects had the opportunity to receive up to 
12 cycles of treatment or terminated the study early, and (2) the final analysis after all 
subjects have ended the study. 
10.4.1 
Interim Analyses and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations.  In DLRMs, Amgen, 
in consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
decisions.  As a sensitivity analysis, a 1-parameter Continual Reassessment Method 
(CRM) model may be used to estimate the dose-toxicity relationship to help making dose 
escalation decisions.  Adverse events and DLTs observed in all subjects will be 
evaluated continually and fully integrated into all DLRMs and considered in all enrollment 
and dosing decisions. 
Ad-hoc interim analysis for efficacy parameters will be conducted after dose escalation is 
completed.  Once preliminary MTD and R2PD is established, FDA will be provided with 
brief interim results of the dose escalation phase. 
10.4.2 
Dose Level Review Team (DLRT) 
DLRMs will be held to review data, monitor safety, and make decisions on dose 
escalation/change, or changes in pre-medication.  If a cohort extension of up to 
6 subjects initiates, a DLRT meeting will be conducted after completion of the Japan 
cohort extension.  The DLRT will be composed of the investigators or designees, and 
the following Amgen representatives: early development leader, global safety officer or 
designee, clinical study manager, biostatistician, PK scientist (optional), and other 
functional area representatives as appropriate.  The following members are responsible 
for DLRT recommendations: investigators, Amgen medical monitor, and global safety 
officer or designee.  All available study data, including data collected after the initial DLT 
window, and including demographics, investigational product administration, medical 
history, concomitant medications, adverse events, ECGs, vital signs, laboratory data, 
and PK/PD information will be reviewed.  In addition to DLTs, all  grade 3 toxicities not 
meeting DLT criteria will be reviewed and may be considered in DLRT 
recommendations.  Modeling of available potential safety risk data (eg, for 


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thrombocytopenia) to predict safety risk for dose escalation decisions may also be 
considered. 
A quorum as defined below must be in attendance for the DLRM.  The quorum is defined 
as  50 of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator possessing written documentation [eg, e-mail] of the 
investigator`s vote), as well as  50 of Amgen representatives listed above.  The early 
development leader or designee must attend for the quorum to be reached.  The DLRM 
will be rescheduled if a quorum is not reached.   
The following recommendations will be made by the DLRT: 
 
dose escalation/de-escalation decisions  
 
administration of additional doses on D12/D19 of a cycle 
 
number of subjects per cohort 
 
continuation, delay or termination of dosing 
 
implementation of dose step(s) 
 
change of the D1/D3/ D5/D12/D19 dosing scheme within the pre-specified window of 
 1-3 days 
 
extension of the treatment-free interval between treatment cycles 
 
If grade 5 event is fatal and suspected to be related to investigational product, study 
may be put on hold if recommended by DLRM. 
Additionally, the DLRT will review safety data for each of the Japan cohort extension 
subjects, at regular intervals as part of ongoing DLRMs.  
Subjects’ cytogenetic profiles (eg, potentially higher cytokine release in monocytic AML) 
should be taken into consideration for DLRT recommendations.   
In the expansion phase, all available study data will be reviewed (with recruitment 
ongoing) by the DLRT once every 6th subject has at least completed their first treatment 
cycle plus 2 weeks or dropped out of treatment/study, whichever occurs earlier.  Ad hoc 
meetings may be convened any time in case of important safety events. 
10.4.3 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject had 
the opportunity to receive up to 12 cycles of treatment or terminated the study early.   


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10.4.4 
Final Analysis 
A final analysis is planned after all dose-escalation cohorts and dose-expansion subjects 
have ended the study.  Primary and final analysis may be combined in case all subjects 
have ended study close to the time point of the primary analysis.  
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD 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.  Graphical 
summaries of the data may also be presented.  A 2-parameter BLRM will be used to 
estimate the dose-toxicity relationship.  See Appendix H for the description of the 
2 parameter-BLRM design.  
10.5.2 
Primary Endpoint 
Safety Endpoints 
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the safety analysis set, which includes subjects that are enrolled and 
received at least 1 dose of AMG 427. 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels. 
Adverse Events 
Subject incidence of all treatment-emergent and treatment-related adverse events will 
be tabulated by system organ class, preferred term, and worst severity grade.  The 
number and percentage of subjects reporting adverse events will be evaluated overall 
and by dose level and will also be tabulated by relationship to study drug. 
Tables of treatment-emergent and treatment-related fatal adverse events, serious 
adverse events, and adverse events leading to withdrawal from investigational product 
or other protocol-required therapies will also be provided. 
Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be presented and reviewed for 
each subject.  Values outside the normal laboratory reference ranges will be flagged as 
high or low on the listings.  Depending on the size and scope of changes in laboratory 


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data, summaries of laboratory data over time and/or changes from baseline over time 
may be provided.  Tables of maximum shifts from baseline for selected laboratory values 
may also be provided. 
Vital Signs 
Vital signs data will be presented and reviewed for each subject.  Depending on the size 
and scope of changes, summaries of vital signs data over time and/or changes from 
baseline over time may be provided. 
Electrocardiograms 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.   
Subjects’ maximum change from baseline in QT interval corrected by Fridericia’s formula 
will be categorized and the number and percentage of subjects in each cohort will be 
summarized. 
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each cohort will be summarized. 
All on-study ECG data will be presented, and select parameters of interest may be 
plotted. 
10.5.3 
Secondary Endpoints 
10.5.3.1 
Pharmacokinetics Data Analysis 
For AMG 427, pharmacokinetic parameters will be determined from the 
time-concentration profile using standard non-compartmental approaches and 
considering the profile over the complete sampling interval.  Based on the review of the 
data, analyses to describe the relationship between AMG 427 exposure and either 
pharmacodynamic effect and/or clinical outcome may also be performed. 
10.5.3.2 
Efficacy Endpoint Analyses 
For R/R AML, the proportion of subjects with a CR/CRi/morphologic 
leukemia-free/CRh/Partial remission state with corresponding exact 80 CI will be 
calculated using the Clopper-Pearson method (Clopper and Pearson, 1934) by cohort 
and tabulated for all subjects treated at the MTD.  A Kaplan Meier curve may be 
presented for duration of response with estimates for rates and 80 CI at selected 
weeks for subjects in expansion cohort.  For MRD AML, the MRD conversion rate will 
be presented with corresponding exact 80 CI and tabulated by cohort and for all 


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subjects treated at the MTD.  A Kaplan Meier curve may be presented for relapse free 
survival and overall survival with estimates for rates and 80 CI at selected weeks for 
subjects in expansion cohort.  
 will be 
considered exploratory.   
10.5.4 
Exploratory Endpoints 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen study manager to the investigator.  The written ICF is 
to be prepared in the language(s) of the potential subject population. 


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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/are 
administered.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician is 
to be documented in the subject’s medical records, and the ICF is to be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion.  The original signed ICF is to be retained in accordance with institutional 
policy, and a copy of the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document, that Amgen distributes to the site.  The investigator is to notify the IRB/IEC 
of deviations from the protocol or serious adverse events occurring at the site and other 
adverse event reports received from Amgen, in accordance with local procedures. 


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The investigator is responsible for obtaining annual IRB/IEC approval /renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment.   
 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in strict 
confidence by the investigator, except as described below. 
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   


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Elements to include: 
 
Subject files containing completed CRF, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
 
Non-investigational product(s), and/or medical device(s) documentation. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The clinical monitor is responsible for verifying the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
clinical monitor is to have access to subject medical records and other study related 
records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 


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Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail.” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the eCRF, the data queries, and agrees with the content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 10 to Table 23), the investigator can search publicly 
available records [where permitted]) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
CRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.  All written information and other 
material to be used by subjects and investigative staff must use vocabulary and 
language that are clearly understood.   
12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 


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work are appropriately investigated and resolved.  Authors should meet conditions 
1, 2, 3 and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the informed consent that 
is available as a separate document. 


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de Lima M, Porter D, Battiwalla M et al.  Proceedings from the National Cancer 
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Enbrel USPI 
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Estey EH.  Treatment of relapsed and refractory acute myelogenous leukemia.  
Leukemia 2000;14:476-9. 
Everds NE and Tarrant JM.  Unexpected hematologic effects of biotherapeutics in 
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FDA Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
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Grupp SA, Kalos M, Barrett D, et al.  Chimeric antigen receptor-modified T cells for 
acute lymphoid leukemia.  N Engl J Med.  2013;368:1509–1518. 
Gust J, Hay KA, Hanafi LA, et al.  Endothelial activation and blood–brain barrier 
disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells.  
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ICH Harmonized Tripartite Guideline.  S6 (R1):  Addendum to ICH S6:  Preclinical safety 
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Jen EY, Xu Q, Schetter A, et al.  FDA Approval: Blinatumomab for Patients with B-cell 
Precursor Acute Lymphoblastic Leukemia in Morphologic Remission with Minimal 
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Jetani H, Garcia-Cadenas I, Nerreter T et al.  CAR T-cells targeting FLT3 have potent 
activity against FLT3-ITD AML and act synergistically with the FLT3-inhibitor 
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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE version 4 will be used for grading all adverse events (other than cytokine 
release syndrome [see Table 6] and ICANS will be graded according to the criteria 
referenced in the publication by Lee et al, 2019 [see Table 8]).  The CTCAE can be 
found at:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf  
Drug-induced Liver Injury Reporting & Additional Assessments Reporting 
To facilitate appropriate monitoring for potential signals of drug-induced liver injury 
(DILI), cases of concurrent AST or ALT and TBIL and/or INR elevation according to the 
criteria specified in Section 6.4 require the following:   
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.4.1 and Section 6.4.2 or who experience AST or ALT elevations  3 x ULN or 
2-fold increase above baseline values for subjects with evaluated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:   
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
 
In cases of TBIL  2x ULN or INR  1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic 


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 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBIL.  The following are to be considered depending on the clinical situation: 
 
Complete blood count (CBC) with differential to assess for eosinophilia 
 
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
CPK, haptoglobin, LDH, and peripheral blood smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
 
Follow the subject and the laboratory tests (ALT, AST, TBIL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


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Appendix B.  Sample Serious Adverse Event Form and eSerious Event 
Contingency Form 
 


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Appendix C.  Pregnancy and Lactation Notification Forms 
 


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Appendix D.  World Health Organization Classification for Acute Myeloid 
Leukemias 
Definition AML:   20 myeloblasts in blood or in bone marrow 
Abnormal promyelocytes in acute promyelocytic leukemia, promonocytes in AML with 
monocytic differentiation and megakaryoblasts in acute megakaryocytic leukemia are 
considered blast equivalents.  Patients with APML are not eligible for this study. 
First, AML should be classified as AML with recurrent cytogenetic abnormalities.  If this 
is not applicable the leukemia is classified as AML with multilineage dysplasia or therapy 
related and if this subtype is also not applicable as AML not otherwise categorized. 
Acute Myeloid Leukemia and Related Precursor Neoplasms, and Acute Leukemias 
of Ambiguous Lineage (WHO, 2016) 
Categories 
Acute myeloid leukemia with recurrent genetic abnormalities 
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
APL with PML-RARA* 
AML with t(9;11)(p22;q23); MLLT3-KMT2A 
AML with t(6;9)(p23;q34); DEK-NUP214 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21;q26.2); GATA2, MECOM 
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 
Provisional entity:  AML with BCR-ABL1; AML with mutated NPM1 
AML with biallelic mutation of CEBPA 
Provisional entity: AML with mutated RUNX1 
Acute myeloid leukemia with myelodysplasia-related changes‡ 
Therapy-related myeloid neoplasms§ 
Acute myeloid leukemia, not otherwise specified 
Acute myeloid leukemia with minimal differentiation 
Acute myeloid leukemia without maturation 
Acute myeloid leukemia with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/monocytic leukemia 
Pure erythroid leukemia 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis (syn.: acute myelofibrosis; acute myelosclerosis) 
Page 1 of 2 
Footnote defined on next page 


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Categories 
Myeloid sarcoma (syn.: extramedullary myeloid tumor; granulocytic sarcoma; chloroma) 
Myeloid proliferations related to Down syndrome 
Transient abnormal myelopoiesis (syn.: transient myeloproliferative disorder) 
Myeloid leukemia associated with Down syndrome 
Blastic plasmacytoid dendritic cell neoplasm 
Acute leukemias of ambiguous lineage 
Acute undifferentiated leukemia 
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1ǁ 
Mixed phenotype acute leukemia with t(v;11q23); KMT2A rearranged 
Mixed phenotype acute leukemia, B/myeloid, NOS 
Mixed phenotype acute leukemia, T/myeloid, NOS 
Page 2 of 2 
Adopted from Arber et al, 2016; for a diagnosis of AML, a marrow blast count of  20 is required, except 
for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv(16) or t(16;16) and some cases of 
erythroleukemia. 
* Other recurring translocations involving RARA should be reported accordingly: for example, AML with 
t(11;17)(q23;q12); ZBTB16-RARA; AML with t(11;17)(q13; q12); NUMA1-RARA;AML with 
t(5;17)(q35;q12); NPM1-RARA; or AML with STAT5BRARA (the latter having a normal chromosome 17 on 
conventional cytogenetic analysis). 
† Other translocations involving MLL should be reported accordingly: for example, AML with 
t(6;11)(q27;q23); MLLT4-MLL; AML with t(11;19)(q23;p13.3); MLLMLLT1; AML with t(11;19)(q23;p13.1); 
MLL-ELL;AML with t(10;11)(p12;q23); MLLT10-MLL. 
‡ More than 20 blood or marrow blasts AND any of the following: previous history of myelodysplastic 
syndrome (MDS), or myelodysplastic/myeloproliferative neoplasm (MDS/MPN); myelodysplasia-related 
cytogenetic abnormality (see below); multilineage dysplasia; AND absence of both prior cytotoxic therapy 
for unrelated disease and aforementioned recurring genetic abnormalities; cytogenetic abnormalities 
sufficient to diagnose AML with myelodysplasia-related changes are: 
- Complex karyotype (defined as 3 or more chromosomal abnormalities). 
- Unbalanced changes: _7 or del(7q); _5 or del(5q); i(17q) or t(17p); _13 or del(13q); del(11q); del(12p) or 
t(12p); del(9q); idic(X)(q13). 
- Balanced changes: t(11;16)(q23;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3; q21.1); t(2;11)(p21;q23); 
t(5;12)(q33;p12); t(5;7)(q33;q11.2); t(5;17)(q33;p13); t(5;10)(q33;q21); t(3;5)(q25;q34). 
§ Cytotoxic agents implicated in therapy-related hematologic neoplasms: alkylating agents; ionizing radiation 
therapy; topoisomerase II inhibitors; others. 
ǁ BCR-ABL1–positive leukemia may present as mixed phenotype acute leukemia, but should be treated as 
BCR-ABL1–positive acute lymphoblastic leukemia. 


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Appendix E.  Revised International Working Group Response Criteria  
Category 
Definition 
Complete 
remission (CR)1 
Bone marrow blasts  5; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count  1.0 x 109/L; platelet 
count  100 x 109/L; independence of red cell transfusions 
CR with 
incomplete 
recovery (CRi)2 
All CR criteria except for residual neutropenia ( 1.0 x 109/L) or 
thrombocytopenia ( 100 x 109/L) 
Morphologic 
leukemia-free 
state3 
Bone marrow blasts  5; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
Partial remission 
Relevant in the setting of phase 1 and 2 clinical trials only; all 
hematologic criteria of CR; decrease of bone marrow blast percentage to 
5 to 25; and decrease of pretreatment bone marrow blast percentage 
by at least 50 
Cytogenetic CR4 
Reversion to a normal karyotype at the time of morphologic CR (or CRi) 
in cases with an abnormal karyotype at the time of diagnosis; based on 
the evaluation of 20 metaphase cells from bone marrow 
Molecular CR5 
No standard definition; depends on molecular target 


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Treatment Failure Criteria 
Category 
Definition 
Resistant disease 
(RD) 
Failure to achieve CR or CRi (general practice; phase 2/III trials), or 
failure to achieve CR, CRi, or PR (phase 1 trials); only includes patients 
surviving  7 days following completion of initial treatment, with evidence 
of persistent leukemia by blood and/or bone marrow examination 
Death in aplasia 
Deaths occurring  7 days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 
7 days of death, without evidence of persistent leukemia 
Death from 
indeterminate 
cause 
Deaths occurring before completion of therapy, or 7 days following its 
completion; or deaths occurring  7 days following completion of initial 
therapy with no blasts in the blood, but no bone marrow examination 
available 
Patients who do not complete the first course of therapy 
Relapse6 
Bone marrow blasts  5; or reappearance of blasts in the blood; or 
development of extramedullary disease 
Molecular or 
cytogenetic 
relapse 
Reappearance of molecular or cytogenetic abnormality 
1 All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an 
aspirate with spicules; if ambiguous, consider repeat examination after 5 to 7 days; flow cytometric 
evaluation may help to distinguish between persistent leukemia and regenerating normal marrow; a 
marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum 
duration of response required. 
2 The criterion of CRi is of value in protocols using intensified induction or double induction strategies, in 
which hematologic recovery is not awaited, but intensive therapy will be continued.  In such protocols, CR 
may even not be achieved in the course of the entire treatment plan.  In these instances, the overall 
remission rate should include CR and CRi patients.  Some patients may not achieve complete hematologic 
recovery upon longer observation times. 
3 This category may be useful in the clinical development of novel agents within phase 1 clinical trials, in 
which a transient morphologic leukemia-free state may be achieved at the time of early response 
assessment. 
4 Four studies showed that failure to convert to a normal karyotype at the time of CR predicts inferior 
outcome. 
5 As an example, in CBF AML low-level PCR-positivity can be detected in patients even in long-term 
remission.  Normalizing to 104 copies of ABL1 in accordance with standardized criteria, transcript levels 
below 12 to 10 copies appear to be predictive for long-term remission. 
6 In cases with low blast percentages (5-10), a repeat marrow should be performed to confirm relapse.  
Appearance of new dysplastic changes should be closely monitored for emerging relapse.  In a patient 
who has been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy 
effect and recovery of hematopoiesis.  Cytogenetics should be tested to distinguish true relapse from 
therapy-related MDS/AML. 
 CRh (complete response/remission with partial hematologic recovery) will also be reported as an outcome 
measure.  CRh is defined as 5 blasts in bone marrow, no evidence of circulating blasts or 
extramedullary disease and partial recovery of peripheral blood counts (platelets  50,000/L, hemoglobin 
 7g/dL and absolute neutrophil count 500/L). 


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Progressive Disease* 
Progressive disease for patients with AML is defined as: 
 
Greater than 50 increase in bone marrow blasts from the best assessment and at 
least 20 marrow blasts. 
 
Greater than 50 increase in the peripheral blood absolute blast count and at least 
an absolute blast count of 1000/cmm. 
 
Development of extramedullary disease.  If the patient has extramedullary disease at 
baseline, then the development of a new site of disease. 
 
In patients who present with a bone marrow blast percentage sufficiently high to 
preclude the ability to determine disease progression by a  50 increase in the 
marrow blast percentage, then disease progression will be determined by peripheral 
blood criteria or the development of new sites of extramedullary disease. 
* Patients may remain on study treatment if the investigator believes the patient is deriving some benefit. 
Relapse Criteria 
Relapse after complete remission (CR) for patients with AML is defined as: 
 
recurrence of blasts in the marrow of  5 (excluding increased blasts in the context 
of regenerating marrow) 
 
recurrence of leukemic blasts in the peripheral blood 
 
recurrence of leukemia at an extramedullary site 
 
recurrence of pre-treatment characteristic signs of morphological dysplasia 
 
recurrence of Auer rods 
These response criteria were published in the 2010 paper, "Diagnosis and management 
of acute myeloid leukemia in adults:  recommendations from an international expert 
panel, on behalf of the European LeukemiaNet" (Dohner et al, 2010), and are based on 
Revised IWG recommendations published in 2003 (Cheson et al, 2003).   


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Appendix F.  Performance Status According to Eastern Cooperative Oncology 
Group (ECOG) 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 MM, Creech RH, Tormey DC et al.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group.  Am J Clin Oncol 1982; 5: 649-655 


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Appendix G.  2017 ELN Risk Stratification by Genetics 
Risk category* 
Genetic abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1   
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11  
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†  
Biallelic mutated CEBPA  
Intermediate 
Mutated NPM1 and FLT3-ITDhigh†  
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk 
genetic lesions)  
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡  
Cytogenetic abnormalities not classified as favorable or adverse  
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214  
t(v;11q23.3); KMT2A rearranged  
t(9;22)(q34.1;q11.2); BCR-ABL1  
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)  
−E or del(5q); −or −or del(5q); 
Complex karyotype,§ monosomal karyotype||  
Wild-type NPM1 and FLT3-ITDhigh†  
Mutated RUNX1¶  
Mutated ASXL1¶  
Mutated TP53  
Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient 
numbers are available, by specific genetic lesions indicated. 
* Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
† Low, low allelic ratio (0.5); high, high allelic ratio (0.5); semiquantitative assessment of FLT3-ITD allelic 
ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided 
by area under the curve “FLT3-wild type”; recent studies indicate that AML with NPM1 mutation 
and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should not routinely 
be assigned to allogeneic HCT.57-59,77  
‡ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene 
mutations. 
§ Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring 
translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or 
t(3;3); AML with BCR-ABL1. 
|| Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 
1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML).116  
¶ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk 
AML subtypes. 
 TP53 mutations are significantly associated with AML with complex and monosomal karyotype. 
 
 


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Appendix H.  Two-Parameter BLRM Design 
A 2-parameter Bayesian logistic regression model (BLRM,  
Neuenschwander et al, 2008) is used to guide dose escalation.  The MTD target Toxicity 
Probability Interval (TPI) for DLT is (0.20, 0.33) and TPIs of (0.33, 0.60) and (0.60, 1.00) 
are defined as excessive and unacceptable, respectively.  The design seeks to identify a 
dose most likely to have a DLT rate in the target TPI, but with overdose control that limits 
the possibility the dose has an excessive or unacceptable DLT rate (Babb et al, 1998).  
The probability of a DLT at dose level di is assumed to follow a Bernoulli distribution with 
probability pi where the logit of pi increases linearly with the log of the standardized dose 
in the following 2-parameter logistic model: 
 
log [pi/(1-pi)]  logit(pi)  log[a]  exp(log[b]) log (di/dref) 
where a and b are random variables and dref is 1 of the planned dose selected as the 
reference dose.   
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta  (log a, log b) where the probability that the true DLT rate is  0.40 at 
 g is 
0.90 and the probability the true DLT rate is  0.05 at the reference dose (
 g) is 
0.05.  Additionally, the prior is such that pi is approximately 0.05 for the 
 g dose and 
0.25 for the reference dose.  Once the 
 g is deemed safe by Dose Level Review 
Team (DLRT), the reference dose will be updated to the highest planned dose level. 
The operating characteristics of the 2-parameter BLRM design were evaluated via 
simulation.  The cohort size was fixed to 2 or 4 subjects.  All simulated studies start with 
the multiple subject cohorts.  The initial multiple subject dose level is 
 g and 
subsequent doses were selected based on the following rules: 
 
After each cohort, the next dose is the one with the highest probability of the target 
TPI, but with a less than 0.25 probability of an excessive or unacceptable TPI. 
 
Skipping dose levels is not allowed. 
Dose escalation was stopped given 1 or more of the following conditions: 
 
There have been at least 6 subjects treated at the dose recommended by the model. 
 
A maximum number of 36 subjects in the multiple subject cohorts is evaluated (note: 
this assumes that n  4 subjects treated in single subject cohorts). 


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Operating characteristics are described below. 
Operating characteristics  
A total of  dose levels (unit:  g) were considered:  
 and 
 in these simulations of the multiple subject cohorts. 
The design was evaluated for 3 possible dose-response scenarios:  “Low,” “Mid,” and 
“High” MTD.  Table 30 shows the dose level and true probability of DLT for each 
scenario used in the simulated studies estimating the MTD.  Table 31 reports the 
operating characteristics from 10 000 simulated studies estimating the MTD when the 
target TPI is (0.20, 0.33).  The rate of MTD selected and the number of subjects 
assigned to each dose level are presented in Table 32. 


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Table 31.  Operating Characteristics by Scenario for Simulated Studies Estimating 
the MTD When the Target TPI is (0.20, 0.33) 
MTD Scenario 
High 
Mid 
Low 
 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
Number of Subjects 
 Median (IQR) 
24 
(20 to 32) 
14 
(12 to 16) 
20 
(16 to 28) 
14 
(8 to 16) 
16 
(8 to 20) 
10 
(6 to 16) 
Number of DLTs 
 Median (IQR) 
3 
(2 to 5) 
2 
(1 to 3) 
4 
(3 to 5) 
2 
(1 to 3) 
6 
(5 to 7) 
4 
(3 to 5) 
Proportion of DLT () 
 Median (IQR) 
14 
(10 to 19) 
14 
(7 to 21) 
20 
(16 to 25) 
21 
(17 to 40) 
40 
(31 to 50) 
42 
(30 to 50) 
Percentage of studies recommending dose with DLT probability of: 
  10  
3.3 
24.7 
2.8 
13.8 
0.9 
9.0 
  10 and  20 
31.8 
42.0 
26.7 
37.5 
25.0 
35.7 
  20 and  33 
64.9 
33.3 
70.5 
48.7 
74.1 
55.3 
  33 
0 
0 
0 
0 
0 
0 
Probability of 
identifying MTD to 
have 15 to 33 DLT 
probability 
86.7 
60.6 
88.8 
76.1 
94.6 
82.7 
DLT  dose-limiting toxicity; IQR  interquartile range; MTD  maximum tolerated dose; TPI  toxicity 
probability interval. 


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Extremely Toxic Case  
In addition, the performance of BLRM under the extremely toxic scenario was evaluated 
through simulations, where the DLT rate is expected to be high (the DLT rate exceeds 
0.33 at all the tested dose levels) as shown in Table 33.  In this extremely toxic scenario, 
it is highly likely to have a Grade  2 treatment-related adverse event or DLT observed 
at the initial dose levels.  Therefore, simulation results are presented in Table 34 and 
Table 35 by the dose level for initiation of the multiple subject cohorts. 
 


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Operating Characteristics for Standard 33 Design  
As a comparison, the operating characteristics from 10 000 simulated studies estimating the MTD when using a standard 33 design are 
reported in Table 36. 
Table 36.  Operating Characteristics by Scenario for Simulated Studies Estimating the MTD Using a 33 Design 
MTD Scenario 
High 
Mid 
Low 
Extreme 
Number of Subjects 
 Median (IQR) 
14 
(7 to 19) 
15 
(12 to 20) 
14 
(10 to 19) 
12 
(6 to 17) 
Number of DLTs 
 Median (IQR) 
3 
(0 to 4) 
3 
(2 to 5) 
4 
(3 o 6) 
4 
(3 to 6) 
Proportion of DLT () 
 Median (IQR) 
17 
(0 to 21) 
23  
(18 to 29) 
30 
(23 to 35) 
36 
(30 to 50) 
Percentage of studies recommending dose with DLT probability of: 
 
  10  
37.4 
39.8 
37.0 
23.7 
  10 and  20 
62.6 
60.2 
63.0 
76.3 
  20 and  33 
0 
0 
0 
0 
  33 
0 
0 
0 
0 
Probability of identifying MTD 
to have 15 to 33 DLT 
probability 
28.7 
18.4 
12.3 
14.3 
DLT  dose-limiting toxicity; IQR  interquartile range; MTD  maximum tolerated dose 
 


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Summary 
The simulation results are summarized in Table 31 and Table 36.  By comparing results 
in Table 31 and Table 36, we can see that while having a similar performance in 
controlling the number of DLTs in the trial, the 2-parameter BLRM design with the target 
TPI of (0.20, 0.33) has a similar or better performance in selecting the MTD, compared 
with the 33 design in the 3 scenarios.   


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Appendix I.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as an FDA IND safety report by the sponsor.  
Identification and reporting of anticipated serious adverse events is the responsibility of 
the sponsor; the investigator is responsible for reporting adverse events and serious 
adverse events as described in Section 9.   
Anticipated Serious Adverse Events for Study 20170528 
Cancer Pain 
Metastasis 
Acute Myeloid Leukaemia 
1 MedDRA Version 24.0 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 7 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With Acute 
Myeloid Leukemia 
 
Amgen Protocol Number (AMG 427) 20170528 
IND number BB-IND 138440 
NCT Number:  NCT03541369 
Eudra CT:  2018-001389-40 
 
Amendment Date: 
16 March 2022 
 
Rationale: 
This protocol is being amended to include additional risk mitigation measures for cytokine 
release syndrome (CRS).  Changes related to enhanced CRS risk mitigation were mandated by 
the United States Food and Drug Administration (FDA) in a Partial Clinical Hold letter dated 
19 July 2021 that resulted from the observation of a fatal event of grade 5 CRS observed in the 
study.  Additionally, changes to the protocol include those requested by FDA and agreed upon 
by Amgen during the 30-day review period of Amgen’s Complete Response submission dated 
12 October 2021 (SN 0045). 
The following changes were made to the protocol: 
 
Changes in risk mitigation measures by CRS grades to enhance patient monitoring 
 
Updated dose modification criteria to adapt the dosing strategy when events of CRS occur 
 
Changed the safety stopping rule during expansion based on grade 4 and above adverse 
events to a stopping rule based on dose-limiting toxicity (DLT) rate, to allow safety stopping 
due to grade 2 and 3 CRS events which qualify as DLT and to prevent excess stopping due 
to non-treatment related grade 4 events 
 
Additional pharmacologic interventions were added to the protocol to ensure prompt 
treatment of CRS when it does occur 
 
Adjustment of dosing strategy upon study restart (eIV infusion and lowered target doses)  


Product:  AMG 427 
Protocol Number:  20170528 
Date:  16 March 2022 
Page 2 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Added exclusion criterion and table related to severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) 
 
Revised tables and language to reflect update to American Society for Transplantation and 
Cellular Therapy (ASTCT) Consensus Grading criteria for CRS and immune-effector 
associated neurotoxicity syndrome (ICANS) 
 
Added language in other protocol required therapies to include methylprednisone, 
siltuximab, and anakinra, and updated dose modification criteria regarding treatment 
interruption and re-start in case of adverse events during the infusion treatment interruption 
and re-start in case of adverse events during the infusion 
 
Added stopping rule for siltuximab dosing 
 
Globally, removed subcutaneous AMG 427 dosing cohorts from the study 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  24 March 2021 
Page 1 of 90 
CONFIDENTIAL 
Amendment 6 
Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Acute Myeloid Leukemia 
AMG 427 
Amgen Protocol Number 20170528 
IND number BB-IND 138440 
Amendment Date: 
24 March 2021 
Rationale: 
This protocol is being amended to allow for the enrollment of acute myeloid AML 
subjects with minimal/measurable residual disease (MRD). 
The following changes were made to the original protocol, dated 22 March 2018: 

References to “Relapsed/Refractory” in the protocol title and in relevant sections
of the protocol were removed to indicate that subjects with relapsed/refractory
AML as well as subjects with MRD-positive AML will be evaluated in this trial

Statistical considerations updated to account for MRD-positive AML subjects

Schedule of assessments updated to include Day 8 assessments for Schedule C

Schedule of assessments updated to include bone marrow assessments at
safety follow-up and long-term follow-up visits where applicable

Addition of extended intravenous (IV) and subcutaneous injection cohorts, using
dose level review meeting (DLRM) approved doses

Safety reporting language updated for adherence to current Amgen standard
operating procedures (SOPs)

References to Investigational Product Instruction Manual removed for adherence to
current Amgen SOPs

Update to References section

Minor corrections and clarifications throughout


Product:  AMG 427 
Protocol Number:  20170528 
Date:  17 September 2020 
Page 1 of 80 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Amendment  5 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Relapsed/Refractory Acute Myeloid Leukemia 
 
Amgen Protocol Number AMG 427 20170528 
IND number BB-IND 138440 
NCT Number:  NCT03541369 
Eudra CT:  2018-001389-40 
 
Amendment Date: 
17 September 2020 
 
Rationale: 
The following changes were incorporated into the study: 
 
Addition of dose escalation cohorts, increasing the escalation sample size to n  90 
(previously n  65). 
 
To provide clarification for Intra-subject dose escalation (ISDE), Etanercept (Enbrel) 
Vials and Etanercept (Enbrel) Substudy.   
 
Updates on safety risk language to align with the Informed Consent Form (ICF) and 
Investigator’s Brochure (IB) v2. 
 
Administrative, editorial updates, clarifications, and typographical corrections.  
As of 13 August 2020, a total of 29 subjects were enrolled and had received at least 
1 dose of AMG 427 in the ongoing first-in human (FIH) study.  Subjects were evaluated 
across  cohorts per Schedule A and Schedule C: 
The study is currently enrolling
  
Preliminary clinical data from the FIH trial shows an acceptable safety profile up to doses 
of 
ug.  The ongoing FIH dose escalation has seen a total of 1 dose limiting toxicity 
(DLT), which occurred after a subject was dosed with 
 ug of AMG 427 on day 1 
(resulting from cytokine release syndrome [CRS] grade 3 [liver alanine aminotransferase 
(ALT) grade 4 by Common Terminology for Adverse Events (CTCAE) scale, that did not 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  17 September 2020 
Page 2 of 80 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
resolve to grade 1 or less in 7 days]).  Low-grade CRS represents the most commonly 
occurring treatment-related adverse event, with CRS grade 2 seen in approximately 50 
to 75 of subjects at the most recent dose cohorts.  Other reported treatment-related 
adverse events include isolated lab abnormalities including mild hypofibrinogenemia & 
thrombocytopenia, and mild increases in lipase and bilirubin. 
The FIH trial has seen one subject experience a morphologic leukemia free state 
(MLFS) at the most recent dose cohort of 
 g, however no CR/CRi’s have been 
achieved.  Several more subjects throughout dose escalation have experienced 
transient decreases in peripheral blasts, but these did not translate to clinically 
meaningful responses. 
Preliminary pharmacokinetic (PK) analysis from the ongoing FIH study suggests dose-
related increases in free AMG 427 maximum observed concentration (Cmax) and area 
under the concentration-time curve (AUC).  Preliminary geometric mean terminal half-life 
estimates range from 0.6 to 2.1 days over the evaluated range of doses up to 
 
ug/day. Higher doses and exposures may be needed to provide thorough coverage of 
predicted minimally efficacious exposures estimated from in vitro AMG 427-mediated 
cell cytotoxicity in FLT3-expressing AML cell lines.   
The emerging clinical safety and PK data from the ongoing FIH study support the 
exploration of additional dose levels (
 ug) in the 
dose escalation part of the study to determine the MTD for AMG 427.  
Recommendations to explore additional dose levels will be made by the Dose Level 
Review Team (DLRT) following review of the PK, safety, and efficacy data for each 
enrolled cohort. 
 
 
 
 
 
 
 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  17 February 2020 
Page 1 of 34 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Relapsed/Refractory Acute Myeloid Leukemia 
 
Amgen Protocol Number (AMG 427) 20170528 
 
Amendment Date: 
17 February 2020 
 
Rationale: 
The protocol is being amended according to guidance provided by Food and Drug 
Administration (FDA). 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  26 November 2019 
Page 1 of 60 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title: A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Relapsed/Refractory Acute Myeloid Leukemia 
 
Amgen Protocol Number: AMG 427 20170528 
Amendment Date: 
26 November 2019 
Rationale: 
The following updates were made to the protocol, dated 08 June 2018: 
 
New dosing schedule with an additional Day 3 infusion to current dosing 
regimen. Addition made based on pharmacological data, in order to provide 
sustained exposure of AMG 427 above the predicted minimally efficacious 
exposure for the entire treatment cycle. 
 
Schedule of assessments updated to include bone marrow assessments at 
safety follow-up and long-term follow-up visits where applicable 
 
Disease-related events and all associated references were removed for the 
purpose of adherence to current Amgen SOPs 
 
Reference to self-evident corrections (SEC) were removed for the purpose of 
adherence to current Amgen SOPs 
 
Update to References section 
 
Minor corrections and clarifications throughout 
 
Addition of Substudy adding Enbrel (etanercept) as pre-medication, in order to 
explore better safety, tolerability, and efficacy of BiTE therapy.   


Product:  AMG 427 
Protocol Number:  20170528 
Date:  30 April 2019 
Page 1 of 27 
CONFIDENTIAL 
 
 
Amendment 2 
Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Acute Myeloid Leukemia 
 
AMG 427 
Amgen Protocol Number 20170528 
IND number BB-IND 138440 
 
Amendment Date: 
30-April-2019 
Rationale:   
This protocol is being amended to allow for the enrollment of AML subjects with 
measurable/minimal residual disease (MRD). 
The following changes were made to the original protocol, dated 08 June 2018: 
 
References to “Relapsed/Refractory” in the protocol title and in relevant sections 
of the protocol were removed to indicate that subjects with relapsed/refractory 
AML as well as subjects with measurable/minimal residual disease  
(MRD)-positive AML will be evaluated in this trial 
 
Statistical considerations updated to account for MRD-positive AML subjects 
 
Schedule of assessments updated to include bone marrow assessments at 
safety follow-up and long-term follow-up visits where applicable 
 
Disease-related events and all associated references were removed for the 
purpose of adherence to current Amgen SOPs 
 
Reference to self-evident corrections (SEC) were removed for the purpose of 
adherence to current Amgen SOPs 
 
Update to References section 
 
Minor corrections and clarifications throughout 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  08 June 2018 
Page 1 of 22 
CONFIDENTIAL 
Amendment 1 
Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With 
Relapsed/Refractory Acute Myeloid Leukemia 
AMG 427 
Amgen Protocol Number 20170528 
IND number BB-IND 138440 
Amendment Date: 
08 June 2018 
Rationale:  This protocol is being amended based on comments received from the FDA 
upon submission of the US IND on April 9, 2018.  All updates are in line with changes 
requested by the agency. 
The following changes were made to the original protocol, dated 22 March 2018: 
•
Eligibility criteria was revised to include patients who have failed treatment with,
are intolerant to, or are not candidates for available therapies for treatment of
relapsed or refractory AML
•
Dose Limiting Toxicity (DLT) window will start on D1 (start of the administration of
the first infusion) and last for 28 days for all cohorts.
•
Confirmed Hy’s Law cases will be included as DLTs.
•
Subjects experiencing a Grade 4 adverse event during infusion will be
permanently discontinued from investigational product
•
Dosing instructions for tocilizumab are updated such that subjects can be given
up to 3 additional doses of tocilizumab, 8 hours apart, if needed.
•
Cohort size in dose expansion is modified to n=6
•
Early stopping rules and efficacy futility rules have been implemented in dose
expansion phase based on DLT criteria; enrollment to dose expansion will be
paused or possibly terminated if these rules are met.  Secondary endpoint
(efficacy parameters) has been updated to reflect the efficacy futility rules.
•
Adverse events will be recorded starting from the time of consent, rather than
from the time of dosing.  Schedule of events was updated to reflect this change.
•
Statement added to indicate that FDA will be provided with brief interim results of
the dose escalation phase once MTD and RP2D is established.
•
Clarifications/minor corrections to Schedule of Assessments
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 1 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1 First-In-Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 427 in 
Subjects With Acute Myeloid Leukemia 
Short Protocol Title: 
FIH study to evaluate safety, tolerability, PK, PD & 
Efficacy of AMG 427 
Protocol Number: 
20170528 
NCT Number: 
NCT03541369 
Authors: 
, Global Biostatistical Science 
 Global Biostatistical Science 
 Global Biostatistical Science 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805 447 1000 
SAP Date: 
Document Version 
Date 
Amendment 2 (v3.0) 
Amendment 1 (v2.0)          
Original (v1.0)                    
25 April 2022 
07 Dec 2020 
22 Oct 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 2 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
22OCT2018 
NA 
Amendment 1 (v2.0) 
07Dec2020 
 
Add the design and analysis for 
Schedule B 
 
Update the endpoints, planned doses, 
sample size to be consistent with 
protocol 
 
Make a few clarifications on definition 
and analysis methods 
 
Other administrative changes 
Amendment 2 (v3.0) 
25Apr2022 
 
Updated the study design for MRD 
AML and eIV groups according to 
protocol 
 
Updated the sample size section 
 
Added the definition and analysis 
for MRD AML and eIV groups 
 
Added database disposition for 
each planned analysis 
 
Updated the imputation rules as 
per new DES SAP template 
 
Removed the QTcF threshold 
definitions. 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 3 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints ............................................................................ 8 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 11 
3.1 
Study Design ............................................................................................. 11 
3.2 
Sample Size .............................................................................................. 16 
3.3 
Adaptive Design ........................................................................................ 17 
4. 
Covariates and Subgroups ................................................................................... 22 
4.1 
Planned Covariates ................................................................................... 22 
4.2 
Subgroups ................................................................................................. 22 
5. 
Definitions ............................................................................................................. 22 
6. 
Analysis Sets ........................................................................................................ 26 
6.1 
Full Analysis Set........................................................................................ 26 
6.2 
Safety Analysis Set ................................................................................... 26 
6.3 
Per Protocol Set(s) .................................................................................... 26 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 26 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 26 
6.6 
Interim Analyses Set(s) ............................................................................. 26 
6.7 
Study-specific Analysis Sets...................................................................... 26 
7. 
Planned Analyses ................................................................................................. 27 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 27 
7.2 
Primary Analysis ....................................................................................... 28 
7.3 
Final Analysis ............................................................................................ 29 
8. 
Data Screening and Acceptance ........................................................................... 29 
8.1 
General Principles ..................................................................................... 29 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 29 
8.3 
Handling of Missing and Incomplete Data ................................................. 29 
8.4 
Detection of Bias ....................................................................................... 29 
8.5 
Outliers ..................................................................................................... 30 
8.6 
Distributional Characteristics ..................................................................... 30 
8.7 
Validation of Statistical Analyses ............................................................... 30 
9. 
Statistical Methods of Analysis.............................................................................. 30 
9.1 
General Considerations ............................................................................. 30 
9.2 
Subject Accountability ............................................................................... 31 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 4 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
9.3 
Important Protocol Deviations ................................................................... 31 
9.4 
Demographic and Baseline Characteristics ............................................... 31 
9.5 
Efficacy Analyses ...................................................................................... 32 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 32 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 32 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 32 
9.6 
Safety Analyses ........................................................................................ 32 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 32 
9.6.2 
Adverse Events ......................................................................... 32 
9.6.3 
Laboratory Test Results ............................................................ 33 
9.6.4 
Vital Signs ................................................................................. 33 
9.6.5 
Physical Measurements ............................................................ 33 
9.6.6 
Electrocardiogram ..................................................................... 34 
9.6.8 
Exposure to Investigational Product .......................................... 34 
9.6.9 
Exposure to Non-investigational Product ................................... 34 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 34 
9.6.11 
Exposure to Concomitant Medication ........................................ 34 
9.7 
Other Analyses ......................................................................................... 34 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 35 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 35 
9.7.3 
Analyses of Health Economic Endpoints ................................... 35 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 35 
10. 
Changes From Protocol-specified Analyses.......................................................... 35 
11. 
Literature Citations / References ........................................................................... 35 
12. 
Prioritization of Analyses....................................................................................... 36 
13. 
Data Not Covered by This Plan............................................................................. 36 
14. 
Appendices ........................................................................................................... 37 
Appendix A.  Reference Values/Toxicity Grades ................................................... 37 
Appendix B.  Concomitant Medications ................................................................. 38 
Appendix C.  Clinical Outcome Assessment Forms/Instruments ........................... 39 
Appendix D.  Health Economic Forms/Instruments ............................................... 40 
Appendix E.  Details of PK or PK/PD Methods for Modeling ................................. 41 
Appendix F.  Analytical Windows .......................................................................... 42 
Appendix G.  Handling of Dates, Incomplete Dates and Missing Dates ................ 43 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 5 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
List of Tables 
Table 1.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80% DLT Limit of 20% ............................................................................ 19 
Table 2.  Operating Characteristics with Batch Size of 6 Subjects ................................. 19 
Table 3.  Probability of Early Stopping and the Average Sample Size in R/R 
AML Dose Expansion ............................................................................. 20 
Table 4. Probability of Early Stopping and the Average Sample Size in MRD+ 
AML Dose Expansion ............................................................................. 21 
 
List of Figures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 6 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
List of Abbreviations 
 
Abbreviation 
Explanation 
AML 
Acute Myeloid Leukemia 
AUC 
Area under concentration time curve 
Cmax 
maximum observed concentration 
CRF 
case report form 
CRS 
Cytokine Release Syndrome 
DLRM 
dose level review meeting 
DLT 
dose limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
end of study for individual 
subject  
defined as the last date that protocol-specified procedures are 
conducted for an individual subject 
end of treatment 
defined as the date of final assessment for the protocol specified 
treatment phase of the study for an individual subject 
end of study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the purposes of final collection of 
data for the primary endpoint(s).   
FIH 
First in Human 
Ig 
Immunoglobulin 
ICF 
informed consent form 
IP 
Investigational Product 
MRD 
Minimal/measurable Residual Disease 
NA 
Not Applicable 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PR 
the interval measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by electrocardiogram 
QRS 
the interval between the Q wave and the S wave in the heart’s 
electrical cycle as measured by electrocardiogram; represents 
the time it takes for depolarization of the ventricles 
QT 
measure of the time between the start of the Q wave and the 
end of the T wave in the heart’s electrical cycle as measured by 
electrocardiogram 
QTc 
QT interval corrected for heart rate using accepted methodology 
RFS 
Relapse Free Survival 
R/R 
Relapsed/Refractory 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 7 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
study day 1 
defined as the first day that protocol specified investigational 
product is administered to the subject 
tmax 
time to maximum concentration 
 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 8 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
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 7 for study 20170528, 
AMG 427 dated 16 March 2022. The scope of this plan includes the interim analysis, the 
primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. PK, 
PD/biomarker analyses will be provided by Clinical Pharmacology, Modeling and 
Simulation (CPMS) group and clinical biomarker group in Department of Translational 
Medicine, respectively. Separate SSAP will be created to prespecify additional analysis 
required to support assessment of an alternative for prophylaxis of cytokine release 
syndrome (CRS), the main on-target toxicity identified for AMG 427, in schedule B, in 
subjects with R/R AML. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability 
of AMG 427 in adult subjects with 
relapsed/refractory (R/R) AML or 
minimal/measurable residual 
disease-positive (MRD+) AML 
 
Estimate the maximum tolerated 
dose (MTD) and / or a biologically 
optimal dose (eg, recommended 
phase 2 dose [RP2D]) 
 
Evaluate the safety and 
tolerability of extended 
intravenous (eIV) administration 
of AMG 427 
 
 
 
Safety: Dose-limiting toxicities 
(DLTs), treatment-emergent 
adverse events (TEAEs) and 
treatment-related adverse events 
(TRAEs) 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 9 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Secondary 
 
Characterize the 
pharmacokinetics (PK) of 
AMG 427 
 
AMG 427 PK parameters 
including, but not limited to, 
maximum serum concentration 
(Cmax), minimum serum 
concentration (Cmin), area under 
the concentration-time curve 
(AUC), and if feasible, half-life (t½) 
of AMG 427 
 
Evaluate the anti-leukemia activity 
of AMG 427 
 
Efficacy parameters for (R/R) 
AML: Subject response to 
treatment with AMG 427 
(response defined as complete 
response/remission [CR] / 
complete response/remission with 
incomplete recovery of peripheral 
blood counts [CRi] / morphologic 
leukemia-free state, partial 
remission [per modified 
International Working Group 
(IWG) criteria], complete 
response/remission with partial 
hematologic recovery [CRh]) and 
duration of response (duration of 
response will only be measured 
for subjects in the expansion 
cohort). 
 
Efficacy parameters for MRD+ 
AML: Subject response to 
treatment with AMG 427 
(response refers to conversion 
from MRD + status to MRD - 
status), relapse free survival, 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 10 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
and overall survival (relapse 
free survival and overall 
survival will only be measured 
for subjects in expansion 
cohort). 
 
 
Exploratory 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 11 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
 
2.2 
Hypotheses and/or Estimations 
AMG 427 will demonstrate evidence of anti-leukemic activity at a safe and well-tolerated 
dose in subjects with MRD+ or R/R AML. 
3. 
Study Overview 
3.1 
Study Design 
This is a First in Human (FIH), open-label, phase 1 dose escalation study. AMG 427 will 
be administered as a short intravenous (IV) infusion (eIV infusion may apply) in adult 
subjects with MRD+ or R/R AML. The study will be conducted at approximately 15 sites 
in the US, Australia, Canada, Japan, South Korea, and Germany. Additional countries or 
sites may be added if necessary. 
The study will consist of up to a 14-day screening period, a treatment period, a safety 
follow-up period (SFU), and a long-term follow-up (LTFU) period (for subjects enrolled in 
the dose expansion phase only).  
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) of AMG 427 in subjects with MRD+ or R/R AML using a 
Bayesian logistic regression model (BLRM: Neuenschwander et al, 2008). Planned dose 
levels (dose per infusion) for the dose-escalation cohorts are as follows 
 
 μg. 
Additionally, an option for cohort escalation will be available for confirming the 
safety in Japanese population, at sponsor discretion, for up to a maximum of 
6 subjects.  The sponsor will notify Japanese sites, if applicable, when the 
extended slots for a cohort are open for enrollment (after the Dose Level Review 
Team [DLRT] has confirmed the dose level is safe). The starting dose for the 
 


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 12 of 44 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
cohort will be 
 µg administered as short term IV infusions on day 1 (D1) and day 5 
(D5). The doses administered for the cohorts following cohort  will be recommended by 
the Dose Level Review Team (DLRT). The initial several cohorts will receive 2-3 doses 
(1 each on D1, D3 [if applicable], and D5, and D8 [if applicable]). After reviewing the 
emerging PK, safety and efficacy data, the DLRT may recommend the administration of 
an additional doses on D3 and D8, to comprise a 2-week cycle with doses on 
D1/D3/D5/D8. At completion of the dose escalation cohorts, additional subjects 
(approximately 90 subjects, with approximately 40 subjects in the FIH cohorts and 
50 subjects in the MRD+ cohorts) will be enrolled in a dose expansion cohort to gain 
further clinical experience, safety, and efficacy data in subjects administered AMG 427. 
The study will consist of 3 groups: 
 
FIH Group: AMG 427 administered as short term IV infusions in R/R AML 
subjects.  
- 
(CLOSED) Etanercept (Enbrel) substudy: Etanercept will be administered 
for CRS prophylaxis 2 days prior to each cycle of AMG 427 short term IV 
infusions in R/R AML subjects in the US. (Etanercept may be implemented 
to FIH expansion groups based on emerging data). 
 
eIV Infusion Group: AMG 427 eIV infusions administered on days 1 and 2, and 
3, with short term IV infusions on days 5 and 8 in R/R AML subjects. (eIV 
infusion may be implemented to FIH expansion groups based on emerging 
data). 
 
MRD+ Group: AMG 427 administered in short term IV infusions in MRD+ AML 
subjects.  
The study will have three alternative dosing schedules: 
 
Schedule A: - CLOSED 
- 
D1/D5 or D1/D5/D12/D19 (dexamethasone prophylaxis)  
 
Schedule B: Etanercept Substudy (R/R AML) - CLOSED 
- 
D1/D5 or D1/D5/D12/D19 (etanercept 2 days prior to each cycle) Etanercept 
(Enbrel) substudy used etanercept 2 days prior to infusion of each cycle D1, and 
if applicable, 2 days prior to infusion on D12. 
 
.  
 
Schedule C: (Protocol Table 16 through Table 21) FIH, eIV (R/R AML), and MRD+ 
Group (MRD+ AML)  


Product:  AMG 427 
Protocol Number:  20170528 
Date:  25 April 2022 
Page 13 of 44 
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Confidential Clinical Trials 
- 
D1/D3/D5/D8 or D1/D3/D5/D8/D12/D19 (dexamethasone prophylaxis) 
Note: 
 
The MRD group will use Schedule C for all cycle collections and Table 22 (from 
protocol) for additional whole blood MRD collection, or Table 23 (from protocol), as 
applicable. 
After reviewing additional PK, safety, and efficacy data, the DLRT may recommend the 
administration of additional doses on day 12 and day 19, to comprise a 4-week cycle 
with doses on either D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19. Once the DLRT 
recommends a 4 or 6 dose schedule (D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19), all 
subsequent cohorts will be treated with a 4 or 6 dose schedule. If on Schedule A 
(CLOSED) or C, all subjects will be pre-treated with an 8-mg dose of IV dexamethasone 
within 1 hour prior to D1, D3 (if applicable), and D5, and D8 (if applicable) AMG 427 
doses and each dose step. A dose step is any AMG 427 dose that is higher for a given 
subject than the subject has previously received. A dose step will be triggered by the 
observation of CRS or infusion/injection related reaction at the first dose (see example 
in Figure 1). Dose steps may occur at the D3, D5, D8, D12 or D19 infusions. Each cycle 
will last for approximately 14 days for cohorts receiving 2 or 4 doses (D1/D5 or 
D1/D3/D5/D8), and approximately 28 days for cohorts receiving 4 or 6 doses 
(D1/D5/D12/D19 or D1/D3/D5/D8/D12/D19). Subjects will be assessed for DLTs for 28 
days. Cycle will be followed by a treatment-free interval for 1-2 weeks (depending on 
response), which may be extended for up to 7 weeks or longer for the cohorts at higher 
doses, based on a dose level review meeting (DLRM) recommendation. The D3, D5, D8 
doses, and the D12 and D19 doses (if applicable) may be at the same dose as the 
preceding dose or may be at a higher dose level (dose step). This will be based on 
tolerability of the lower dose level and other clinical signs, pharmacological, and PD 
results and will be recommended by the DLRT. For a schematic description of the 
different dose step options see Figure 1. For logistical reasons, there is a ± 1-3 day 
window for dosing days. 


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Dose Escalation Cohorts 
Dose escalation will be conducted in 2 stages: a single subject stage and a multiple 
subject stage. Single subjects will be enrolled at initial dose levels. Multiple subject 
cohorts, which will enroll 2 - 4 subjects per cohort, will be triggered by any evidence of 
pharmacologic activity, including, but not limited to infusion reactions, CRS, tumor lysis 
syndrome (TLS), or depletion of peripheral blasts and/or white blood cells. The Bayesian 
logistic regression model (BLRM) design will be used to guide dose escalation. The 
actual dose selected at each dose cohort may be at or below the model’s recommended 
dose as determined by the DLRT after considering all information. Subjects will be 
assessed for DLTs for 28 days. Subjects in the etanercept (Enbrel) substudy (CLOSED) 
can intra-subject dose escalate after 1 cycle to the first-in-human (FIH) study (eg, move 
from schedule B to schedule C), if subjects show evidence of disease progression after 
discussion with the Sponsor (eg, use of hydroxyurea to control increasing WBC). 
Subjects who complete the DLT period may proceed to a higher dose level for the 
following treatment cycle once the next dose cohort has been deemed safe by the 
DLRT, after consultation with the Sponsor, if no DLT was reported during or after the 
completion of the DLT period for that subject.  
Estimation of initial and target MTDs 
It is anticipated that 2 to 3 MTDs may be estimated: 1 for the initial dosing and 1 - 3 for 
the subsequent dosing.  Should the initial dose be limited by adverse events related to 
first dose effects and/or cytokine release syndrome, the second MTD (dose step) for the 
target dose will be estimated after giving the initial dose at MTD1.  Each MTD will be 
estimated following the dose escalation guided by BLRM described above. A second 


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dose step may also be implemented in a cycle if this was considered appropriate and 
necessary to allow further dose escalation. This second dose step would be performed 
the same way as described above. In this case, a third MTD would be estimated for the 
dose to be administered after the second dose step. 
Once the dose escalation phase has determined a final MTD, tocilizumab may be 
evaluated as an alternative prophylaxis to prevent / reduce the severity of CRS. A cohort 
of 3 subjects may be treated with AMG 427 at the final MTD dose level and a single 
dose of 8 mg/kg IV tocilizumab will be administered prior to the dose of AMG 427 
replacing pretreatment with dexamethasone. If no DLTs are observed, 3 additional 
subjects will be included in this cohort. The use of tocilizumab may be further explored 
based on observed tolerability and other clinical and pharmacological data.   
Expansion Cohort 
At completion of the dose escalation cohorts, approximately 90 additional subjects 
(approximately 40 R/R AML subjects in the FIH cohorts and 50 MRD+ AML 
subjects in the MRD+ cohorts) will be enrolled in a dose expansion cohort to gain 
further clinical experience, safety, and efficacy data in subjects administered AMG 427. 
The dose to be evaluated will be at or below the MTD estimated in the dose escalation 
cohorts. Based on emerging safety data, the planned dose level and dose schedule may 
be modified during the conduct of the expansion phase. Additionally, enrollment to dose 
expansion will be paused and possibly terminated if safety stopping rules and/or efficacy 
futility rules are met. A final estimate of the MTD and RP2D will be evaluated and 
confirmed utilizing all DLT-evaluable subjects from the dose escalation and the dose 
expansion cohorts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Design and Treatment Schema 
 
3.2 
Sample Size 
It is anticipated that approximately 200 subjects will be enrolled in this study, with 
approximately 110 subjects enrolled in the dose escalation cohorts and 90 subjects in 
the dose expansion cohort:  
Dose escalation cohorts:  
 
FIH (R/R AML): approximately 90 subjects  
- 
(CLOSED) etanercept substudy (R/R AML): approximately 25 subjects  
 
eIV (R/R AML): approximately 10 subjects  
 
MRD Group (MRD+): approximately 10 subjects  
Dose expansion cohorts:  
 
FIH (R/R AML): approximately 40 subjects  
 
MRD Group (MRD+): approximately 50 subjects  
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. 


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With 2 subjects per cohort, there is a 19% to 55% probability of observing at least 1 DLT. 
With 3 subjects per cohort, there is a 27% to 70% probability of observing at least 1 DLT 
if the true DLT rate is 10% to 33% and with 4 subjects per cohort, there is a 34% to 80% 
probability. 
In the dose expansion cohort, a subject number of 40 will provide an 87% probability of 
observing at least 1 adverse event with 5% incidence rate and 99% probability of 
observing at least 1 adverse event with 10% incidence rate. A subject number of 50 
will provide a 92.3% probability of observing at least 1 adverse event with 5% 
incidence rate and 99.5% probability of observing at least 1 adverse event with 
10% incidence rate. These probabilities will be 64% and 88% respectively with a 
subject number of 20. An exact 80% binomial confidence interval (CI) will be provided for 
response rate. With the 20 subjects and 20% response rate, the expected 80% CI would 
be 9% to 36%. With 40 subjects and 20% response rate, the expected 80% CI would be 
12% and 30%. With 50 subjects and a 40% response rate, the expected 80% CI 
would be 30.6% and 50.1%. 
3.3 
Adaptive Design 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK and PD of 
AMG 427 in subjects with MRD+ or R/R AML using a Bayesian logistic regression model 
(BLRM: Neuenschwander et al, 2008). See Protocol Appendix H for the description of 
the two-parameter BLRM design. 
During dose expansion, Amgen will conduct evaluations of the ongoing DLT event rate 
and the ongoing overall response rate. 
Safety Stopping Rules during Dose Expansion: 
During dose expansion, Amgen will conduct evaluations of the ongoing DLT event rate 
to assess if the threshold for pausing enrollment has been reached. If these stopping 
rules are met, then enrollment to the dose expansion will be paused pending a review of 
safety data and available pharmacokinetic, pharmacodynamics, and efficacy data by the 
DLRT. This review may result in early termination of the study, notification to Health 
Authorities, or may result in re-initiation of enrollment. The DLRT may implement 
additional measures, as appropriate, to reduce the risk of toxicity or to adapt and 
manage the toxicity. The stopping rules to pause enrollment use a Bayesian approach 
proposed by Thall, et al (1995); enrollment to dose expansion will be halted if the 
posterior probability that the DLT event rate is greater than 20% is > 80%. The stopping 
boundaries assuming a prior distribution of Beta (0.40, 1.60) are presented in Table 1 


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and the operating characteristics with pre-specified batch size of 6 new subjects per 
batch are presented in Table 2. The evaluations could occur more frequently if 
necessary to address emerging safety concerns. 


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Table 1.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80% DLT Limit of 20% 
Number of subjects 
Pause study enrolment if observing the number 
of these many DLT events 
6 
≥ 3 
12 
≥ 4 
18 
≥ 6 
24 
≥ 7 
30 
≥ 9 
36 
≥ 10 
40 
R/R AML expansion cohort completes 
42 
≥ 11 
48 
≥ 13 
50 
MRD+ AML expansion cohort completes 
AML = acute myeloid leukemia, MRD+ = minimal/measurable residual disease-positive, R/R = 
relapsed/refractory. 
Table 2.  Operating Characteristics with Batch Size of 6 Subjects 
 
R/R AML 
MRD+ AML 
True DLT 
rate 
Probability of 
early stopping of 
dose expansion 
Average dose 
expansion 
sample size* 
Probability of 
early stopping 
of dose 
expansion 
Average dose 
expansion sample size* 
0.10 
3.8 
38.9 
3.9 
48.5 
0.20 
34.0 
31.5 
37.8 
37.8 
0.25 
58.2 
25.6 
64.9 
29.4 
0.30 
78.9 
19.9 
85.5 
21.6 
0.35 
91.6 
15.4 
95.7 
16.0 
0.40 
97.4 
12.2 
99.1 
12.3 
0.50 
99.9 
8.7 
100 
8.7 
AML = acute myeloid leukemia, MRD+ = minimal/measurable residual disease-positive, R/R = 
relapsed/refractory. 
* The average dose expansion sample size assumes early termination of the study whenever the rules to 
pause study enrollment are met. 
Efficacy Futility Rules during Dose Expansion 
During dose expansion, Amgen will conduct evaluations of the ongoing overall response 
rate to assess if the threshold for early trial termination for futility has been reached. For 
R/R AML, a response consists of any of the following efficacious outcomes: CR, CR with 
incomplete recovery of peripheral blood counts (CRi), morphologic leukemia-free state, 


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partial remission and complete response/remission with partial hematologic recovery 
(CRh). An overall response rate less than 15% is considered insufficient efficacy. Amgen 
proposes stopping enrollment to the dose expansion cohorts early if any of the following 
occurs. 
 
None of the initial 12 subjects treated experience a response 
 
2 or fewer of the initial 18 subjects treated experience a response 
 
3 or fewer of the initial 24 subjects treated experience a response 
Using these futility stopping rules, Table 3 shows the probability of early stopping and 
the average sample size in dose expansion 
Table 3.  Probability of Early Stopping and the Average Sample Size in R/R AML 
Dose Expansion 
True overall 
response 
rate 
Probability of 
early stopping 
after 12 or fewer 
subjects 
Probability of 
early stopping 
after 18 or fewer 
subjects 
Probability of 
early 
stopping 
after 24 or 
fewer 
subjects 
Average 
sample size 
0.05 
0.54 
0.94 
0.98 
15.5 
0.10 
0.28 
0.74 
0.82 
20.7 
0.15 
0.14 
0.49 
0.58 
27.0 
0.20 
0.07 
0.28 
0.34 
32.5 
0.30 
0.01 
0.06 
0.07 
38.3 
 
. A 
conversion rate from MRD+ to MRD- < 25% is considered insufficient efficacy. 
Amgen proposes stopping enrollment to the dose expansion cohorts early if any 
of the following occurs:  
 
2 or fewer of the initial 12 subjects treated experience a response  
 
4 or fewer of the initial 18 subjects treated experience a response  
 
5 or fewer of the initial 24 subjects treated experience a response  
Using these futility stopping rules, Table 4 shows the probability of early stopping 
and the average sample size in dose expansion. 


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Table 4. Probability of Early Stopping and the Average Sample Size in MRD+ AML 
Dose Expansion 
True overall 
response 
rate 
Probability of 
early stopping 
after 12 or fewer 
subjects 
Probability of 
early stopping 
after 18 or fewer 
subjects 
Probability of 
early 
stopping 
after 24 or 
fewer 
subjects 
Average 
sample size 
0.05 
0.98 
1.00 
1 
12.1 
0.15 
0.74 
0.90 
0.92 
16.2 
0.25 
0.39 
0.56 
0.60 
28.7 
0.35 
0.15 
0.23 
0.24 
41.4 
0.45 
0.04 
0.06 
0.06 
47.7 
Siltuximab Safety Stopping Rules: 
Amgen will conduct evaluations of the treatment and outcome of the CRS events 
treated with siltuximab on an ongoing basis to assess if the threshold for pausing 
siltuximab treatment has been reached as outlined in the table below. If these 
stopping rules are met, an adhoc DLRM will be triggered to review safety data and 
available pharmacokinetic, pharmacodynamics, and efficacy data. If 
recommended by DLRT, the use of siltuximab will resume. The stopping rules to 
trigger an adhoc DLRM to review siltuximab treatment use a Bayesian approach 
proposed by Thall, et al (1995); an adhoc DLRM will be triggered if the posterior 
probability that the CRS progression to Grade 3 rate is greater than 20% is > 80% 
or the posterior probability that the CRS progression to Grade 4 rate is greater 
than 7.5% is > 80%; or observation of any grade 5 CRS after the event has been 
treated with siltuximab. The stopping boundaries presented below assume a prior 
distribution of Beta (0.4, 1.6) for progression to grade 3 CRS and a prior 
distribution of Beta (0.15, 1.85) for progression to grade 4 CRS. The evaluations 
could occur more frequently if necessary to address emerging safety concerns. If 
the triggered adhoc DLRM coincide with regular DLRM, they may be combined. 
Number of Subjects 
Treated with Siltuximab 
Trigger DLRM if severity of any CRS event treated with 
siltuximab progresses to Grade 5  
Or this number of subjects 
with severity of CRS 
progressed to Grade 3 after 
being treated with siltuximab 
Or this number of 
subjects with severity 
of CRS progressed to 
Grade 4 after being 
treated with siltuximab 
5 
≥ 3 
≥ 2 


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10 
≥ 4 
≥ 2 
15 
≥ 5 
≥ 3 
20 
≥ 6 
≥ 3 
25 
≥ 7 
≥ 4 
30 
≥ 9 
≥ 4 
35 
≥ 10 
≥ 5 
40 
≥ 11 
≥ 5 
CRS = cytokine release syndrome; DLRM = dose level review meeting. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
4.2 
Subgroups 
Subgroup analysis for those treated with siltuximab will be evaluated, including 
CRS outcomes, safety, and PK data. 
5. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be collected using the age in years in the clinical 
database.  
AUC0-last  
Area under the concentration-time curve from time 0 (time of investigational product 
administration) to the time of the last quantifiable concentration. 
Baseline  
Except ECG for any variable, unless otherwise defined, baseline is the last assessment 
taken prior to the first investigational product administration. 
ECG analysis value 
The mean value of triplicate will be calculated and used in the analysis.  If an ECG is 
missing within a triplicate, all available data will be averaged for that time point. Further, 
unscheduled ECG measurements taken up to 5 minutes after the last assessment of a 
triplicate at a time point will be included in the mean for that time point. 


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Baseline ECG 
Baseline ECGs will be collected ≥ 30 minutes apart, with each baseline ECG in triplicate 
(ie, triplicate must be done approximately 30 seconds apart) 
 
2 sets collected at screening, and 
 
1 set collected pre-dose on cycle 1 day 1 [ie, total ≥ 9 ECGs]) 
The mean of the values within a triplicate should be calculated before taking the mean of 
the triplicate averages. Where an ECG is missing within a triplicate, all available data will 
be averaged for that time point.  
Percent Change from Baseline 
Percent change from Baseline is the arithmetic difference between post-Baseline and 
Baseline divided by Baseline values times 100. 
Percent change from baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
Fold change from Baseline 
Fold change from Baseline equals the post-Baseline value divide by the Baseline value. 
Fold change from baseline = Post-baseline Value / Baseline Value 
Cmax 
Maximum observed serum concentration. 
Cmin 
Minimum observed serum concentration 
End of Study (For an Individual Subject) 
An individual subject is considered to have completed the study if he/she has completed 
SFU visit for subjects enrolled in the dose escalation phase, or LTFU visit for subjects 
enrolled in the dose expansion phase as shown in the Schedule of Assessments. The 
SFU visit should occur approximately 4 weeks (or up to 7 days thereafter) after the last 
dose of AMG 427 or prior to the initiation of other AML therapy, whichever occurs earlier.  
End of study (EOS) for an individual subject is defined as the last day that protocol 
specified procedures/assessments are conducted for the individual subject. 
End of Study:  
End of study is defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple parts (eg, 
safety follow-up or survival assessment), the end of study would include these 
additional parts.  
Enrollment Date 


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Enrollment date is defined as the date when the investigator confirms that the subject 
has met all eligibility criteria and will be collected on the enrollment eCRF. 
Change from Baseline 
Change from Baseline is the arithmetic difference between post-Baseline and Baseline. 
Change (absolute) from Baseline= (Post-baseline Value – Baseline Value) 
Study Day 
Post study day 1: 
study day= (date - date of Study Day 1) + 1 
Pre study day 1:       study day= (date – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Day -1.   
Investigational Product 
The term ‘investigational product’ is used in reference to AMG 427. 
Treatment-Emergent Adverse Event (TEAE) 
Treatment-emergent adverse events are events categorized as Adverse Events (AEs) 
starting on or after the first dose of investigational product (AMG 427), as determined by 
the flag indicating if the adverse event started prior to the first dose (AMG 427) on the 
Events CRF and up to and including 30 days after the end of investigational product 
(AMG 427) or the end of study (EOS) date, whichever is earlier. 
Treatment-Related AE  
A treatment-related AE is any treatment-emergent adverse event that per investigator 
review has a reasonable possibility of being caused by the investigational product. 
Event with missing/unknown relationship to treatment will be assumed to be 
treatment-related. 
Dose Limiting Toxicities (DLT) 
A DLT will be defined as any of the events described in protocol section 6.2.1.3 
occurring in a subject during the DLT window. The DLT window will start on D1 (start of 
the administration of the first dose) and last for 28 days for all cohorts. Any adverse 
event occurring outside the DLT window that is determined by the investigator to be 
possibly related to the investigational product, which is seen more frequently or is more 
severe than expected or is persistent despite appropriate management, can be 
determined to be a DLT upon unanimous decision by the DLRT after review of the 
adverse event and all available safety data. Investigators will determine whether an 
adverse event qualifies as a DLT per protocol Section 6.2.1.3 and it will be collected by 
the flag indicating DLT in Events CRF. 


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Maximum Tolerated Dose (MTD) 
The MTD is defined as the highest dose level whose DLT rate has the highest probability 
of the target TPI, an excessive/unacceptable TPI of < 0.25, and a minimum of 6 subjects 
have been treated at the MTD. 
Overall Response (for R/R AML) 
Overall response is defined as any of the following: complete remission (CR), CR with 
incomplete recovery (CRi), morphologic leukemia-free state, partial remission (all 
according to Revised International Working Group [IWG] response criteria) or CR with 
partial hematologic recovery (CRh). 
Duration of Response (DOR) (for R/R AML) 
Duration of response is defined as the number of days between the date of the first 
disease assessment indicating an overall response through the subsequent date of 
progression or relapse as defined by revised IWG response criteria or death due to any 
cause, or where applicable date of censoring [date of first progressive disease 
assessment or relapse or death or date of censoring – date of the first objective 
response result +1]. Subjects who respond and have not progressed or relapse or died 
while on study will be censored at the last adequate disease assessment date. Subjects 
who do not achieve an overall response will be excluded from the analysis of duration of 
response. 
MRD Conversion Rate 
MRD conversion rate is the number of subject achieve MRD- among subjects at 
who are MRD+ at enrollment. 
 
Overall Survival 
Overall survival (OS) is defined as the time from the start of treatment (Study day 
1) until event of death due to any cause.  
OS time (Days) = Date of death – Study Day 1 + 1  
OS time (Months) = (Date of death – Study Day 1 + 1)/30.4 
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 (ie, the data cutoff 
date), the subject will be censored at the analysis trigger date. 
Relapse-free Survival (RFS) (for MRD+ group) 


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RFS time will be calculated from the date of first administration of AMG 427 until 
the date of a hematologic relapse or death, whichever occurs first. Subjects still 
alive and relapse-free will be censored on their last disease assessment date. 
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the 
Safety Analysis Set. 
6.1 
Full Analysis Set 
NA 
6.2 
Safety Analysis Set 
All subjects that are enrolled and received at least 1 dose of AMG 427. 
6.3 
Per Protocol Set(s) 
NA 
6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
NA 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and 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. 
6.6 
Interim Analyses Set(s) 
NA 
6.7 
Study-specific Analysis Sets 
Dose Limiting Toxicity (DLT) Evaluable Analysis Set: 
DLT Evaluable Analysis Set includes all DLT-evaluable subjects defined as all subjects 
who have received the doses planned for the respective cohort, and completed the DLT 
window of 28 days for all cohorts unless he/she drops out before completion of the DLT 
window for reasons other than a DLT; exception: if a subject has received the planned 
doses in cycle 1 and drops out within 1 week of the completion of the DLT period due to 
progressive disease, that subject will be considered DLT-evaluable and will not be 
replaced. The DLT window may also be extended to assess events starting within the 
window in case the DLT definition is time dependent. The analysis of DLT will be 
restricted to DLT Evaluable Analysis Set.  


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7. 
Planned Analyses 
The following data analyses are planned: 
(1) Primary analysis after all dose-escalation and dose-expansion subjects had the 
opportunity to receive up to 12 cycles of treatment or terminated the study early. 
(2) Final analysis after all subjects have ended the study. 
Primary and final analysis may be combined in case all subjects have ended study close 
to the time point of the primary analysis. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis. Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations. In DLRMs, Amgen, in 
consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
decisions. As a sensitivity analysis, a one-parameter Continual Reassessment Method 
(CRM) model may be used to estimate the dose-toxicity relationship to help making dose 
escalation decisions. Adverse events and DLTs observed in all subjects will be 
evaluated continually and fully integrated into all DLRMs and considered in all enrollment 
and dosing decisions. 
Ad-hoc interim analysis for efficacy parameters will be conducted after dose escalation is 
completed. Once preliminary MTD and RP2D are established, FDA will be provided with 
brief interim results of the dose escalation phase. 
Dose Level Review Team (DLRT) 
DLRMs will be held to review data, monitor safety, and make decisions on dose 
escalation / change, or changes in pre-medication. If a cohort extension of up to 6 
subjects initiates, a DLRT meeting will be conducted after completion of the Japan 
cohort extension. The DLRT will be composed of the investigators or designees, and the 
following Amgen representatives: early development leader, global safety officer or 
designee, clinical study manager, biostatistician, PK scientist (optional), and other 
functional area representatives as appropriate. The following members are responsible 
for DLRT decisions: investigators, Amgen medical monitor, and global safety officer or 
designee. All available study data, including data collected after the initial DLT window, 
and including demographics, investigational product administration, medical history, 
concomitant medications, adverse events, ECGs, vital signs, laboratory data, and PK/PD 
information will be reviewed. In addition to DLTs, all grade 3 toxicities not meeting DLT 
criteria will be reviewed and may be considered in DLRT decisions. Modeling of 


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available potential safety risk data (eg, for thrombocytopenia) to predict safety risk for 
dose escalation decisions may also be considered. 
A quorum as defined below must be in attendance for the DLRM. The quorum is defined 
as > 50% of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator possessing written documentation [eg e-mail] of the 
investigator`s vote), as well as > 50% of Amgen representatives listed above. The early 
development leader or designee must attend for the quorum to be reached. The DLRM 
will be rescheduled if a quorum is not reached. 
The following decisions will be made by the DLRT: 
 
dose escalation / de-escalation decisions 
 
administration of additional doses on D12 / D19 of a cycle 
 
number of subjects per cohort 
 
continuation, delay or termination of dosing 
 
implementation of dose step(s) 
 
change of the D1 / D3 / D5 / D12 / D19 dosing scheme within the pre-specified 
window of ± 1-3 day 
 
extension of the treatment-free interval between treatment cycles 
 
If grade 5 event is fatal and suspected to be related to investigational 
product, study may be put on hold if recommended by DLRM.  
Additionally, the DLRT will review safety data for each of the Japan cohort extension 
subjects, at regular intervals as part of ongoing Dose Level Review Meetings (DLRMs). 
Subjects’ cytogenetic profiles (eg, potentially higher cytokine release in monocytic AML) 
should be taken into consideration for DLRT decisions. 
In the expansion phase, all available study data will be reviewed (with recruitment 
ongoing) by the DLRT once every 6th subject has at least completed their first treatment 
cycle plus 2 weeks or dropped out of treatment / study, whichever occurs earlier. Ad hoc 
meetings may be convened any time in case of important safety events. 
DLRM analysis is based on as-is snapshot including all data up to the data cutoff. 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment is completed and each subject 
had the opportunity to receive up to 12 cycles of treatment or terminated the study early. 
Primary analysis is based on locked database. 


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7.3 
Final Analysis 
A final analysis is planned after all dose-escalation cohorts and dose-expansion subjects 
have ended the study. Primary and final analysis may be combined in case all subjects 
have ended study close to the time point of the primary analysis. Final analysis is 
based on final locked database to prevent future change. 
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 
The following imputation for missing or incomplete data will be performed if required: 
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix G. 
 
Non-pharmacokinetic measurements (eg. biomarker data) that are below the lower 
limit of quantification will be considered equal to half of the lower limit of 
quantification for all analyses unless specified otherwise. 
 
Laboratory measurements that are below the quantification limits will be considered 
equal to the lower limit of quantification for all analyses unless explicitly noted 
otherwise.  
 
PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters 
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 in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 


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8.5 
Outliers 
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
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 
Descriptive statistics will be provided for selected demographics, safety, PK, PD 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. Graphical 
summaries of the data may also be presented. A two-parameter BLRM will be used to 
estimate the dose-toxicity relationship. Separate BLRM analysis will be conducted for 
each dose regimen, eg, MTD1 and MTD2 if there is one dose step. 
A two-parameter Bayesian logistic regression model (BLRM, Neuenschwander et al, 
2008) is used to guide dose escalation. The MTD target Toxicity Probability Interval 
(TPI) for DLT is (0.20, 0.33) and TPIs of (0.33, 0.60) and (0.60, 1.00) are defined as 
excessive and unacceptable, respectively. The design seeks to identify a dose most 
likely to have a DLT rate in the target TPI, but with overdose control that limits the 
possibility the dose has an excessive or unacceptable DLT rate (Babb et al, 1998). The 
probability of a DLT at dose level di is assumed to follow a Bernoulli distribution with 
probability pi where the logit of pi increases linearly with the log of the standardized dose 
in the following 2-parameter logistic model: 


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log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is one of the planned dose selected as the 
reference dose. 
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at 
 µg is 
0.90 and the probability the true DLT rate is ≤ 0.05 at the reference dose (
 µg) is 
0.05. Additionally, the prior is such that pi is approximately 0.05 for the 
 µg dose and 
0.25 for the reference dose. Once the 
 ug is deemed safe by Dose Level Review 
Team (DLRT), the reference dose will be updated to the highest planned dose level. For 
more details of BLRM, please refer the Appendix H in the protocol. 
9.2 
Subject Accountability 
The number and percent of subjects who were screened, enrolled, received at least one 
dose of AMG 427, completed investigational product, discontinued from investigational 
product (including reasons for discontinuing), completed study, discontinued the study 
(including reasons for discontinuing) will be summarized overall and by dose cohort.  
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. A subject listing and summary noting inclusion in each 
analysis subset will be provided for all subjects enrolled. A subject listing noting, reason 
for discontinuation of treatment, and reason for discontinuing the study will be provided. 
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 summary of IPDs table and 
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 
Demographic (i.e., age, age groups [18-64, 65-74, 75-84 and >= 85], sex, race, ethnicity) 
and baseline characteristics will be summarized by dose cohort and overall using 
descriptive statistics. If multiple races have been reported for a subject, the subject will 
be categorized as multiple-race as well as by the combination of race. 


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9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
NA 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
For R/R AML, the proportion of subjects with an overall response with corresponding 
exact 80% CI will be calculated using the Clopper-Pearson method (Clopper and 
Pearson, 1934) by cohort and tabulated for all subjects treated at the MTD/RP2D. DOR 
will be analyzed using Kaplan-Meier method. Kaplan-Meier curves and estimates for 
rates and 80% CI at selected time points will be presented for subjects in dose-
expansion cohort. Only subjects with an overall response will be analyzed for DOR.  
For MRD+ AML, the MRD conversion rate will be presented with corresponding 
exact 80% CI and tabulated by cohort and for all subjects treated at the 
MTD/RP2D. Relapse free survival and overall survival will be analyzed using 
Kaplan-Meier method. Kaplan-Meier curves and estimates for rates and 80% CI at 
selected time points will be presented for subjects in dose-expansion cohort. 
 will be considered exploratory. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels at DLRM.  Separate BLRM analysis will be 
conducted for each dose regimen, eg, MTD1 and MTD2 if there is one dose step. The 
BLRM analysis will be performed based on the Section 9.1 in Statistical Analysis Plan. 
Summary of the subject incidence of DLT will be provided. 
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. The severity of each adverse event will be graded using CTCAE version 
4.0 or later. For Cytokine release syndrome (CRS) events, grading is based on Lee et al, 


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2014 for Cohort 
 and Etanercept substudy in FIH group; and is based on Lee et al, 
2019 for Cohort 
 onwards in FIH group, eIV group and MRD group, per protocol. The 
number and percentage of subjects reporting adverse events will be evaluated overall 
and by dose level and will also be tabulated by relationship to study drug. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events (TEAE), treatment-related adverse events, serious adverse events 
(SAEs), grade 3 and above adverse events, adverse events leading to withdrawal of 
investigational product, adverse events leading to interruption of investigational product 
and fatal adverse events by system organ class, preferred term, and worst severity 
grade. Also, all TEAEs, treatment-related adverse events, SAEs and grade 3 and 
above adverse events will be summarized by preferred term only in descending order of 
frequency.  
Treatment-emergent events of interest (EOIs) 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, fatal, leading to withdrawal of investigational product, leading to 
interruption of investigational product will be summarized. 
The safety analysis will be provided for FIH, eIV and MRD groups separately. 
9.6.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be presented and reviewed for 
each subject in DLRM. Values outside the normal laboratory reference ranges will be 
flagged as high or low on the listings. 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment may be provided for selected laboratory parameters of interest. 
Shifts tables indicating the change between the baseline and the maximum post dose 
CTCAE grades (CTCAE version 4.0 or later) for an increased value, and the maximum 
post dose grade for a decreased value will be provided for selected laboratory 
parameters of interest. 
9.6.4 
Vital Signs 
Vital signs data will be listed and reviewed for each subject in DLRM. Depending on the 
size and scope of changes, summaries of vital signs data over time and/or changes from 
baseline over time may be provided. 
9.6.5 
Physical Measurements 
NA 


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9.6.6 
Electrocardiogram 
All on-study electrocardiogram (ECG) data will be listed and selected parameters of 
interest may be presented using mean plots. 
Summaries over time and/or changes from baseline over time will be provided for PR, 
QRS, QT, QTc, RR. 
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. The number of cycles started, number of doses of investigational 
product, cumulative dose, cumulative dose per cycle, the total dose and duration of 
exposure will be summarized.  
Details for each AMG 427 administration will be listed for every subject. In addition, a 
listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided. 
9.6.9 
Exposure to Non-investigational Product  
NA 
9.6.10 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to dexamethasone. The 
number of doses of dexamethasone and the total dose in mg will be summarized. 
9.6.11 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medication will be 
summarized by preferred term as coded by the World Health Organization Drug (WHO 
DRUG) dictionary. 
9.7 
Other Analyses 
Analysis for the Enbrel substudy will be described in Supplemental Statistical analysis 
plan (SSAP). 


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9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Serum concentrations of AMG 427 will be determined using a validated assay.  
PK parameters will include, but are not limited to half-life (t1/2; if feasible), maximum 
observed concentration (Cmax), minimum observed concentration (Cmin) and area under 
the concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUC0-last). Pharmacokinetic parameters will be estimated using standard 
non-compartmental approaches and summarized by dose level using means, standard 
deviations, medians, minimums, and maximums. 
Serum concentrations below the lower limit of quantifications will be set to zero for the 
estimation of the pharmacokinetic parameters for each subject and for the calculation of 
the summary statistic for each time point. Actual dosing and sampling time will be used 
for all calculations. The reasons for excluding any sample from the analyses will be 
provided.  
Individual concentration-time data will be summarized by dose level. Individual 
concentration-time data will also be tabulated and presented graphically. Summary 
statistics will be computed for each sampling time and parameter as appropriate. 
Additional PK analyses, including but not limited to analysis of the relationship between 
AMG 427 dose and exposure parameters (AUC and Cmax) and dose proportionality 
assessments, may also be conducted. Based on the review of the data, analyses to 
describe the relationship between AMG 427 exposure and either Pharmacodynamic 
effect and/or clinical outcome may also be performed. 
9.7.2 
Analyses of Clinical Outcome Assessments 
NA 
9.7.3 
Analyses of Health Economic Endpoints 
NA 
9.7.4 
Analyses of Biomarker Endpoints 
Analyses of biomarker endpoints will be performed by Clinical Biomarker and 
Diagnostics (CBD) function and details will be captured in a separate data analysis plan. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Babb J, Rogatko A, Zacks S. Cancer Phase I Clinical Trias: Efficient Dose Escalation 
with Overdose Control. Statistics in Medicine 1998;17:1103-1120. 


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Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria, 
treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642-9. 
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka 1934;26:404-13. 
Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-195. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Statistics in Medicine 2008;27:2420-2439. 
Oken MM, Creech RH, Tormey DC et al.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Thall P, Simon R, Estey E. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Statistics in Medicine. 1995;14, 357-379/. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park 
JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, 
Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. 
ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity 
Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 
Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 
30592986. 
12. 
Prioritization of Analyses 
NA 
13. 
Data Not Covered by This Plan 
NA 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
NA 
 


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Appendix B.  Concomitant Medications 
NA 
 


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Appendix C.  Clinical Outcome Assessment Forms/Instruments 
NA 
 


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Appendix D.  Health Economic Forms/Instruments 
NA 
 


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Appendix E.  Details of PK or PK/PD Methods for Modeling 
NA 
 


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Appendix F.  Analytical Windows 
NA 
 


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Appendix G.  Handling of Dates, Incomplete Dates and Missing Dates 
Below imputation rules will be used to impute start date and stop date of AE and 
Concomitant medication. Date of prior anti-cancer therapy, PD-1, PD-L1 and 
metastasis will be imputed using the same rule when only the date is missing (no 
imputation when month or year is missing). 
Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose[ of study drug]. 
 
 
 
 
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 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
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: 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 or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that 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 the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 


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 
If yyyymm for the date last known to be alive equals yyyymm for death date, 
set death date to the day after the date last known to be alive. 
 
If yyyymm for the date last known to be alive is less than the yyyymm for death 
date, set death date to the first day of the death month. 
 
[If yyyymm for the date last known to be alive is greater than yyyymm for death 
date, assume date last known to be alive is in error, set death date to the first 
day of the death month. 
If month and day are missing and year of death is known: 
 
If yyyy for the date last known to be alive equals yyyy for death date, set death 
date to the day after last known to be alive date. 
 
If yyyy for the date last known to be alive is less than yyyy for death date, set 
death date to the first day of the death year. 
 
If yyyy for the date last known to be alive is greater than yyyy for death date, 
assume date last known to be alive is in error, set death date to the first day of 
the death year. 
If a death date is totally missing: 
Do not impute and censor the subject survival time.