Conditions: Relapsed/Refractory AML Minimal Residual Disease Positive AML Myelodysplastic Syndrome
Keywords: Amgen Phase 1 Clinical Trial Oncology/Hematology Relapsed/Refractory AML Immunotherapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 95
Healthy volunteers: no

Brief summary:
The purpose of this First-in-Human Phase 1 study is to determine if AMG 330 given as a continuous IV infusion is safe and tolerable in adult subjects that have myeloid malignancies, and to determine the maximum tolerated dose and/or a biologically active dose. The study will be conducted in multiple sites and test increasing doses of AMG 330. The safety of subjects will be monitored by intensive assessment of vital signs, electrocardiograms, physical examinations, and laboratory tests.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: AMG 330
Intervention descriptions: intervention 1: 0.5 µg/day - 1.6 mg/day cIV infusion administered in cycles from 14 to 28 days.

Protocol document:
Prot_000.pdf: 
Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 1 of 193 
CONFIDENTIAL 
Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Myeloid Malignancies  
AMG 330 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND 125 331 
EudraCT number 2014-004462-20 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: 1 805-447-1000 
Key Sponsor Contacts: 
, MD, PhD 
Early Development Leader 
Phone:
E-Mail: 
, PhD 
Clinical Research Study Manager 
Phone:
E-mail: 
Date: 
Amendment 1 Date: 
23 February 2015 
21 May 2015 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
Amendment 5 Date: 
Amendment 6 Date: 
Amendment 7 Date: 
Amendment 8 Date: 
19 August 2015 
19 October 2016 
28 June 2018 
06 May 2019 
28 August 2019 
10 April 2020 
04 June 2020 
Amendment 9 Date: 
15 February 2021 
NCT Number: NCT02520427
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 2 of 193 
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:  US sites, 1- 800-77-AMGEN; Germany, 49 800 
264 36-44; Netherlands, 31 76 5732500; Amgen’s general number in the US 
(1-805-447-1000). 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 3 of 193 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase 1 First-in-Human Study Evaluating 
the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of 
AMG 330 Administered as Continuous Intravenous Infusion in Subjects with Myeloid 
Malignancies”, dated 15 February 2021 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 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 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 4 of 193 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1 First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 330 Administered as Continuous Intravenous Infusion 
in Subjects with Myeloid Malignancies 
Study Phase:  1 
Indication:  Relapsed/Refractory Acute Myeloid Leukemia (AML), Minimal Residual Disease 
Positive (MRD) AML, Myelodysplastic Syndrome (MDS) 
Primary Objectives: 
 
Evaluate the safety and tolerability of AMG 330 in adult subjects with relapsed/refractory 
AML, MRD AML and MDS  
 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
(eg, recommended phase 2 dose [RP2D]) of AMG 330 in adults with relapsed/refractory 
AML, MRD AML and MDS 
Secondary Objectives: 
 
Evaluate the pharmacokinetics (PK) of AMG 330 
 
Determine the formation of anti-AMG 330 antibodies 
 
Evaluate the anti-leukemia activity of AMG 330 by evaluating 
 
the number and proportion of subjects who respond to treatment with AMG 330.  
Response is defined as any of the following: complete remission (CR), CR with 
incomplete recovery (CRi) or morphologic leukemia-free state (all according to 
Revised International Working Group [IWG] response criteria) or CR with partial 
hematologic recovery (CRh). 
 
the number and proportion of subjects with MDS who respond to treatment with 
AMG 330.  Response is defined as any of the following: CR or marrow CR (all 
according to Revised IWG response criteria).  
 
the number and proportion of subjects with MRD-positive AML (Group 2) who 
respond to treatment with AMG 330.  Response is defined as conversion from MRD 
status with 0.1 threshold to MRD-. 
 
the duration of response, time to progression, and time to response 
Exploratory Objectives: 
 
Evaluate the protein, nucleic acid, and cellular biomarkers in blood and / or bone marrow, as 
applicable (eg, cytokines, lymphocyte subsets, minimal residual disease [MRD – Group 1 
only], leukemic stem cells [LSCs]) 
 
Evaluate effects of genetic variations in and phenotype of cancer genes, including apoptotic 
markers, on adverse event profile and treatment response 
 
Evaluate mechanisms of resistance 
 
Evaluate potential measures of clinical benefit including number of blood products transfused 
and days of antibiotic treatment of infection 
 
Evaluate the relationship between AMG 330 exposure and response to treatment 
 
 
 
 
 
Explore additional thresholds of conversion to MRD- status in MRD AML subjects as an 
efficacy measure for AMG 330 treatment 
Hypotheses:  AMG 330 will demonstrate evidence of anti-leukemic activity at a well-tolerated 
dose in subjects with AML and MDS. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 5 of 193 
CONFIDENTIAL 
 
 
Primary Endpoint:   
 
Safety:  subject incidence and grade of adverse events (AEs) and dose limiting toxicities 
(DLTs) 
Secondary Endpoints:   
 
Pharmacokinetic parameters:  half-life, steady state concentration, volume of distribution and 
clearance of AMG 330 
 
Incidence of anti-AMG 330 antibody formation 
 
Efficacy parameters for R/R AML:  response rate (response defined as CR/CRi/morphologic 
leukemia-free state [per modified IWG criteria] or CRh), duration of response, time to 
progression, time to response  
 
Efficacy parameters for MRD-positive AML: response rate (response defined as conversion 
from MRD status with 0.1 threshold to MRD-), duration of response, time to response 
 
Efficacy parameters for MDS: response rate (response defined as CR or marrow complete 
remission [per International Working Group (IWG) standardized response criteria]), duration 
of response, time to progression, time to response 
Exploratory Endpoints:   
 
Depletion of LSCs 
 
MRD response  
 
Lymphocyte counts, cluster of differentiation (CD) 33 monocytes and T cells, as well as 
T cell activation (including T cell subsets).  Other immune subsets may also be examined. 
 
 
 
Changes in serum cytokine levels 
 
Frequency and severity of cytokine release syndrome (CRS) and other AEs following 
 premedication, and alternative dose step schedules of 
AMG330 
 
Study Design:   
This is a first-in-human, open-label, phase 1 sequential dose escalation study.  AMG 330 will be 
evaluated as a continuous intravenous (cIV) infusion in adult subjects with relapsed/refractory 
(R/R) AML (Group 1), MRD AML (Group 2) and MDS (Group 3).  The study will be conducted at 
approximately 17 sites in Germany, the Netherlands, Japan, Canada and the United States. 
The dose-escalation cohorts will estimate the MTD/biologically active dose, safety, tolerability, 
PK, and pharmacodynamics (PD) of AMG 330. 
For R/R AML (Group 1), planned dose levels for the dose-escalation cohorts are as follows: 0.5, 
 and 960 g/day.  Intermediate and/or higher 
dose level(s) up to 1.6 mg of AMG 330 may be evaluated as necessary to reach MTD.  The same 
dose level may be tested in multiple cohorts, but with different dose steps and/or different cycle 
lengths. 
For MRD AML (Group 2), planned target dose levels for the dose-escalation cohorts are as 
follows:  
 and 960 g/day.  Each target dose level will be preceded by dose steps. 
Intermediate dose steps and additional target dose level(s) up to 1.6 mg of AMG 330 may be 
evaluated as necessary.  Escalation can continue until the biologically active dose for MRD AML 
is established.  Selected target dose levels, with the exception of the maximal tested dose, 
that have been deemed safe in subjects with R/R AML (Group 1) could be skipped in 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 6 of 193 
CONFIDENTIAL 
 
 
Group 2 phase 1a dose escalation cohorts based on available safety, PK, and PD data if 
recommended by the Dose Level Review Team (DLRT).  
For MDS (Group 3), planned target dose levels for dose-escalation cohorts are as follows:  
 
 and 960 g/day.  Each target dose will be preceded by dose steps.  Intermediate dose 
steps and additional dose level(s) up to 1.6 mg of AMG 330 may be evaluated as necessary.  
Escalation can continue until MTD for MDS is established.  Selected target dose levels, with 
the exception of the maximal tested dose, that have been deemed safe in subjects with 
R/R AML (Group 1) could be skipped in Group 3 phase 1a dose escalation cohorts based 
on available safety, PK, and PD data if recommended by the DLRT.   
It is anticipated that more than one MTD per indication may be estimated, one for each dose step 
and one for the target dose.  Should the initial dose be limited by adverse events related to first 
dose effects (eg, cytokine release syndrome [CRS]), the second MTD for the target dose will be 
estimated after giving the initial dose at MTD (dose step).  Starting with cohort 6 (R/R AML, 
Group 1), a dose step in each cycle is mandatory for all newly enrolled subjects.  Administration 
of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 hour prior to the dose step for 
prevention of cytokine release is mandatory.  The additional assessments described in the 
schedule of assessments for dose steps (Table 14) apply.   
Dose Escalation 
For Group 1 (R/R AML), dose escalation will be conducted in two stages.  In the single subject 
cohorts, single subjects will be enrolled at dose levels anticipated to be lower than those at which 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 7 of 193 
CONFIDENTIAL 
 
 
adverse events related to AMG 330 will be observed.  Once higher dose levels are open for 
enrollment or drug related safety or efficacy signals are observed, multiple subject cohorts of up 
to 6 evaluable subjects per dose level will open for enrollment (33 design).  Subjects who 
complete the DLT period may proceed to a higher dose level for the following treatment cycle if 
no DLT has been reported for either this subject or any other subject in this dose cohort after 
completion of the DLT period, and once the next dose cohort is open for enrollment (see 
Section 7.2.2 for details on assessments applicable in case of intra-subject dose escalation).  
In Group 1 (R/R AML), should the initial dose be limited by adverse events related to first dose 
effects (eg, CRS), dose steps will be implemented.  An optimal dose step schedule and MTD for 
the target dose will be estimated following decision rules.   
For Groups 2 and 3 (MRD AML and MDS), each dose escalation cohort will enroll a minimum of 
3 to a maximum of 9 evaluable subjects.  Dose escalation will be guided by a modified toxicity 
probability interval approach (mTPI-2; Guo et al, 2017).  The DLRT will review all available safety, 
laboratory, PK, and PD data and provide dose-finding recommendations. 
For Groups 1, 2, and 3, enrollment will occur simultaneously, and each Group will progress from 
dose escalation to dose expansion independently.  The total number of subjects to be enrolled for 
the dose escalation will depend on the toxicities observed as the study progresses.  Additional 
subjects may be required if other dose levels or alternate treatment schedules are explored. 
Enrollment in Group 4 is independent from enrollment in Groups 1, 2 and 3.  For Group 4, 
enrollment in Arm 1 will occur first.  Once all subjects in Arm 1 have initiated treatment, 
enrollment into Arm 2 will begin.  Once all Group 4 subjects have completed the DLT period, 
enrollment into Group 5 can commence.  If there are 2 arms in Group 5, all subjects in Arm 1 
must have initiated treatment before enrollment into Arm 2 can begin. 
Expansion Cohorts 
At completion of the dose escalation cohorts, additional subjects will be enrolled in a dose 
expansion cohort to gain further clinical experience, safety and efficacy data in subjects with 
AMG 330.  The dose to be evaluated will be at or below the MTD estimated in the dose 
escalation cohorts.  If there is at least 1 responding subject in the first 10 subjects enrolled in the 
expansion cohort, additional (up to 20) subjects will be enrolled after evaluating safety, tolerability 
and anti-leukemia activity of AMG 330 using all available cumulative data.  Additional expansion 
cohorts testing alternative dose levels or biologic subsets may be considered by amendment. 
For each Group, a final estimate of the MTD and/or RP2D will be evaluated and confirmed 
utilizing all DLT-evaluable subjects from the dose escalation and the dose expansion cohorts. 
Sample Size: 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
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CONFIDENTIAL 
 
 
Summary of Subject Eligibility Criteria:  Male or female subjects must be  18 years of age at the 
time of signing the informed consent. For Groups 1, 4 and 5, subjects who have AML as defined 
by World Health Organization (WHO) Classification (Appendix D) persisting or recurring following 
one or more treatment courses except promyelocytic leukemia (APML).  Subjects must also have 
more than 5 blasts in bone marrow.  For Group 2, MRD AML, subjects who have AML as 
defined by WHO Classification (Appendix D) treated with 1L therapy achieving CR/CRi with 
detectable MRD and not eligible for HSCT.  For Group 3, subjects with MDS as defined by WHO 
Classification (Appendix I) with intermediate, high and very high risk per revised International 
Prognostic Scoring System (IPSS-R) (Appendix J) unresponsive to standard therapy with 
hypomethylating agents (HMA) and not eligible for HSCT.  For a full list of eligibility criteria, 
please refer to Section 4.1 and Section 4.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration: 
AMG 330 and the 
 will be manufactured and packaged by 
Amgen Inc. and distributed using Amgen clinical study drug distribution procedures. 
AMG 330 solution for infusion will be prepared in bags for IV infusion and delivered through 
infusion lines.  The drug will be administered as a cIV infusion at a constant flow rate over 2 to 
4 weeks followed by an infusion-free interval prior to the following treatment cycle.  The 
infusion-free interval will have a duration of 0 to 4 weeks (depending on safety and treatment 
response, see Section 6.2.1.1), but may be extended to up to 6 weeks in case of prolonged 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 9 of 193 
CONFIDENTIAL 
 
 
marrow aplasia and aleukemic cytopenias after consultation with the sponsor.  It may also be 
extended for up to three days from the planned duration if necessary for logistical reasons.   
Subjects will be hospitalized for a minimum of 72 hours (R/R AML Group 1 and MDS Group 3) 
or 48 hours (MRD AML Group 2) under the following circumstances: 
 
at the start of the first 2 infusion cycles 
 
at each dose step in cycle 1 
 
at dose increase in case of intra-subject dose escalation 
In addition, subjects will be hospitalized for a minimum of 48 hours after treatment interruption 
requiring restart of treatment in the hospital.  At the start of infusion in the first cycle, a 
hospitalization of 9 to 12 days is recommended for R/R AML subjects in Group 1, based on 
the AMG 330 schedule of administration.  Starting from cycle 3 and higher, hospitalization 
is at the discretion of an investigator for all groups.   
The planned target dose levels for the R/R AML (Group 1) dose escalation cohorts are: 0.5, 
 
 and 960 g/day.
, 
planned target dose levels for the dose-escalation cohorts are
 and 960 g/day.  
For MDS (Group 3), planned dose levels for dose-escalation cohorts are 
 and 
960 g/day. 
After completion of a first cycle without DLT, up to 5 additional treatment cycles can be 
administered as long as, in the judgment of the investigator, the subject is deriving benefit. 
Subjects in Group 4 will receive AMG 330 at a dose of 
 g/day for  days, 
 g/day for  days 
and 
 g/day for  days for a total cycle of 
 days.  In Group 4 Arm 1, 
 will be 
administered 
.  In Group 4 Arm 2, 
 will 
be administered 
 
. 
Subjects in Group 5 will receive 
 AMG 330 
using either mini or maxi dose steps.  Group 5 Arm 1 will be administered AMG 330 with daily 
mini step doses at 
 g/day, followed by the target dose of 
 g/day for 
 days (for a 28 day cycle).  Subjects in Group 5, Arm 2 will be administered 
AMG 330 using maxi step doses of 
 g for  days followed by the target dose of 
 g for 
 days (for a 28 day cycle). 
Procedures: 
After providing informed consent, eligible subjects will undergo the following assessments during 
this study: Clinical evaluation (physical examination, Eastern Cooperative Oncology Group 
[ECOG] status, height, and weight), vital signs, pulse oximetry, electrocardiogram (ECG) triplicate 
measurement, laboratory assessments (including serum pregnancy test, if applicable, 
coagulation, hematology, chemistry, urinalysis, hepatitis serology, and anti-AMG 330 antibody 
test), biomarker and PK assessments, and bone marrow aspirate / biopsy assessments.  For a 
full list of study procedures, including the timing of each procedure, please refer to Section 7 and 
the Schedule of Assessments (Table 8 - Table 23). 
Statistical Considerations: 
All subjects who are enrolled and receive at least one administration of the investigational product 
(AMG 330) will be included in the analysis, unless otherwise specified.  The analysis will be 
performed by Group.  The primary analysis will occur when target enrollment is complete and 
each subject either completes 6 months on study 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 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 10 of 193 
CONFIDENTIAL 
 
 
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 
listed.  Depending on the size and scope of changes in clinical laboratory, physical examination 
and vital sign data, the summaries of laboratory, 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. 
Positive anti-AMG 330 antibody data will be listed and reviewed for each subject.  Summaries of 
positive anti-AMG 330 antibody test results over time may be provided.  The impact of 
immunogenicity on safety will also be reviewed by assessing adverse events and serious adverse 
events. 
The proportion of responding subjects with corresponding exact 80 CI will be calculated using 
the Clopper-Pearson method (Clopper et al., 1934) and tabulated for subjects treated at the 
estimated MTD.  Efficacy related endpoints (duration of the response, time to response) will be 
listed 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 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 11 of 193 
CONFIDENTIAL 
 
 
Overall Study Design (All Groups) 
N ≤ 36 
(4 dose escalation 
cohorts)a 
Arm 1: 
 (N=6) 
 
Arm 2: 
 (N=6) 
Arm 1: Mini-step dosing + 
(N=6) 
               ORc 
Arm 2: Maxi-Step dosing + 
 (N=6) 
 
cOnly Arm 1 or 2 will be selected based on results from Group 4 
Enrollment (Day 1) 
End of Treatment 
End of Study (30d after last dose of AMG 330) 
Screening (14 days) 
 
 
 
 
 
 
 
 
Phase 1a Dose Escalation 
 
 
 
Phase 1b Dose Expansion 
 
Group 1: R/R AML 
 
 
Group 2: MRD+ AML 
 
Group 3: MDS 
N = 70 
(19 dose escalation 
cohorts)a 
N ≤ 36 
(4 dose escalation 
cohorts)a 
N = 30 
N = 30 
N = 30 
 
Group 4: R/R AML – 
premedication with cytokine 
blocker  
Group 5: R/R AML – 
optimization of step dosingb 
aAdditional cohorts may be added per 
DLRT decision based on available 
safety, PK, and PD data 


Product:  AMG 330 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for R/R AML (Group 1) 
DOSE ESCALATION  
 
Cohort 1 – 3 (single subject cohorts): (0.5,
µg/day) 
Cohorts 4 – 19a (3+3 design): (
, 
960 µg/day)  
 
Number of cohorts and actual doses dependent upon observance of DLTs 
Starting with cohort 6, a dose step in each cycle is implemented 
Same dose level may be tested in multiple cohorts with different dose steps 
and/or different cycle lengths 
Enrollment (Day 1) 
End of Treatment 
End of Study (30d after last dose of AMG 330) 
Screening (14 days) 
Single subject 
cohorts 
(n=1) 
Multiple subject cohorts 
3+3 design (n = 3 to 6) 
 
DOSE 
EXPANSION 
 
Will begin at or below 
the MTD or highest 
tested dose 
n=30 
 
aAdditional cohorts may be added per DLRT decision based on available safety, PK, and PD data 


Product:  AMG 330 
Protocol Number:  20120252 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for MRD AML (Group 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSE ESCALATION  
 
Cohorts 1-4a (
 and 960 µg/day)  
 
Each target dose level will be preceded by step 
doses of 
 µg/day for up to  days and 
 µg/day for up to
 days. Escalation can 
continue until the biologically active dose for MRD+ 
AML is established. 
 
Enrollment (Day 1) 
End of Treatment 
End of Study (30d after last dose of AMG 330) 
Screening (14 days) 
DOSE EXPANSION 
Will begin at or below the MTD or highest 
tested dose 
n=30 
Multiple subject cohorts 
mTPI-2 design (n=3 to 9) 
aNumber of cohorts will depend on DLRT decision based on available safety, PK, and PD 
data 


Product:  AMG 330 
Protocol Number:  20120252 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for MDS (Group 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSE ESCALATION  
Cohorts 1-4a (
and 960 g/day  
Each target dose will be preceded by a step of 
 µg/day for up to  days followed by a second 
step dose of 
 µg/day for up to  days.Escalation 
can continue until MTD for MDS is established. 
Enrollment (Day 1) 
End of Treatment 
End of Study (30d after last dose of AMG 330) 
DOSE EXPANSION 
Will begin at or below the MTD or highest 
tested dose 
n=30 
Screening (14 days) 
Multiple subject cohorts 
mTPI-2 design (n = 3 to 9) 
aNumber of cohorts will depend on DLRT decision based on available safety, PK, and PD 
data 


Product:  AMG 330 
Protocol Number:  20120252 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for R/R AML With Alternative CRS Prophylaxis (Group 4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment (Day 1) 
Cycle 1: 
 
AMG 330:
 µg/day, 
 µg/day, 
 µg/day 
 
In combination with: 
 
Arm 1 (n=6):
  
 
 
Arm 2 (n=6):
  
 
 
End of Treatment
End of Study (30d after 
last dose of AMG 330) 
Screening (14 days) 
Cycles 2-6: 
 
Receive AMG 330 
using any dosing 
schedule  demonstrated 
as safe and tolerable in 
Group 1, in combination 
with dexamethasone 
premedication 
OR 
End of Treatment 
End of Study (30d after 
last dose of AMG 330) 


Product:  AMG 330 
Protocol Number:  20120252 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for R/R AML With Alternative CRS Prophylaxis and Mini or Maxi Dose Steps (Group 5) 
 
 
Arm 1 (n=6):  
+ 
AMG 330 administered with daily mini-step doses at 
, 
 g,and 
 g, followed by 
 g for 
 days. 
 
 
AND/OR 
 
 
Arm 2 (n=6):  
+ 
AMG 330 administered with maxi-step doses of 
 g for  days 
followed by 
 g for 
 days 
 
Enrollment (Day 1) 
End of Treatment 
End of Study (30d after last dose of AMG 330) 
Screening (14 days) 


Product:  AMG 330 
Protocol Number:  20120252 
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Page 17 of 193 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term Definition/Explanation 
ALL 
Acute lymphoblastic leukemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
APML 
Promyelocytic leukemia 
AST 
Aspartate aminotransferase 
AT III   
Antithrombin III 
BiTE 
BLRM 
Bispecific T-cell engager 
Bayesian Logistic Regression Model  
Morphologic 
leukemia-free state 
Less than 5 blasts in bone marrow without recovery of peripheral blood 
counts (see Appendix E for details) 
CD 
Cluster of differentiation 
CI 
Confidence interval 
cIV 
Continuous intravenous 
CL 
Systemic clearance 
CNS 
Central nervous system 
Css 
Steady-state drug concentration in plasma during constant-rate infusion 
CR 
Complete response/remission (see Appendix E) 
CRh 
Complete response/remission with partial recovery of peripheral blood 
counts (ANC  500/L, platelets  50,000/L) (Topp et al., 2015) 
CRi 
Complete response/remission with incomplete recovery of peripheral 
blood counts (see Appendix E) 
CRP 
C reactive protein 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
Drug-induced liver injury 
DLRM 
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DLT 
Dose-limiting toxicity  
DNA 
Deoxyribonucleic acid 
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 


Product:  AMG 330 
Protocol Number:  20120252 
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Abbreviation or Term Definition/Explanation 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
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 are conducted 
for an individual subject 
EOI 
End of infusion 
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 
eSAE 
Electronic serious adverse event (form) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GO 
Gemtuzumab ozogamicin 
Heart rate 
Number of cardiac cycles per unit of time 
HepBsAg 
Hepatitis B surface antigen 
HepCAb 
Hepatitis C virus antibody 
HED 
Human equivalent dose for safety 
HiDAC 
High dose cytarabine 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HSCT 
Hematopoietic stem cell transplantation 
ICF 
Informed consent form 
ICMJE 
International Committee of Medical Journal Editors 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
INR 
International normalized ratio 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 


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Abbreviation or Term Definition/Explanation 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
 
 
IWG 
International Working Group 
LAIP 
Leukemia-associated immunophenotype 
LDH 
Lactate dehydrogenase 
LSC 
Leukemic stem cell 
MABEL 
Minimum Anticipated Biological Effect Level 
MDS 
Myelodysplastic Syndrome 
MRD 
Minimal Residual Disease 
MRI 
Contrast-enhanced magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI 
Modified toxicity probability interval 
NHL 
Non-Hodgkin’s lymphoma 
NK 
Natural killer cell 
NOD/SCID 
Non-obese diabetic/severe combined immunodeficiency disease 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
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 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
RR interval 
The time elapsed between 2 consecutive R waves as measured by ECG 
SC 
Subcutaneous(ly) 
 
 


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Abbreviation or Term Definition/Explanation 
SCR 
Screening 
SD 
Standard deviation 
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 
t1/2 
Terminal-phase elimination half-life 
TBL 
Total bilirubin 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
US 
United States 
Vss 
Apparent volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 


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Table of Contents 
Protocol Synopsis ............................................................................................................ 4 
Overall Study Design (All Groups) ................................................................................. 11 
Study Design and Treatment Schema for R/R AML (Group 1) ....................................... 12 
Study Design and Treatment Schema for MRD AML (Group 2) ................................... 13 
Study Design and Treatment Schema for MDS (Group 3) ............................................. 14 
Study Design and Treatment Schema for R/R AML With Alternative CRS 
Prophylaxis (Group 4) ........................................................................................... 15 
Study Design and Treatment Schema for R/R AML With Alternative CRS 
Prophylaxis and Mini or Maxi Dose Steps (Group 5) ............................................. 16 
Study Glossary .............................................................................................................. 17 
1. 
OBJECTIVES ....................................................................................................... 28 
1.1 
Primary ..................................................................................................... 28 
1.2 
Secondary ................................................................................................. 28 
1.3 
Exploratory ................................................................................................ 28 
2. 
BACKGROUND AND RATIONALE ...................................................................... 29 
2.1 
Disease ..................................................................................................... 29 
2.1.1 
Acute Myeloid Leukemia (AML) ................................................. 29 
2.1.2 
Myelodysplastic Syndrome ........................................................ 31 
2.1.3 
Cytokine Release Syndrome (CRS) Prophylaxis ....................... 33 
2.1.3.1 
Blocking Biological Effects of 
............................ 33 
2.1.3.2 
Blocking Biological Effects of 
....................... 34 
2.2 
Amgen Investigational Product Background .............................................. 35 
2.2.1 
Nonclinical Pharmacology ......................................................... 35 
2.2.2 
Nonclinical Pharmacokinetics .................................................... 36 
2.2.3 
Nonclinical Toxicology ............................................................... 37 
2.2.4 
Dosing Experience With Other BiTE Antibody 
Constructs ................................................................................. 37 
2.3 
Risk Assessment ....................................................................................... 39 
2.4 
Rationale ................................................................................................... 40 
2.5 
Clinical Hypotheses ................................................................................... 44 
3. 
EXPERIMENTAL PLAN ........................................................................................ 44 
3.1 
Study Design ............................................................................................. 44 
3.1.1 
Design of Group 1: R/R AML ..................................................... 44 
3.1.2 
Design of Group 2: MRD AML ................................................. 50 
3.1.3 
Design of Group 3: MDS ........................................................... 51 
3.1.4 
Dose Escalation Rules for Groups 2 and 3 ................................ 51 
3.1.5 
Expansion Cohorts for Groups 1, 2 and 3 .................................. 52 


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3.1.6 
Design of Alternative Cytokine Release Syndrome 
(CRS) Prophylaxis Groups ........................................................ 52 
3.1.6.1 
Group 4 Design ....................................................... 53 
3.1.6.2 
Group 5 Design ....................................................... 55 
3.2 
Number of Sites ........................................................................................ 56 
3.3 
Number of Subjects ................................................................................... 56 
3.4 
Replacement of Subjects .......................................................................... 56 
3.5 
Estimated Study Duration .......................................................................... 57 
3.5.1 
Study Duration for Subjects ....................................................... 57 
3.5.2 
End of Study .............................................................................. 57 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 58 
4.1 
Inclusion Criteria ....................................................................................... 58 
4.2 
Exclusion Criteria ...................................................................................... 59 
5. 
SUBJECT ENROLLMENT .................................................................................... 61 
5.1 
Treatment Assignment .............................................................................. 62 
6. 
TREATMENT PROCEDURES .............................................................................. 63 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 63 
6.2 
Investigational Product .............................................................................. 64 
6.2.1 
Amgen Investigational Product AMG 330 and 
 .................. 64 
6.2.1.1 
Dosage, Administration, and Schedule – 
AMG 330 and 
 ................................................. 64 
6.2.1.2 
Overdose ................................................................ 67 
6.2.1.3 
AMG 330 Outpatient Dosing .................................... 68 
6.2.1.4 
Dose-cohort Study Escalation and 
Stopping Rules, Dose-limiting Toxicities 
(DLTs) ..................................................................... 69 
6.2.1.5 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 72 
6.2.2 
Marketed Investigational Products – 
 
 ............................................................................... 76 
............................................................ 77 
............................................................ 78 
6.3 
Other Protocol-required Therapies ............................................................ 78 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 79 
6.4.1 
Criteria for Permanent Withholding of Amgen 
Investigational Product due to Potential Hepatotoxicity ............. 79 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product due to Potential Hepatotoxicity ............. 79 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product After Potential Hepatotoxicity ....................................... 80 
6.5 
Concomitant Therapy ................................................................................ 80 


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6.6 
Specific Recommendations for Cytokine Release Syndrome, 
Tumor Lysis Syndrome and Infection Prophylaxis ..................................... 81 
6.7 
Medical Devices ........................................................................................ 86 
6.8 
Product Complaints ................................................................................... 86 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 87 
7. 
STUDY PROCEDURES ....................................................................................... 87 
7.1 
Schedule of Assessments ......................................................................... 87 
7.2 
General Study Procedures ...................................................................... 123 
7.2.1 
Screening ................................................................................ 124 
7.2.2 
Treatment ................................................................................ 125 
7.2.3 
End of Treatment ..................................................................... 127 
7.2.4 
End of Study Visit .................................................................... 128 
7.3 
Description of Study Procedures ............................................................. 129 
7.3.1 
Informed Consent .................................................................... 129 
7.3.2 
Demographic Data................................................................... 129 
7.3.3 
Medical History and Prior Therapy ........................................... 129 
7.3.4 
Concomitant Medications ........................................................ 129 
7.3.5 
Clinical Evaluation ................................................................... 129 
7.3.5.1 
Physical Examination ............................................ 129 
7.3.5.2 
ECOG Performance Status ................................... 130 
7.3.5.3 
Height Measurements ........................................... 130 
7.3.5.4 
Weight Measurements .......................................... 130 
7.3.6 
Vital Signs ............................................................................... 130 
7.3.7 
Pulse Oximetry ........................................................................ 130 
7.3.8 
Electrocardiogram Performed in Triplicate ............................... 131 
7.3.9 
Clinical Laboratory Tests ......................................................... 131 
7.3.9.1 
Serum Pregnancy Test .......................................... 132 
7.3.10 
Events ..................................................................................... 133 
7.3.11 
MRI Cranial ............................................................................. 133 
7.3.12 
Pharmacokinetic Blood Sampling ............................................ 133 
7.4 
Antibody Testing Procedures .................................................................. 133 
7.5 
Biomarker Development .......................................................................... 134 
7.5.1 
Bone Marrow Aspirate and Biopsy Assessments ..................... 134 
7.5.2 
Phenotyping and Genotyping of AML Blasts and 
Assessment of MRD ................................................................ 135 
7.5.2.1 
MRD Testing for Screening/Eligibility for 
Subjects in Group 2 ............................................... 136 
7.5.2.2 
MRD Testing During Treatment ............................. 136 
7.6 
Disease Response .................................................................................. 137 
7.7 
Blood and Bone Marrow Samples ........................................................... 140 
7.8 
Pharmacogenetic Studies ....................................................................... 141 
7.9 
Sample Storage and Destruction ............................................................. 141 


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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 142 
8.1 
Subjects’ Decision to Withdraw ............................................................... 142 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 143 
8.3 
Reasons for Removal From Treatment or Study ..................................... 143 
8.3.1 
Reasons for Removal From Treatment .................................... 143 
8.3.2 
Reasons for Removal From Study ........................................... 144 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 144 
9.1 
Definition of Safety Events ...................................................................... 144 
9.1.1 
Disease-related Events ........................................................... 144 
9.1.2 
Adverse Events ....................................................................... 144 
9.1.3 
Adverse Device Effects ........................................................... 145 
9.1.4 
Serious Adverse Events .......................................................... 146 
9.2 
Safety Event Reporting Procedures ........................................................ 146 
9.2.1 
Reporting Procedures for Disease-related Events ................... 146 
9.2.2 
Adverse Events ....................................................................... 147 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .......................... 147 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ................................................................... 148 
9.2.2.3 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 149 
9.2.2.4 
Safety Monitoring Plan .......................................... 150 
9.3 
Pregnancy and Lactation Reporting ........................................................ 150 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 151 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 151 
10.1.1 
Study Endpoints ...................................................................... 151 
10.1.2 
Analysis Sets ........................................................................... 152 
10.1.3 
Covariates and Subgroups ...................................................... 152 
10.2 
Sample Size Considerations ................................................................... 152 
10.3 
Planned Analyses ................................................................................... 153 
10.3.1 
Interim Analysis and Early Stopping Guidelines ....................... 153 
10.3.2 
Dose Level Review Team (DLRT) ........................................... 154 
10.3.3 
Primary Analysis ...................................................................... 155 
10.3.4 
Final Analysis .......................................................................... 155 
10.4 
Planned Methods of Analysis .................................................................. 156 
10.4.1 
General Considerations ........................................................... 156 
10.4.2 
Primary Endpoint ..................................................................... 156 
10.4.3 
Secondary Endpoints .............................................................. 157 
10.4.3.1 
Pharmacokinetics Data Analysis ........................... 157 
10.4.3.2 
Efficacy Endpoint Analyses ................................... 157 
10.4.3.3 
Anti-AMG 330 Antibodies ...................................... 157 


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10.4.4 
Exploratory Endpoints ............................................................. 158 
11. 
REGULATORY OBLIGATIONS .......................................................................... 158 
11.1 
Informed Consent .................................................................................... 158 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 159 
11.3 
Subject Confidentiality ............................................................................. 159 
11.4 
Investigator Signatory Obligations ........................................................... 160 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 160 
12.1 
Protocol Amendments and Study Termination ........................................ 160 
12.2 
Study Documentation and Archive .......................................................... 161 
12.3 
Study Monitoring and Data Collection ..................................................... 161 
12.4 
Investigator Responsibilities for Data Collection ...................................... 162 
12.5 
Language ................................................................................................ 163 
12.6 
Publication Policy .................................................................................... 163 
12.7 
Compensation ......................................................................................... 163 
13. 
REFERENCES ................................................................................................... 164 
14. 
APPENDICES .................................................................................................... 169 
List of Tables 
Table 1.  Potential Risks of AMG 330 ............................................................................ 39 
Table 2.  Identified Risks of AMG 330 ........................................................................... 40 
... 43 
... 48 
Table 5.  33 Dose Level Decision Rules ...................................................................... 50 
Table 6.  Assessments to be Performed After Infusion Interruption and 
Restart .................................................................................................... 74 
Table 7.  Grading and Management of Cytokine Release Syndrome ............................. 83 
Table 8.  Schedule of Assessments for Cohorts With 14 Day Infusion 
Duration Screening and Treatment Cycle 1 ............................................ 88 
Table 9.  Schedule of Assessments for Cohorts With 14 Day Infusion 
Duration Treatment Cycle 2 and Following to End of Study .................... 90 
Table 10.  Schedule of Assessments for Cohorts With 21 Day Infusion 
Duration Screening and Treatment Cycle 1 ............................................ 92 
Table 11.  Schedule of Assessments for Cohorts With 21 Day Infusion 
Duration Treatment Cycle 2 and Following to End of Study .................... 94 
Table 12.  Schedule of Assessments for Cohorts With 28 Day Infusion 
Duration Screening and Treatment Cycle 1 ............................................ 96 
Table 13.  Schedule of Assessments for Cohorts With 28 Day Infusion 
Duration Treatment Cycle 2 and Following to End of Study .................... 99 


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Table 14.  Additional Assessments Applicable in Case of Dose Step 
(Regardless of Treatment Cycle) .......................................................... 101 
Table 15.  Schedule of Assessments for Group 4, Arm 1 (
 
) – Cycle 1 ...................................................................... 102 
Table 16.  Schedule of Assessments for Group 4, Arm 2 (
 
) – Cycle 1 .................................................................... 104 
Table 17.  Schedule of Assessments for Group 5, Arm 1 
(
 and Mini-step Dosing Approach) 
Cycle 1 ................................................................................................. 106 
Table 18.  Biomarker Collection Schedule for Group 5, Arm 1, Cycle 1 ....................... 109 
Table 19.  Schedule of Assessments for Group 5, Arm 1 
(
 and Mini-step Dosing Approach) 
Cycle 2 ................................................................................................. 110 
Table 20.  Schedule of Assessments for Group 5, Arm 1 
(
 and Mini-step Dosing Approach) 
Cycle 3 and Following to End of Study ................................................. 112 
Table 21.  Schedule of Assessments for Group 5, Arm 2 
(
 and Maxi-step Dosing Approach) 
Cycle 1 ................................................................................................. 115 
Table 22.  Schedule of Assessments for Group 5, Arm 2 
(
 and Maxi-step Dosing Approach) 
Cycle 2 ................................................................................................. 118 
Table 23.  Schedule of Assessments for Group 5, Arm 2 
(
 and Maxi-step Dosing Approach) 
Cycle 3 and Following to End of Study ................................................. 120 
Table 24.  List of Analytes ........................................................................................... 132 
List of Figures 
.... 41 
.... 44 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 170 
Appendix B.  Electronic Serious Adverse Event Contingency Form ............................. 172 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 177 
Appendix D.  World Health Organization Classification for Acute Myeloid 
Leukemias ............................................................................................ 179 
Appendix E.  Revised International Working Group Response Criteria for 
AML ...................................................................................................... 181 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ............................................................ 184 


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Appendix G.  Expected Disease-related Events by System Organ Class 
(SOC) ................................................................................................... 185 
Appendix H.  mTPI-2 Guidelines for Dose Escalation/De-escalation ........................... 186 
Appendix I.  2016 WHO Myelodysplastic Syndrome Subtypes .................................... 187 
Appendix J.  Revised International Prognostic Scoring System (IPSS-R) in 
MDS ..................................................................................................... 189 
Appendix K.  Modified International Working Group Response Criteria for 
MDS ..................................................................................................... 190 
Appendix L.  MDS Cytogenetic Scoring System: International Prognostic 
Scoring System, Revised ...................................................................... 191 
Appendix M.  Recurring Chromosomal Abnormalities in Adults With MDS .................. 192 
Appendix N.  2017 ELN Risk Stratification by Genetics for AML .................................. 193 
 


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1. 
OBJECTIVES 
1.1 
Primary 
The primary objectives of this study are to: 
 
Evaluate the safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory acute myeloid leukemia (R/R AML), MRD AML and MDS 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
(eg, recommended phase 2 dose [RP2D]) of AMG 330 in adult subjects with R/R 
AML, MRD AML, and MDS 
1.2 
Secondary 
The secondary objectives of this study are to: 
 
Evaluate the pharmacokinetics (PK) of AMG 330 
 
Determine the formation of anti-AMG 330 antibodies 
 
Evaluate the anti-leukemia activity of AMG 330 by evaluating 
 
the number and proportion of subjects with R/R AML who respond to treatment 
with AMG 330.  Response is defined as any of the following: complete remission 
(CR), CR with incomplete recovery (CRi), or morphologic leukemia-free state (all 
according to Revised International Working Group [IWG] response criteria), or 
CR with partial hematologic recovery (CRh) 
 
the number and proportion of subjects with MDS who respond to treatment with 
AMG 330.  Response is defined as any of the following: CR or marrow CR (all 
according to Revised IWG response criteria) 
 
the number and proportion of subjects with MRD-positive AML who respond to 
treatment with AMG 330.  MRD response is defined as conversion from 
MRD with 0.1 threshold to MRD- status 
 
the duration of response, time to progression, and time to response. 
1.3 
Exploratory 
The exploratory objectives of this study are to: 
 
Evaluate the protein, nucleic acid, and cellular biomarkers in blood and / or bone 
marrow, as applicable (eg, cytokines, lymphocyte subsets, minimal residual disease 
[MRD – Group 1 only], leukemic stem cells [LSCs]) 
 
Evaluate effects of genetic variations in and phenotype of cancer genes, including 
apoptotic markers, on adverse event profile and treatment response 
 
Evaluate mechanisms of resistance 
 
Evaluate potential measures of clinical benefit including number of blood products 
transfused and days of antibiotic treatment of infection 
 
Evaluate the relationship between AMG 330 exposure and response to treatment 
 
Evaluate effect of 
 on safety and tolerability of AMG 330 
in adult subjects with relapsed/refractory AML (Group 4) 


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 
Evaluate the effect of 
 in combination with smaller or larger 
dose steps on safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory AML (Group 5) 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
2.1.1 
Acute Myeloid Leukemia (AML) 
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, and an increase in the population of cancer survivors previously exposed to 
chemotherapy and therapeutic radiation.  In 2014, an estimated 18,860 new cases of 
AML were expected in the US with approximately 10,460 deaths from this disease 
(American Cancer Society, 2014). 
Outcomes for most patients with AML remain poor (Burnett et al, 2011a).  In particular, 
relapsed disease is associated with unsatisfactory outcomes in the majority of patients 
(Ravandi, 2013).  Although the majority of patients with AML initially achieve CR, over 
60 will eventually relapse after a variable period of remission.  Using the traditional 
cytotoxic chemotherapy regimens, the likelihood of achieving a second CR is low 
especially if the first CR was short in duration, particularly if less than one year 
(Estey et al, 1996).  This is particularly true for patients who have primary refractory 
disease and have never achieved a morphological response.  For example, patients with 
AML refractory to one course of high dose cytarabine (HiDAC) containing regimen have 
a median overall survival of only 3.8 months (Ravandi et al, 2010).  Patients whose initial 
CR duration is more than one 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 hematopoietic stem cell transplant (HSCT) performed 
in second CR (Estey, 2000).  Apart from duration of first CR, other predictors of outcome 
in first relapse include age, cytogenetics, and whether the patient received an allogeneic 
HSCT in 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. 
Cluster of differentiation 33 (CD33) provides a useful target antigen for the treatment of 
patients with AML, as it is expressed on the cell surface of more than 80 of leukemia 


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isolates from patients with AML with a very high average antigen density 
(Tanimoto et al, 1989; Scheinberg et al, 1989).  It is not expressed on tissues other than 
the hematopoietic system and whether it is expressed by the normal multipotent 
hematopoietic stem cells has been a point of debate (Taussig et al, 2005; 
Pearce et al, 2006).  Caron et al (1994) and others have shown that the prototype 
unconjugated monoclonal antibody against CD33, HuM195, upon binding the antigen, 
rapidly internalizes into target cells.  Calicheamicin, a potent anti-tumor antibiotic, was 
conjugated to the CD33 antibody and the resultant gemtuzumab ozogamicin (GO) was 
effective in producing responses in about 30 of older patients ( 60 years) with AML in 
first relapse (Sievers et al, 1999).  This led to the accelerated approval of the drug as a 
single agent for the same population.  However, failure to demonstrate a clinical benefit 
in the confirmatory trial, together with concern about an increased risk of veno-occlusive 
disease led to its voluntary withdrawal from the market by the manufacturers 
(Ravandi, 2011).  However, its efficacy, when combined in low doses with 
chemotherapy, has been demonstrated in a number of randomized European trials, 
demonstrating that CD33 is a significant target for therapeutic drug development in AML 
(Castaigne et al, 2012; Ravandi et al, 2012, Burnett et al, 2011b). 
Measurable/minimal residual disease (MRD) is defined as the persistence of detectable 
leukemic blasts below the threshold for complete remission (CR).  MRD is a proven risk 
factor for relapse and poor survival in patients with acute lymphoblastic leukemia (ALL), 
and the concept of MRD is gaining wider acceptance in the AML community 
(Richard-Carpentier et al, 2019; Buccisano et al, 2018).  The National Comprehensive 
Cancer Network (NCCN) Guidelines recommend testing for MRD after induction therapy 
(NCCN AML Guideline, 2019), and the European LeukemiaNet endorses the 
achievement of MRD-negative (MRD-) complete remission, noting the strong correlation 
between MRD negativity and increased survival (Schuurhuis et al, 2018).  While the 
CD19/CD3 BiTE antibody construct blinatumomab (Blincyto) is highly effective at 
converting MRD-positive (MRD) status and prolonging survival in patients with ALL 
(Jen et al, 2019), no approved treatment options exist for AML patients with MRD. 
Research has highlighted the prognostic value of MRD status after completion of 
chemotherapy.  A large study of 427 patients  60 years of age found that 
MRD patients had significantly lower 3-year survival from CR compared with 
MRD- patients (26 versus 42, respectively, after course 1; 18 versus 38, 
respectively, after course 2; p  0.001 for each) and a higher cumulative incidence of 


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relapse (83 versus 71 , respectively, after course 1; 91 versus 79, respectively, 
after course 2; p  0.001 for each) (Freeman et al, 2013).  In addition, a retrospective 
French study of 59 AML patients with inv(16)/t(16;16) who had achieved first CR found 
that 13 of patients who were MRD at the end of consolidation therapy had a 2-year 
continuous CR, compared with 85 of MRD- patients (Guièze et al, 2010). 
Allogeneic HSCT outcomes vary based on MRD status such that AML patients who are 
MRD at the time of allogenic HSCT have a higher incidence of relapse and decreased 
overall survival (OS) compared with those who are MRD-.  In a recent study of 
82 patients with AML who underwent allogenic HSCT, the average OS after allogenic 
HSCT was 22.52  5.72 months for MRD patients and 42.86  2.83 months for 
MRD- patients (p  0.008).  Moreover, the relapse rate was 80 in MRD patients and 
6.5 in MRD- patients, respectively (Hao et al, 2018).  In another study, researchers 
retrospectively reviewed 359 consecutive patients who underwent allogenic HSCT and 
found that the 3-year OS rate was 26 among patients who were MRD prior to HSCT 
versus 73 among those who were MRD-.  Similarly, 3-year relapse rates were 67 
and 22 in MRD and MRD- patients, respectively (Araki et al, 2016).  These data 
provide evidence that the success of allogenic HSCT is lower among MRD patients, 
which suggests that the development of therapies targeting MRD AML may improve 
post-transplant outcomes for these patients. 
Based on the above, subjects who received at least one line (1L) of therapy considered 
as standard of care (SOC) or not eligible to some SOC treatments may enroll in this 
study.  1L may include induction, consolidation, maintenance, and conditioning followed 
by allogenic hematopoietic stem cells transplant (HSCT).  If patients are not eligible to 
HSCT or consolidation, they must receive minimum 2 cycles of induction therapy 
considered as SOC and achieve MRD CR (eg, venetoclax combined with decitabine or 
azacitidine in elderly patients). 
2.1.2 
Myelodysplastic Syndrome 
Myelodysplastic syndrome represents the most common class of acquired bone marrow 
failure syndromes in adults and are defined by a diverse group of clonal disorders of 
hematopoietic progenitor cells.  MDS is characterized by cytopenias, abnormal cell 
morphology, and progression to AML, with up to 30 of MDS cases progressing to AML 
(Greenberg et al, 1997).  Approximately 40 000 new cases of MDS occur annually, with 


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an estimated prevalence of 60 000 to 120 000 cases in the US (Bejar and 
Steensma, 2014). 
Prognosis of patients with MDS is limited and can be predicted using various scoring 
systems, including the revised International Prognostic Scoring System (IPSS-R), World 
Health Organization (WHO) prognostic scoring system (WPSS), and MD Anderson 
Cancer Center (MDACC) lower-risk MDS prognostic scoring system (MDA-LR) 
(Greenberg et al, 2012; Garcia-Manero et al, 2008; Vardiman et al, 2002).   
The selection of therapy for MDS is based on several factors, such as prognostic risk 
category, age, and performance status.  Treatment goals range from managing 
cytopenias and improving quality of life in patients with lower-risk MDS, to prolonging 
survival in those with higher-risk MDS (Cheson et al, 2006).  Current treatment options 
for patients with MDS range from growth factor support or lenalidomide in low-risk 
patients, to intensive chemotherapy with the HMAs azacitidine or decitabine plus 
allogeneic HSCT in patients with high-risk disease. 
Hypomethylating agents are considered standard of care treatment for MDS, although 
only half of MDS patients respond to this treatment (Gil-Perez and 
Montalban-Bravo, 2019).  In higher-risk MDS, HMAs delay progression to AML and 
improve OS (Adès et al, 2014; Fenaux et al, 2009).  However, HMA treatment is not 
curative, and all patients will eventually have treatment failure, with loss of response 
occurring within 2 years (Gil-Perez and Montalban-Bravo, 2019).  Upon loss of 
response, patients have a very poor prognosis, with a median OS of 14 months in 
low-risk patients and 4 to 6 months in high-risk patients (Ball et al, 2018; 
Duong et al, 2013; Prébet et al, 2011; Jabbour et al, 2010). 
Patients with loss of response to HMAs have limited therapeutic options, as there are no 
approved interventions for patients with HMA-refractory MDS (Montalban-Bravo and 
Garcia-Manero, 2018).  A limited number of studies have evaluated the outcome of 
chemotherapy after HMA failure, and results suggest these patients have a poor 
prognosis, with a median OS ranging from 5 to 16 months (Jabbour et al, 2014; 
Jalgal et al, 2014; Yee et al, 2014; Prébet et al, 2011).  An international, retrospective 
study of 307 MDS patients who received induction therapy after HMA treatment failure 
had overall response rates of 41 and a median OS of 10.8 months, with no difference 
in median OS or 8-week mortality rates between the 3 different induction therapy groups 
(7  3, intermediate- to high-dose cytarabine, or purine nucleoside analog-based 
regimens) (Ball et al, 2018).  Therefore, novel therapeutic options are needed for 


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patients with MDS who have progressive or refractory disease following treatment with 
HMAs. 
Although allogenic HSCT is potentially curative, it is typically only available to younger, 
fit patients due to the high risk of HSCT associated morbidity and mortality.  As such, the 
Center for International Bone Marrow Transplant Registry (CIBMTR) reported 
approximately 1150 transplants for MDS and myeloproliferative neoplasms in the US in 
2017 (D’Souza and Fretham, 2018).  When considered in the context of the entire 
patient population of high-risk MDS patients in the US, statistics suggest a low use of 
transplantation in this population, with a cross-sectional survey and prospective 
feasibility study reporting 4 to 5 of MDS patients receiving transplants (Sekeres et 
al, 2008; Estey et al, 2007).  Data from the Center for International Blood and Marrow 
Transplant Research indicate that MDS patients who underwent allogeneic HCST from 
human leukocyte antigen-matched related donors had transplant-related mortality and 
relapse rates of 30 (each) and a 3-year survival rate of 40 (Saber et al, 2013).  A 
recent retrospective analysis of MDS patients found that only 40 of the 126 patients 
who had responded to HMA treatment were able to bridge to allogenic HSCT.  MDS 
patients who received allogenic HSCT had improved OS compared with nontransplanted 
patients (23 months versus 10 months, respectively; p  0.01) (Ball et al, 2018).  
Because allogenic HSCT is potentially curative and considered standard of care, 
patients with MDS who are eligible for allogenic HSCT will be excluded from the study. 
Based on the above, subjects with higher risk MDS (ie, intermediate, hight and very 
high) not responding to standard treatment with HMA and not eligible to allogenic HSCT 
may participate in this study.  Per NCCN guidelines, the minimum number of courses 
prior to considering the treatment a failure should be 4 courses for decitabine or 
6 courses for azacitidine. 
2.1.3 
Cytokine Release Syndrome (CRS) Prophylaxis 
CRS has been identified as a frequent toxicity in patients with R/R AML in response to 
AMG 330 administration.  Symptoms are mediated by cytokines including IL-6 and 
TNF- (Grupp et al, 2013). 
2.1.3.1 
Blocking Biological Effects of 
 
Preliminary results from phase 1a of Study 20120252 demonstrate that 
 
 
 


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  Results from the safety expansion cohort showed that subjects 
who received prophylactic 
 
had a lower incidence of severe CRS compared with the full cohort (3 and 13, 
respectively).  In addition, subgroup analysis indicated that activity of axicabtagene 
ciloleucel was not affected by use of 
 Blocking interactions 
 
 as a premedication may prevent CRS or decrease the 
frequency and severity of symptoms. 
2.1.3.2 
Blocking Biological Effects of
  Furthermore, clinical data from the published literature 


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 blocking 
with 
 premedication may prevent CRS or decrease the frequency and severity of 
symptoms without compromising the efficacy of AMG 330. 
2.2 
Amgen Investigational Product Background 
BiTEs (bispecific T cell engagers) have been designed to direct T effector memory cells 
towards target cells.  The proximity induced by the BITE triggers target cell specific 
cytotoxicity which closely resembles standard cytotoxic T lymphocyte activation.  The 
bispecific T cell engager, blinatumomab, which specifically targets cells which express 
the lymphoid surface antigen CD19, has demonstrated clinical activity in acute 
lymphoblastic leukemia.  Clinical responses have been seen in both adults and children 
(Amgen clinical studies 103-206, 103-205 and 103-211) confirming the activity of BiTEs 
in B cell malignancies. 
AMG 330, targeting the surface antigen CD33, is a novel BiTE which is being 
developed with the intent to treat patients with AML.  Other CD33 expressing myeloid 
diseases, myelodysplastic syndrome and chronic myeloid leukemia, may be evaluated 
later in clinical development. 
2.2.1 
Nonclinical Pharmacology 
In vitro Pharmacology: 
AMG 330 is a highly potent molecule selectively mediating redirected lysis of 
CD33 cells, while viability of target-negative cells remains unaltered.  The cytotoxic 
effect of AMG 330 is time- and dose-dependent, with mean concentrations inducing 
half-maximal target cell lysis ranging from 24 to 200 pg/mL (0.4 to 3.7 pM) with human 
effector cells. 
In the presence of target cells, AMG 330 induced a polyclonal activation of T cells, which 
resulted in an up-regulation of the T cell activation markers CD25 and CD69, induction of 
granzyme B and perforin synthesis, T cell proliferation and release of cytokines like 
interferon-, tumor necrosis factor (TNF), interleukin (IL)-2, IL-10, and IL-6. 
In primary AML samples AMG 330 induced an expansion of residual autologous memory 
T cells and an efficient elimination of AML blasts even at low effector cell: target cell 
ratios. 
 
.  A recombinantly produced 


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extracellular domain of CD33 at concentrations of up to 100 ng/mL barely affected 
AMG 330-mediated redirected lysis of target cells and concomitant upregulation of 
CD25. 
Previous studies demonstrated that activated human natural killer and T cells express 
CD33, therefore CD33 expression by human T cells following BiTE-induced activation 
was evaluated.  Neoexpression of CD33 on T cells activated by the unrelated BiTE 
blinatumomab was negligible as it was limited to 6 of T cells in only three out of 
ten human donors tested.  Although the CD33 T cells are potential targets for AMG 330 
the removal of this small cell population will most likely not affect the anti-tumor activity 
of AMG 330 in cancer patients. 
In vivo Pharmacology 
Anti-tumor activity of AMG 330 was evaluated in acute myeloid leukemia xenograft 
models. 
Intravenous treatment of Non-obese diabetic/severe combined immunodeficiency 
disease (NOD/SCID) mice bearing subcutaneous EOL-1 tumors with 
AMG 330 (1, 10, and 100 g/kg/day) resulted in a statistically significant and 
dose -dependent tumor growth delay. 
In an orthotopic AML model NOD/SCID mice were intravenously injected with 
MOLM-13 tumor cells.  Administration of AMG 330 (2, 20, and 200 g/kg/day) resulted in 
a significant prolonged survival even at a dose of 2 g/kg/day AMG 330.  In animals 
which survived until study termination on day 111, no CD33-positive target cells were 
detectable in blood, spleen, and bone marrow.   
2.2.2 
Nonclinical Pharmacokinetics 
After single intravenous (IV) administration, AMG 330 clearance (CL) was higher in 
mouse (53.5 mL/hour/kg) than in monkey (32 mL/hour/kg).  The mean terminal half-life 
(T1/2,z) of AMG 330 after a single intravenous bolus in mouse and 7 or 28 days of 
subcutaneous dosing in monkey was similar between these two species (4 to 8 hours); 
after 28 days of continuous intravenous (cIV) dosing t1/2,z of AMG 330 was 1.6 to 
2.7 hours.  The bioavailability of AMG 330 after subcutaneous dosing was 22 and 
40 in mouse and monkey, respectively.  Dose proportionality was observed for 
exposure in both species after a single IV bolus injection in mouse and 7 days of cIV 
dosing in monkey; loss of exposure was observed after 28 days of cIV dosing due to the 
formation of anti-drug antibodies. 


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2.2.3 
Nonclinical Toxicology 
The potential toxicity of AMG 330 was evaluated in a Good Laboratory Practice 
(GLP)-compliant 28-day cynomolgus monkey toxicology study.  AMG 330 was 
administered daily by cIV at 0, 3, 10, or 30 g/kg or subcutaneously (SC) at 25 g/kg.  
Two 30 g/kg-cIV females were euthanized on Days 10 and 11 due to infections along 
the catheter port tract and/or at the skin contact points of the infusion jacket.  The 
infections along the catheter port tract precluded further dosing by cIV route so the 
animals were euthanized.  The infections were considered secondary to 
AMG 330-related decreases in mature myeloid cells in the bone marrow and in 
circulating leukocytes.  Other AMG 330-related findings were consistent with its 
expected pharmacology and included decreased leukocytes, which correlated with 
decreased T-lymphocytes, along with expected increased activated T-lymphocytes, and 
increased cytokine levels in all dose groups.  There was a transient decrease in body 
temperature at 25 g/kg SC, which was also considered to be a pharmacological effect 
of AMG 330.  Some animals at 30 g/kg cIV and 25 g/kg SC had clinical signs 
associated with inflammation/infection at the dose administration site that resolved after 
topical antimicrobial application and were able to complete the intended 28-day dose 
administration.  In animals that survived to scheduled termination, there were no 
AMG 330-related macroscopic, organ weight or light microscopic changes.  The 
changes observed in this study were consistent with the expected pharmacology of 
AMG 330.  The highest non-severely toxic dose (HNSTD) was considered to be 
10 g/kg/day cIV and 25 g/kg/day SC. 
2.2.4 
Dosing Experience With Other BiTE Antibody Constructs 
BiTE antibodies exert a unique but also uniform mechanism of action independent from 
their respective target.  Consequently, experiences with other BiTE antibody constructs 
are regarded as being relevant for AMG 330. 
Most clinical experience exists with a BiTE molecule called blinatumomab (specificity 
for CD3 and CD19) which has shown that administration of BiTE by cIV infusion can be 
performed with an acceptable safety profile and can lead to clinical responses in 
subjects with late-stage hematological malignancies (Nagorsen et al, 2012).  
Blinatumomab was granted breakthrough status by FDA and subsequently is approved 
in the US under the tradename BLINCYTO for the treatment of Philadelphia 
chromosome-negative relapsed or refractory B cell precursor acute lymphoblastic 
leukemia (ALL).  The most common adverse reactions ( 20) were pyrexia, headache, 


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peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, and 
constipation.  According to the US prescribing information, additional adverse reactions 
included cytokine release syndrome, neurological toxicities, infections, tumor lysis 
syndrome, neutropenia and febrile neutropenia, effects on ability to drive and use 
machines, elevated liver enzymes, leukoencephalopathy, and preparation/administration 
errors. 
In preceding short-term infusion studies blinatumomab was tested at doses ranging from 
0.75 to 13 μg/m², and was in all cases administered once, twice, or 3 times weekly as a 
2- or 4-hour IV infusion.  The most common adverse events were pyrexia, rigor, and 
fatigue.  The most frequent laboratory abnormalities were mild-to-moderate changes in 
hematologic or coagulation parameters.  All 3 short-term infusion studies were 
terminated early based on assessments of the overall benefit/risk profile.  Neurologic 
adverse events, cytokine release syndrome, and infections were observed in subjects in 
the absence of objective clinical responses or robust signs of biological activity such as a 
sustained reduction of peripheral CD19 B-cell (Nagorsen et al, 2012). 
Consequently, in following studies in subjects with Non-Hodgkin’s lymphoma (NHL) or 
ALL, blinatumomab was administered as a cIV infusion over a period of 4 or 8 weeks to 
achieve a constant exposure to blinatumomab in serum at highly predictable drug levels 
over the entire infusion period, confirmed by PK analyses which also showed dose 
linearity.  First complete responses to blinatumomab monotherapy, as assessed by 
Cheson criteria, were observed at a dose level of 15 μg/m² per day (Bargou et al, 2008).  
This dose level led to a sustained serum level of 0.6 to 1 ng/mL.  Response rates of 
83 in NHL (10/12 subjects) and 71 (5/7 subjects) were reported for follicular 
lymphoma and mantle cell lymphoma, respectively, although no objective responses 
have been seen in subjects treated below a dose of 15 μg/m² per day.  The minimum 
required dose of 15 g/m² per day exceeds approximately 10-fold the observed 
EC50 concentration of blinatumomab of 100 pg/mL (Dreier et al, 2002).  In addition, cIV 
administration of blinatumomab led to encouraging efficacy in relapsed/refractory ALL 
with 43 and 69 CR/CRh rate in two studies respectively (Topp et al., 2014 and 2015).  
In summary, the overall risk/benefit assessment comparing short term intermittent IV 
dosing of blinatumomab with cIV administration clearly favors the cIV administration 
because of proven and clinically relevant anti-tumor activity. 


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Three other BiTE antibody constructs have entered clinical trials.  Adverse events 
common to these three constructs and blinatumomab include fever and fatigue.  
However, the spectrum of neurologic and psychiatric adverse events observed in 
patients treated with blinatumomab (eg, confusion, disorientation) has not been reported 
with these constructs.   
2.3 
Risk Assessment 
As of 16 February 2019, 43 patients have received AMG 330 in the first in human study.  
Based on the mode of action targeting CD33 which is expressed on myeloid cells, 
myelosuppression and particularly neutropenia is expected.  In addition, infections may 
be observed based on the myelosuppressive effect.  Neutropenia and infections are 
conditions that are not unexpected in the setting of AML given the nature of this bone 
marrow disease.  Cytokine release syndrome and respective signs and symptoms were 
observed in a number of subjects treated in the study so far. This is in line with  clinical 
observations with blinatumomab, another BiTE molecule developed for hematological 
malignancies .  For listings of potential and identified risks see Table 1 and Table 2 
below. See also Section 6.6 for specific recommendations for cytokine release 
syndrome, tumor lysis syndrome, and infection prophylaxis.  
Table 1.  Potential Risks of AMG 330 
Potential 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. 
Page 1 of 2 


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Table 1.  Potential Risks of AMG 330 
Potential Risk 
Description 
Medication Errors 
Causes of overdoses may include technical failures (ie, due to misleading 
local labeling software or an error in the pharmacy prescription software, 
and potential malfunction of the pump). Other potential causes of 
overdose may be related to human error (ie, drug administration errors by 
study center personnel, pump manipulation by the subject, and allocation 
of the subject to the wrong dosing cohort). 
Neurotoxicity 
A wide range of commonly observed neurological symptoms have been 
associated with the use of blinatumomab (anti-CD19 BiTE antibody 
construct) in patients with relapsed/refractory ALL and included tremor, 
dizziness, encephalopathy, paresthesia, aphasia, and confusional 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. 
Immunogenicity 
There is the potential for the development of anti-drug antibodies 
following AMG 330 administration. 
Page 2 of 2 
Table 2.  Identified Risks of AMG 330 
Identified Risk 
Description 
Cytokine Release 
Syndrome (CRS)/ 
Infusion reactions  
Signs and symptoms of CRS 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 
Infusion reactions may be clinically indistinguishable from 
manifestations of CRS 
Rash 
Rash has been observed in subjects administered AMG 330 and may 
present as maculo-papular rash, erythematous rash, generalized rash 
along with signs and symptoms such as pruritis, urticaria and erythema 
Aminotransaminase 
elevation 
Elevated aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) levels have been observed in subjects 
administered AMG 330 
See also Section 2.2.3 for nonclinical safety observations. 
2.4 
Rationale 
Clinical experience with blinatumomab, a CD19-targeting BiTE, indicated that sustained 
exposure through cIV infusion for a period of 14 to 56 days provided clinical efficacy and 
therapeutic benefit (Bargou et al, 2008) whereas short term intermittent IV dosing for 
1 week failed to elicit either a pharmacodynamic (PD) response or clinical activity 


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(Nagorsen et al, 2012).  These data show that a certain time of BiTE presence in the 
patient’s body and a stable steady state serum concentration over the dosing period 
seems to be a prerequisite for the induction of objective responses.   


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2.5 
Clinical Hypotheses 
AMG 330 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML and MDS. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a first-in-human, open-label, phase 1 sequential dose escalation study.  
AMG 330 will be evaluated as a cIV infusion in adult subjects with relapsed/refractory 
AML(Group 1), MRD AML (Group 2), and MDS (Group 3).  The study will be conducted 
at approximately 17 sites in Germany, the Netherlands, Japan, Canada, and the United 
States (US).  For all Groups 1-3, enrollment will occur in parallel, and each Group will 
progress from the dose escalation to the dose expansion independently. In addition, 
Groups 4 and 5 will be conducted in US to 
 
 on safety of AMG 330 in subjects with R/R AML.  Group 4 will enroll in 
parallel with Groups 1-3, and Group 5 will enroll after the results of cycle 1 in both arms 
of Group 4 become available. 
3.1.1 
Design of Group 1: R/R AML 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and PD of 
AMG 330.  Planned target dose levels for the dose-escalation cohorts are as follows: 


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0.5, 
, and 960 g/day.  Higher target 
doses, up to 1.6 mg of AMG 330, can be evaluated if 960 g/day is deemed safe.  A 
dose of 1.6 mg of AMG 330 is identified as maximal dose level due to sucrose-
associated toxicity. 
Intermediate dose level(s) may be evaluated as necessary.  In the event that one subject 
experiences a DLT, then the dose administered for successive cohorts will escalate by 
no more than 50 (ie, a dose increment of no more than 1.5 times the previous dose) 
after discussion at the Dose Level Review Meeting (DLRM). 
Should the initial dose level be limited by adverse events related to first dose effects 
(eg, cytokine release syndrome), dose steps will be implemented. It is anticipated that 
more than one MTD per indication will be estimated, one for each dose step and one for 
the target dose.  Each MTD will be estimated following 33 decision rules (see 
Section 6.2.1.4 for definition). Intermediate dose steps can be introduced based on 
DLRM recommendation before a new MTD is reached to allow safer target dose 
escalation.  
The MTD for the subsequent dose-steps and the target dose will be estimated after 
giving the initial dose at MTD (dose step).  Starting with an initial lower dose may 
improve tolerability of subsequently administered higher doses due to initial reduction of 
the bulk of blasts cells, thereby potentially improving efficacy.  For reasons of clarity, the 
term “MTD” (singular) will cover the MTD for the initial dose, the MTD for subsequent 
dose-steps as well as the MTD for the target dose, as applicable, throughout the 
protocol. 
At completion of the dose escalation cohorts, additional subjects will be enrolled in a 
dose expansion cohort to gain further clinical experience, safety and efficacy data in 
subjects with AMG 330.  If there is at least 1 responding subject (defined as any of the 
following: CR, CRi, morphologic leukemia-free state per modified IWG criteria, or CRh) 
in the first 10 subjects enrolled in the expansion cohort, additional (up to 20) subjects will 
be enrolled after evaluating safety, tolerability and anti-leukemia activity of AMG 330 
using all available cumulative data. 
Dose Escalation 
For all MTDs (initial, subsequent and target doses), dose escalation will estimate the 
MTD.  The estimated MTD is defined as the maximum dose at which fewer than 


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one-third of subjects experience a dose limiting toxicity (DLT) (minimum of 6 evaluable 
subjects for the target dose MTD; see Section 3.4 for definition of evaluable). 
Dose Escalation will be conducted in two stages.  In the single subject cohorts, single 
subjects will be enrolled at dose levels anticipated to be lower than those at which 
adverse events will be observed.  Once higher dose levels are open for enrollment or 
when drug related safety or efficacy signals are observed (see below), the 33 design 
will be triggered. 
Subjects who complete the DLT period (see Section 6.2.1.4) may proceed to a higher 
dose level for the following treatment cycle if no DLT has been reported for either this 
subject or any other subject in this dose cohort after completion of the DLT period, and 
once the next higher dose cohort is open for enrollment, after consultation with the 
sponsor (see Section 7.2.2 for details on assessments applicable in case of intra-subject 
dose escalation). DLTs experienced by subjects who proceeded to a higher dose as 
described above will not be considered for 33 decisions.  However, the Dose Level 
Review Team (DLRT) may take this information into account to inform dose escalation 
recommendations. 
Should the initial dose be limited by adverse events related to first dose effects 
(eg, cytokine release syndrome), dose steps will be implemented.  The MTD for the 
target dose will be estimated after giving the initial dose (and subsequent step doses if 
applicable) at their respective MTD(s).  This means that the cohort for which a dose step 
will be implemented will start treatment for the first days at the first MTD assessed in the 
prior cohort.  After this run in phase, there may be a dose increase to the next higher 
dose as per the dosing schedule shown in Table 4 of the protocol.  If a 960 g/day target 
dose is not the MTD, further dose escalation to a higher target dose up to 1.6 mg is 
allowed to reach MTD according to the rules described above.  If this treatment schedule 
is tolerated, following dose cohorts will continue to receive the run in (initial) dose at the 
initial/1st MTD to assess the 2nd MTD.  The target  dose will be increased until a second 
MTD is reached.  This 2nd MTD is the highest subsequent dose (day of dose step until 
end of cycle) with 33 of subjects experiencing a DLT. Each MTD will be estimated 
following 33 decision rules (Table 5).  If additional dose steps are implemented, an 
MTD for each step will be determined using the same algorithm.  To optimize the dose 
step schedule, additional intermediate steps below established MTD levels can be 
introduced based on DLRM recommendation.   


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The 1st run-in dose and each subsequent dose step should be administered for 1 to 
5 days.  The treatment interval for all dose steps will be recommended by the DLRT 
based on the available safety, tolerability, PK, and PD data.  
Starting with cohort 6, if there is an infusion free period of 24 hours between cycles, 
one or more dose steps in each cycle are mandatory for all subjects. Administration of a 
prophylactic steroid dose (8  mg IV dexamethasone) within 1 hour prior to the dose step 
for prevention of cytokine release is mandatory (see also Section 6.5).  The additional 
assessments described in the schedule of assessments for dose steps (Table 14) apply.  
The DLRT may also recommend to implement additional dose steps in a cycle if this was 
considered appropriate and necessary to allow further dose escalation.  The additional 
dose step(s) would be performed the same way as described above.  In this case, an 
additional MTD would be estimated for the dose to be administered after the last dose 
step. 
 


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Single Subject Cohorts 
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.  AMG 330 will initially be 
administered at escalating doses in a 2 weeks on / 1-4 weeks off schedule.  This 
schedule may be modified by DLRT recommendation (see Section 6.2.1.1 for details). 
The 33 design will be triggered if at least 1 subject experiences any of the following 
drug related safety or efficacy signals (whichever is earlier): 
 
Common Terminology Criteria for Adverse Events (CTCAE) grade  2 adverse 
event other than thrombocytopenia, anemia, or neutropenia 
 
DLT 
 
Objective response. 


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Multiple Subject Cohorts (33 Dose Level Decision Rules) 
Based on nonclinical models, the dose for cohort 4 is predicted to be potentially 
efficacious.  It is anticipated that up to 8 additional cohorts will be enrolled using a 
standard 33 design.  Each cohort will enroll up to 6 evaluable subjects.  There will be at 
least a 6-day (144-hour) interval between the start of treatment of the first and second 
subject in each cohort.  On day 6 of this interval, the site investigator will evaluate all 
available safety and laboratory data for the treated subject and will send written 
confirmation on occurrence / non-occurrence of a DLT to the sponsor.  The sponsor will 
only be able to open enrollment for the next subjects in the cohort after receipt of this 
confirmation.  If deemed necessary, the 6-day interval may be extended until sufficient 
data are available to allow an assessment of the feasibility of treatment start of the next 
subject.  The same guidance applies in case of intra-subject dose escalation, if 
applicable.  
Following this, no more than 3 subjects should be enrolled into a cohort in two weeks. 
Dose escalation decisions will be made in accordance with a standard 33 design using 
the rules noted in Table 5. 
 
If no DLT is observed within the DLT window (see Section 6.2.1.4) in the initial 
3 subjects of a cohort, then dose escalation to the next higher dose level cohort will 
occur. 
 
If 1 DLT is observed within the DLT window in the initial 3 subjects of a cohort, then 
the cohort will be expanded to 6 subjects when 2 non-DLT subjects have reached 
the target dose. If no further DLT(s) are observed in the 6 subjects, then dose 
escalation to the next higher dose level cohort will occur.  If  2 subjects experience 
a DLT in a cohort, then enrollment into this cohort will be stopped. 
 
See Section 3.4 for replacement of subjects  
Dose escalation will occur at the planned dose levels until the MTD is determined or until 
the highest dose level is tested.  The MTD is defined as the highest dose level with an 
observed incidence of DLT in  33 of subjects enrolled in a cohort dose level.  At least 
6 subjects will be treated at the MTD or highest tested dose.   


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Table 5.  33 Dose Level Decision Rules 
 Subjectsa 
Subjects with 
DLT 
Decision 
3 
1 
Enroll 3 additional subjects at same dose level 
3 
0 
Escalateb 
3 
 2 
De-escalatec 
6 
1 
Escalateb 
6 
 2 
De-escalatec 
a Subjects who are not DLT-evaluable (see Section 3.4) are excluded from the count of subjects 
b If final dose level has been reached, accrual will be suspended. 
c If 6 subjects already entered at next lower dose level, the estimated MTD has been established. 
3.1.2 
Design of Group 2: MRD AML 
The dose-escalation cohorts will estimate the safety, tolerability, PK, and PD of 
AMG 330 in subjects with MRD AML.  The following dose escalation cohorts will be 
evaluated: 
  Selected 
target dose levels, with the exception of the maximal tested dose, that have been 
deemed safe in subjects with R/R AML (Group 1) could be skipped in Group 2 
dose escalation cohorts based on available safety, PK, and PD data if 
recommended by the DLRT.  Administration of 8 mg IV dexamethasone within 1 hour 
prior to the dose step for prevention of cytokine release is mandatory.  Up to 36 subjects 
with MRD AML will be enrolled in the phase 1a dose escalation cohorts; each dose 
escalation cohort will include a minimum of 3 and a maximum of 9 evaluable subjects. 


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3.1.3 
Design of Group 3: MDS 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and PD of 
AMG 330 in subjects with MDS. The following dose escalation cohorts will be evaluated: 
  Selected 
target dose levels, with the exception of the maximal tested dose, that have been 
deemed safe in subjects with R/R AML (Group 1) could be skipped in Group 3 
dose escalation cohorts based on available safety, PK, and PD data if 
recommended by the DLRT.  Administration of 8 mg IV dexamethasone within 1 hour 
prior to the dose step for prevention of cytokine release is mandatory.  Up to 36 subjects 
with MDS will be enrolled in the phase 1a dose escalation cohorts; each dose escalation 
cohort will enroll a minimum of 3 and a maximum of 9 evaluable subjects. 
3.1.4 
Dose Escalation Rules for Groups 2 and 3 
For both Group 2 and Group 3, a minimum of 3-4 subjects will be enrolled initially into 
each cohort and additional subjects up to a maximum of 9 evaluable subjects will be 
added at the Sponsor’s discretion.  After all subjects in each dose escalation cohort have 
either completed the DLT evaluation period or had a DLT, the DLRT will meet to 
determine whether it is appropriate to escalate or de-escalate the dose, or whether to 
stop the study for safety concerns.  The DLRT will evaluate all available safety, 
laboratory, PK, and PD data to guide their dose-finding recommendations.  Based on 
DLRT recommendation, selected target dose levels, with the exception of the 
maximal tested dose, may be skipped in Groups 2 and 3 dose escalation cohorts if 
these dose levels have been evaluated in subjects with R/R AML (Group 1) and 
deemed safe.  Appendix H shows the mTPI-2 escalation/de-escalation guideline with a 


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target toxicity probability of 0.25 and an acceptable toxicity probability interval of 0.20 to 
0.30.  A dose level will be considered unsafe, with no additional subjects enrolled at that 
dose level, if it has an estimated  95 probability of exceeding the target DLT rate pT 
(ie, P [DLT  𝑝𝑇 | data]  95) with at least 3 subjects treated and evaluated at that dose 
level.  Dose exploration will continue until the current recommended dose cohort 
reaches at least 6 evaluable subjects or until the highest protocol-defined dose has been 
evaluated. 
The MTD will be defined as the dose for which the estimate of the toxicity rate from an 
isotonic regression (Ji et al, 2010) is closest to the target toxicity rate.  The DLRT will 
recommend the RP2D using the totality of the clinical and laboratory data from the dose 
exploration stage. 
3.1.5 
Expansion Cohorts for Groups 1, 2 and 3 
At completion of the dose escalation cohorts, additional subjects will be enrolled in a 
dose expansion cohort to gain further clinical experience, safety and efficacy data in 
subjects with AMG 330.  The dose to be evaluated will be at or below the highest tested 
dose or the MTD estimated in the dose escalation cohorts.  If there are at least 1 subject 
having response in the first 10 subjects enrolled in the expansion cohort, additional (up 
to 20) subjects may be enrolled after evaluating safety, tolerability, and anti-leukemia 
activity of AMG 330 using all available cumulative data. 
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.  For 
definition of DLT-evaluable, see Section 3.4. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.1.6 
Design of Alternative Cytokine Release Syndrome (CRS) 
Prophylaxis Groups  
An alternative  approach for the prophylaxis of CRS will be evaluated in two groups of 
subjects with R/R AML. 
In Group 4, 
 will be evaluated for CRS prophylaxis as 
alternatives to currently used 8 mg dexamethasone premedication administered 1 hour 
before AMG 330 start or step dose. Group 5 will receive an optimized dose step 


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approach with either 
, depending on which premedication 
yields optimal results in Group 4. 
3.1.6.1 
Group 4 Design 
Group 4 will consist of two arms of R/R AML subjects.  In treatment cycle 1, Arm 1 will 
receive prophylaxis with 
 and Arm 2 will receive prophylaxis with 
.  
Subjects in each arm will receive a single agent for pretreatment, and dexamethasone 
will not be used for CRS prophylaxis.  If CRS occurs during treatment with AMG 330, the 
management guidelines in Table 7 should be followed. 
3.1.6.1.1 
Group 4 Design – Cycle 1 (
) 
Arm 1  (
):  AMG 330 will be administered on day  at 
 g/day for  days, 
 g/day for  days and 
 g/day for  days for a total cycle of 
 days with a 
-day DLT period.  
 
. 
Arm 2  (
):  AMG 330 will be administered on day  at 
 g/day for  days, 
 g/day for  days and 
 g/day for  days for a total cycle of 
 days.  
 
. 
Each premedication group will enroll a total of 6 evaluable subjects.  Within each Arm, 
3 subjects will initially be enrolled and administered 
 
 premedication as described above followed by treatment with AMG 330 
(
 g/day).  For these initial 3 subjects in each group, if no more than 1 DLT 
is observed within the DLT window, then the cohort will be expanded to enroll 6 subjects 
for that group.  If 2 subjects have a DLT in either Arm, then, upon resolution of the AE, 
these subjects will be able to proceed with 
  dexamethasone or 
  dexamethasone as a double-agent prophylaxis.  Enrollment of the 
remaining subjects for the Arm will be permitted, and these additional subjects will be 
treated with the double-agent CRS prophylaxis regimen (ie, 
  dexamethasone in Arm 1, and 
  dexamethasone in Arm 2). 
If no more than 1 DLT is observed in the 6 evaluable subjects in either Arm, the 
premedication used in that Arm will be considered safe and tolerable.  If 
 
 is determined to be safe and tolerable, Group 5 will be initiated upon DLRT 
recommendation, in which either 
 (as a single agent or a 
double-agent if combined with dexamethasone) will be further evaluated.  If both 


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 show similar CRS prophylaxis efficiency, both agents may be 
tested in Group 5 upon DLRM recommendation. 
Subjects who receive 
 to administration of AMG 330 will 
be monitored for CRS using the guidance described in Table 7. If a subject treated with 
AMG 330 at the 10-g step dose level develops grade 2 or higher CRS the subject will 
be able to continue the study using both 
 and dexamethasone or 
 
and dexamethasone as premedication prior to the next step dose for CRS prophylaxis.  
This will be done in order to assess whether a double-agent regimen is more effective 
than single-agent for CRS prophylaxis.  If AMG 330 has to be interrupted at the 
-g dose due to CRS and administration is restarted, the subject can receive both 
 and dexamethasone or 
 and dexamethasone as premedication.   
If a subject treated with AMG 330 at the 
-g step dose or 
-g target dose level 
develops grade 3 or higher CRS, AMG 330 will be stopped until the severity of CRS 
decreases to grade 1, at which point the subject will be able to restart the cycle using 
either both 
 and dexamethasone or 
 and dexamethasone as 
premedication for CRS prophylaxis.  If dexamethasone needs to be added to treat any 
grade CRS, the subject will continue using the double-agent prophylaxis of CRS.  A 
maximum of 2 restarts will be allowed. 
3.1.6.1.2 
Group 4 Design – Cycles 2-6 
Subjects who complete 14-day cycle 1 treatment (DLT period) in Group 4 will be allowed 
to proceed with cycle 2.  Dexamethasone will be used in cycle 2 and further for CRS 
prophylaxis.  Subjects may proceed to a 
 g/day dose level and higher if the 
infusion-free interval between 
 g/day (last dose level in cycle 1) and 
 g/day 
(first dose level in cycle 2) is 24 hours.  If the duration of the infusion-free interval is 
24 hours, subjects will start with dose step levels and schedule previously deemed safe 
in Group 1 (eg, 
 g/day).  The schedule to be followed will be a 
joint decision between the investigator and Sponsor based on a safety profile of dose 
escalation in Group 1 (ie, only target dose levels tested in Group 1 and deemed safe by 
DLRM can be used in Group 4, cycle 2-6).  Rules described for the infusion-free interval 
in Section 6.2.1.1 for R/R AML subjects apply after completion of cycle 2.  Subjects in 
Group 4 can continue in the study for a maximum of 6 cycles. 


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3.1.6.2 
Group 5 Design 
Using the rules described above, if the DLRT determines that CRS incidence/severity 
with 
 premedication (with or without dexamethasone) is similar 
to or lower than that observed with dexamethasone premedication alone, then subjects 
with R/R AML will be enrolled into Group 5.  Depending on which premedication regimen 
yields optimal safety results in Group 4 and based on DLRM recommendation, either 
 with or without dexamethasone will 
be selected for CRS prophylaxis.  If a safety assessment in Group 4 shows similar 
results, both 
 may be tested in Group 5 in two separate 
cohorts.  Subjects enrolled in Group 5 can continue in the study for a maximum of 
6 cycles where cycles 2-6 are identical to cycle 1. 
3.1.6.2.1 
Mini Step Dosing Schedule (Arm 1) 
If the best outcome from Group 4 indicates that CRS incidence/severity with 
 
 with or without dexamethasone is similar to that observed with 
dexamethasone premedication alone (ie,  1 DLT and some reported grade 2 CRS 
events in the 
 ams), then a mini-step approach will be tested to 
improve CRS onset dynamics.  With this approach, subjects will be treated with 
 premedication followed by AMG 330 administered with daily 
mini-step doses at 
 g, followed by the target 
dose of 
 g for 
 days with 28-day DLT period.  
 
 
If 
 are used with dexamethasone, 8 mg dexamethasone will be 
administered to patients every other day (Q2D) if AMG 330 dose steps are given daily, 
and before each AMG 330 dose step if the duration of the dose step is extended 1 day 
following discussion and agreement between the investigator and sponsor. 
3.1.6.2.2 
Maxi-Step Dosing Schedule (Arm 2) 
If the best outcome from Group 4 indicates that CRS incidence/severity with 
 
 with or without dexamethasone is lower than that with dexamethasone 
premedication alone (ie, no DLTs and no reported grade 2 CRS events in the 
 
 arms), then a maxi-step approach will be tested to reach the efficacious 
dose faster.  With this approach, subjects will be treated with 
 
premedication, with or without dexamethasone, followed by administration of AMG 330 
at 
 g for  days followed by the target dose of 
 g for 
 days with 28-day DLT 


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period.  
 
 
3.2 
Number of Sites 
Groups 1, 2, and 3 of this study will be conducted at approximately 17 sites in Germany, 
the Netherlands, Japan, Canada, and the US.  Additional countries or sites may be 
added if necessary.  Groups 4 and 5 of this study will be conducted in US only.  
Sites that do not enroll subjects into an open cohort within 6 months of site initiation or 
during last 12 months of the study 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 256 subjects will be enrolled in this study.  For the 
dose escalation cohorts, approximately 70 subjects will be enrolled in Group 1 (R/R 
AML), 36 subjects will be enrolled in Group 2 (MRD AML) and 36 subjects will be 
enrolled in Group 3 (MDS).  Upto 30 additional subjects will be enrolled in a dose 
expansion cohort for each group (up to 90 additional subjects).  In addition, 
approximately 12 additional subjects will be enrolled in Group 4 to assess alternative 
CRS prophylaxis; 6 subjects for each premedication treatment arm, 6-12 subjects will be 
enrolled in Group 5 to assess alternative premedication in combination with mini or maxi 
dose steps (6 if the DLRM recommendation is to proceed with only one premedication 
Arm, and 12 if the recommendation is to proceed with 2 premedication Arms).  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 (ie, subjects who were exposed to investigational product [IP] but post 
hoc were found to be ineligible) may be replaced.  During dose escalation, subjects that 
are not DLT-evaluable will be replaced.  A subject is not DLT-evaluable if he/she drops 
out of cycle 1 before completion of the DLT window for reasons other than an adverse 
event related to study drug or the subject has not received IP treatment for at least 
14 days at the target dose for a 3- or 4-week cycle or at least 7 days at a target 
dose for a 2-week cycle.  Following drug interruptions, if a subject is unable to 


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complete 2 repeat cycles for reasons other than DLT, the subject will not be DLT 
evaluable and can be replaced.  All available safety data for subjects who are not DLT 
evaluable will still be evaluated and considered in DLRM decisions.  No dose escalation 
will occur unless at least 3 subjects have been assessed as DLT evaluable.   
3.5 
Estimated Study Duration 
The duration of this study will be approximately 7 years in total. This includes 
approximately 5 years for enrollment into dose escalation cohorts for Group 1, 1 year for 
the dose escalation cohorts for Groups 2 and 3, 6 months for each of the dose 
expansion cohorts (enrolled in parallel) and up to 6 months of treatment for the last 
subject enrolled in each Group. 
3.5.1 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 6 months 
including a screening period lasting 14 days, a treatment period lasting approximately 
4 months, and a safety follow-up period lasting approximately 4 weeks.  The actual 
duration for individual subjects will vary depending upon tolerability of AMG 330, 
evidence of clinical progression, and willingness to participate in the study. 
After completion of a first cycle without a DLT, up to 5 additional treatment cycles can be 
administered as long as in the judgment of the investigator the subject is deriving 
benefit. 
End of study (EOS) for an individual subject is defined as the date of the final study visit 
(EOS visit) when assessments and procedures are performed.  The EOS visit should 
occur approximately 4 weeks ( 1 week) after the last dose of AMG 330 or prior to the 
initiation of other AML therapy, whichever occurs earlier.  Subjects who complete the 
EOS visit will be considered to have completed the study. 
3.5.2 
End of Study 
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis; the 
primary analysis will occur when target enrollment is complete and each subject either 
completes 6 months on study or terminated the study early. 
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study; the final analysis will occur at this time. 


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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 the start of any study-specific activities/procedures, the appropriate written 
informed consent must be obtained (see Section 11.1). 
4.1 
Inclusion Criteria 
4.1.1 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
4.1.2 
Subjects  18 years of age 
4.1.3 
Relapsed/refractory AML: AML as defined by the WHO Classification 
(Appendix D) persisting or recurring following one or more treatment courses 
except promyelocytic leukemia (APML) For Germany, additional 
requirements are outlined in a country-specific protocol supplement. 
4.1.4 
Relapsed/refractory AML: Blasts in bone marrow  5 
4.1.5 
Eastern Cooperative Oncology Group (ECOG, Appendix F) Performance 
Status of  2 
4.1.6 
Renal function as follows: serum creatinine  2.0 mg/dL and estimated 
glomerular filtration rate  30 mL/min/1.73 m2 
4.1.7 
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) 
4.1.8 
Minimal Residual Disease positive (MRD) AML: AML as defined by the 
WHO Classification(Appendix D).  Exception: promyelocytic leukemia 
(APML); subjects in CR/CRi with  5 blasts in bone marrow and MRD with 
0.1 threshold following  1L; subjects are not eligible for allogenic HSCT 
per current investigator assessment, or currently lacking a donor, or declining 
the offered procedure; if subjects are not eligible for standard consolidation 
therapy, they must receive at least 2 cycles of standard induction therapy.  
4.1.9 
Myelodysplastic Syndrome (MDS) as defined by the WHO Classification 
(Appendix I); subjects with intermediate, high and very high risk MDS per 
IPSS-R (Appendix J), refractory to standard treatment with Hypomethylating 
Agents (HMA), and not eligible for allogenic HSCT per current investigator 
assessment, or currently lacking a donor, or declining the offered procedure 


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4.2 
Exclusion Criteria 
4.2.1 
Active extramedullary AML in testes or central nervous system (CNS) 
4.2.2 
Known hypersensitivity to immunoglobulins or to any other component of the 
IP formulation (eg, sucrose, captisol, potassium, polysorbate 80, citrate, 
lysine) 
4.2.3 
Prior malignancy (other than in situ cancer) unless treated with curative intent 
and without evidence of disease for  1 years before screening 
4.2.4 
Autologous HSCT within six weeks prior to start of AMG 330 treatment 
4.2.5 
Allogeneic HSCT within three months prior to start of AMG 330 treatment 
4.2.6 
History or evidence of cardiovascular risk including any of the following: 
 
History or evidence of clinically significant arrhythmias (ventricular 
fibrillation, ventricular tachycardia, supraventricular tachycardia, atrial 
tachycardia/flutter, atrial fibrillation with rapid ventricular response, 
second or third degree atrioventricular block, and sick sinus syndrome) 
 
Exception: Subjects with controlled atrial fibrillation for  30 days prior to 
study day 1 are eligible.  Controlled atrial fibrillation is defined as atrial 
fibrillation with no rapid ventricular response which requires no change in 
medication/dosage or addition of new medication or hospital admission 
within 30 days prior to study day 1. 
 
History of acute coronary syndromes (eg, myocardial infarction and 
unstable angina) and/or coronary angioplasty within 6 months prior to 
study day 1 
 
History or evidence of  Class II congestive heart failure as defined by 
New York Heart Association (NYHA) 
 
Chronic hypertension (defined as a systolic blood pressure [SBP] 
140 mm Hg and/or diastolic blood pressure [DBP]  90 mm Hg which 
cannot be controlled by anti-hypertensive therapy) 
 
Subjects with intra-cardiac defibrillators 
 
Abnormal cardiac valve morphology ( grade 2) (subjects with 
grade 1 abnormalities [ie, mild regurgitation/stenosis] can be entered on 
study.  Subjects with moderate valvular thickening should not be entered 
on study) 
4.2.7 
History of arterial thrombosis (eg, stroke or transient ischemic attack) in the 
past 3 months 
4.2.8 
Infection requiring intravenous antibiotics within 1 week of study enrollment 
(day 1) 
4.2.9 
Known positive test for Human immunodeficiency virus (HIV) 
4.2.10 
Positive for Hepatitis B 


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4.2.11 
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. 
4.2.12 
Unresolved toxicities from prior antitumor therapy, defined as not having 
resolved to 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 
4.2.13 
Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted 
therapy, retinoid therapy, or investigational agent) within 14 days or 
5 half-lives (whichever is shorter) of day 1.  Exception:  hydroxyurea to 
control peripheral blood leukemic cell counts is allowed for R/R AML subjects 
until start of IP treatment 
4.2.14 
Treatment with systemic immune modulators including, but not limited to, 
nontopical systemic corticosteroids, cyclosporine, and tacrolimus within 
2 weeks before enrollment (day 1) 
Exceptions: physiologic replacement steroids or hydrocortisone for treatment 
of transfusion reactions. 
4.2.15 
All herbal medicines (eg, St. John's wort), vitamins, and supplements 
consumed by the subject within the 30 days prior to receiving the first dose of 
AMG 330, and continuing use if applicable, will be reviewed by the 
investigator and the Amgen medical monitor.  Written documentation of this 
review and Amgen acknowledgment is required for subject participation. 
4.2.16 
Prior treatment with a chimeric antigen receptor T cell (CAR-T) infusion for 
the treatment of AML (CD33 target) 
4.2.17 
Major surgery within 28 days of study day 1 with the exception of biopsy and 
long line insertion 
4.2.18 
White blood cells (WBC)  15,000 cells/mcL at screening 
4.2.19 
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the investigator or Amgen physician, if 
consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures or completion 
4.2.20 
Men and women of reproductive potential who are unwilling to practice a 
highly effective method(s) of birth control while on study through 1 week 
(women) or 12 weeks (men), respectively, after receiving the last dose of 
study drug.  Acceptable methods of highly effective birth control include 


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sexual abstinence (men, women); vasectomy; bilateral tubal 
ligation/occlusion; or a condom with spermicide (men) in combination with 
hormonal birth control or intrauterine device (IUD) (women) 
4.2.21 
Women who are lactating/breastfeeding or who plan to breastfeed while on 
study through 1 week after receiving the last dose of study drug 
4.2.22 
Women with a positive pregnancy test 
4.2.23 
Women planning to become pregnant while on study through 1 week after 
receiving the last dose of study drug 
4.2.24 
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 and investigator’s knowledge 
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, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form (ICF) before 
commencement of study-specific activities/procedures.  Adverse events and 
disease-related events are to be collected for an eligible subject once they are enrolled 
in the study.  After meeting all eligibility criteria, a subject is considered enrolled on day 1 
(cycle 1 day 1) when the cIV infusion with investigational product is started. 
The investigator is to document the enrollment decision and date in the subject’s medical 
record and in/on the enrollment electronic case report form (eCRF). 
Each subject who enters into 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, 252).  The next 5 digits will 
represent the country code and site number (eg, 26001) 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 26001 will receive the number 25226001001, and the second subject at the same 
site will receive the number 25226001002. 


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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. 
All screening tests and procedures should be performed within 14 days before 
enrollment, unless otherwise indicated.  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 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 and should be 
recorded in the screening eCRF. 
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.  Hepatitis serology does not need to 
be repeated in case of re-screening if it was performed within 6 weeks prior to start of 
treatment with AMG 330. 
Subjects who are deemed ineligible will be documented as screen failures. 
Subjects may be eligible to enroll 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.  The Amgen 
representative will acknowledge receipt and send confirmation of cohort and dose level 
assignment for the subject.   
5.1 
Treatment Assignment 
For all Groups, an Amgen representative will notify the site(s) in writing when a cohort is 
open to screen new subjects.   
Group 1 (R/R AML): In the initial dose escalation cohorts in Group 1, only a single 
subject will be enrolled to a cohort because the dose level is not anticipated to be 
clinically active.  If at least 1 subject experiences a drug related safety or efficacy signal 
(CTCAE grade  2 adverse event other than thrombocytopenia, anemia, or neutropenia; 
DLT; and/or objective response) the 33 design will be triggered.  Starting with dose 
level 4 (which is expected to be clinically efficacious based on nonclinical models), 
enrollment will be performed according to the 33 design (see Section 3.1 for details).  
Each cohort will enroll up to 6 evaluable subjects. 


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Group 2 (MRD AML) and Group 3 (MDS): For Groups 2 and 3, in each dose 
escalation cohort, a minimum of 3-4 subjects will be enrolled initially and additional 
subjects up to maximum 9 evaluable subjects will be added at Sponsor’s discretion per 
mTPI-2; (Guo at al, 2017). 
Group 4 (R/R AML), Arms 1 and 2: After 6 subjects have been enrolled in Group 4, 
Arm 1 (
 premedication), enrollment into Arm 2  (
 premedication) 
can be initiated. If necessary for logistical reasons, enrollment to Arm 2 may be initiated 
first.  
Group 5 (R/R AML): 
After the DLRM determines that 
 premedication is safe based 
on Group 4 results, then Group 5 will be initiated in subjects with R/R AML. 
At completion of the dose escalation cohorts, additional subjects will be enrolled in a 
dose expansion cohort to gain further clinical experience, safety and efficacy data in 
subjects with AMG 330.  The dose to be evaluated will be at or below the MTD 
estimated in the dose escalation cohorts. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment eCRF. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
Study treatment is defined as any investigational product (IP), non-investigational 
product, placebo, or medical device intended to be administered to a study subject 
according to the study protocol. 
The Amgen IPs used in this study include AMG 330 and 
 
. 
In Groups 4 and 5, 
 will be used (US only) prophylactically to 
mitigate incidence and severity of CRS. The use of 
 will be 
investigational for these groups only (ie, investigational use of marketed products).  
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product other protocol-required therapies and/or device 
during the study are provided in the Investigational Product Instruction Manual (IPIM). 
The medical devices used in this study include: infusion pump, IV bag, and infusion line 
including a 0.2 μm in-line filter. 


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6.2 
Investigational Product 
All investigational products will be dispensed at the research facility by a qualified staff 
member. 
A physician or nurse trained in emergency medicine 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 330 and 
 
AMG 330 and the 
 will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures. 
6.2.1.1 
Dosage, Administration, and Schedule – AMG 330 and 
 
AMG 330 will be delivered using infusion pumps approved for use by the appropriate 
regulatory authority for the country in which the subject is undergoing treatment. 
AMG 330 infusion for solution will be prepared in bags for IV infusion.  The drug will be 
administered as a cIV infusion at a constant flow rate over 2 to 4 weeks followed by an 
infusion-free interval prior to the following treatment cycle. 
The length of an infusion-free interval between cycles should be made after consultation 
with the sponsor.  The duration of the infusion-free interval will be determined by 
treatment response (including an assessment of percentage of remaining blasts in BM if 
CR is achieved) and safety assessments including recovery of blood counts (see below 


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for details).  It may also be extended for up to three days from the planned duration if 
necessary for logistical reasons. 
Depending on the treatment response, the following scenarios are possible following 
each treatment cycle: 
No infusion-free interval (
): subjects with stable 
or improved peripheral blood counts compared to baseline, who either achieved a 
response at the end of infusion (CR, CRh, CRi, or morphologic leukemia-free state) with 
detectable blasts in BM or experienced a decrease in blast numbers at the end of 
infusion may start their next cycle immediately. 
1 to 2 week infusion-free interval (
 
): subjects who did not respond at the end 
of infusion with decreased peripheral blood cell counts compared to baseline will have a 
hematological assessment one week later.  If blood cell counts have recovered to 
baseline levels, the next treatment cycle can start immediately.  If blood cell counts have 
not improved, the infusion free period can be extended to 2 weeks before the next cycle 
is initiated.  
1 to 4 week infusion-free interval (
 
): subjects who achieved a 
response (CR, CRh, CRi, or morphologic leukemia-free state) with no detectable blasts 
in BM at the end of infusion may have an infusion-free interval of up to 4 weeks.  Weekly 
hematology assessments should be performed to confirm recovery of peripheral blood 
counts.  Once peripheral blood counts have returned to baseline levels, the next 
treatment cycle can be initiated. 
In subjects who achieved a response with no detectable blasts in BM at end of infusion, 
the infusion-free interval may be extended up to a maximum of 6 weeks in case of 
insufficient recovery of peripheral blood counts (neutrophils  500/l, platelets 
 20,000/l without transfusion) and after consultation with the sponsor.  In case the 
infusion-free interval is extended to 4-6 weeks, a bone marrow assessment is 
recommended 4 weeks after the end of the infusion cycle.  In case this assessment 
shows detectable leukemic infiltration of the bone marrow, treatment should be resumed 
immediately even if peripheral blood counts have not yet recovered at this time point. 
For a 2 week cycle, starting with cycle 2, a D15 or D22 bone marrow assessment is not 
mandatory.  Bone marrow will be assessed at D29 to decide if the next cycle should be 


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started immediately or 1-4 weeks later, as per the decision rules described above.  For a 
2 week cycle, if there are clinical signs of disease progression, bone marrow can also be 
assessed at D15 or D22 in order to determine if the subject should immediately receive 
the next treatment cycle or if criteria for permanent discontinuation of study treatment 
are met. 
For longer treatment cycles, refer to schedule of assessments (Table 10 - Table 13) for 
bone marrow assessments. 
The DLRT may recommend to extend the infusion duration instead of escalating the 
dose for a future cohort.
 
The 14-day (or 21-day or 28-day, as applicable) administration schedule has been well 
tolerated and the safety profile allows for longer infusion duration. 
After extension of the infusion duration to 3 or 4 weeks, the DLRT may also recommend 
on further dose escalation for future cohorts. 
Subjects will stay hospitalized for a minimum of 72 hours (R/R AML Group 1 and MDS 
Group 3) or 48 hours (MRD AML Group 2) under the following circumstances: 
 
at start of infusion in cycles 1 and 2 
 
after each dose step in cycle 1 
 
after dose increase in case of intra-subject dose escalation   
At the start of infusion in the first cycle, a hospitalization of 9 to 12 days is recommended 
for R/R AML subjects in Group 1 based on the AMG 330 administration schedule.  
In addition, subjects will be hospitalized for a minimum of 48 hours after treatment 
interruption requiring restart of treatment in the hospital.  Starting from cycle 3 
and higher, hospitalization is at the discretion of an investigator for all groups.  
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 infusion reactions.  If required for logistical reasons (eg, long travel 


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times), subjects may be hospitalized the day before start of dosing (day -1) of any cycle 
and at the end of infusion (EOI) for cycle 1 for required PK samples. 
The planned target dose levels for the dose escalation cohorts are: 0.5, 
 
, and 960 g/day.  If MTD is not reached at 
960 g/day dose level, higher target doses up to 1.6 mg can be tested.  The MTD or 
highest tested dose will be administered in the dose-expansion cohort. 
The start time of infusion should be chosen carefully so as to avoid any interference or 
inconvenience with time points of safety assessments, PK/PD measurements and 
changes of infusion bags.  The site should record any unscheduled interruption of an 
infusion on the eCRF, and provide the start and stop date/time of the infusion and the 
bag change. 
AMG 330 should be administered through a central venous access at a constant flow 
rate.  The drug should not be administered as a bolus and flushing residual drug at the 
time of bag change is prohibited.  In the event that administration through a central 
venous access is not possible, AMG 330 may be administered temporarily through a 
peripheral venous line if the subject is hospitalized.  The final solution for infusion should 
be administered through a sterile 0.2 μm in-line filter. 
Infusion bags should be changed in accordance with local pharmacy standards for 
infusion of compounded sterile products but at least every 4 days.  In the US, infusion 
bags should be changed at least every other day and in no case should be administered 
for more than 48 hours at ambient temperature. 
After completion of a first cycle, up to 5 additional treatment cycles can be administered 
as long as in the judgment of the investigator the subject is deriving benefit. 
The 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 daily AMG 330 dose may be 
up to 10 lower or higher in order to account for possible pump inaccuracies.  A dose of 
up to 10 higher than the intended dose may not require specific intervention. 
In case of overdose or medication error, the infusion should be immediately stopped.  
Consultation with the Amgen medical monitor is strongly recommended for prompt 
reporting of clinically apparent or laboratory adverse events possibly related to 


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overdosage.  Consultation with the Amgen medical monitor is also strongly 
recommended even if there are no adverse events, in order to discuss the minimal 
duration of dose interruption.  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. Resumption of AMG 330 is possible after consultation with the Amgen 
medical monitor and should adhere to the guidelines in Section 6.2.1.5. 
A dose of 10 higher than the intended AMG 330 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 9.2.2.2. 
6.2.1.3 
AMG 330 Outpatient Dosing 
If deemed stable by the investigator, a subject may continue AMG 330 cIV infusion as an 
outpatient. Subjects will receive a patient card indicating that the subject is participating 
in a clinical study.  The patient card will also provide site contact details to be used in 
case of questions on the study or an emergency.  In the outpatient setting, the subject 
will either return to the study site for infusion bag changes or the subject will be visited 
by a well-trained home health care service provider at specific intervals to change the 
infusion bag, measure vital signs, monitor and document adverse events and/or serious 
adverse events, and document any issues with the cIV infusion or infusion pump.  The 
subject and home health care service provider will be trained and will receive written 
instructions for storage of the IV bags, if applicable.  The home health care service 
provider will complete the study delegation log and will be authorized by the investigator 
before any study-related tasks are started. 
Refer to the home health care manual for detailed information on the storage, handling, 
and administration of AMG 330, mandatory procedures, and data collection 
requirements. 
Following each visit or telephone contact by the home health care service provider, the 
information collected will be documented on the Home Health Care Services visit 
worksheet and forwarded to the investigator.  Any unexpected or unusual events as well 
as any deviations will be communicated promptly to the investigator.  If any adverse 
event occurs in the outpatient setting, the home health care service provider should 
directly contact the site for further management.  The home health care service 
professionals provide 24 hour emergency on-call service for any pump related issues.  In 
the event of an interruption of the AMG 330 cIV infusion of  4 hours, restart of the 


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infusion should be performed in the clinic/hospital under the supervision of the 
investigator or designee and the subject should be hospitalized for a minimum of 
48 hours (see Section 6.2.1.5). 
6.2.1.4 
Dose-cohort Study Escalation and Stopping Rules, Dose-limiting 
Toxicities (DLTs) 
For R/R AML (Group 1), dose escalation decisions will be made in accordance with a 
standard 33 design using the rules noted below. 
 
If no DLT is observed within the DLT window in the initial 3 subjects of a cohort, then 
dose escalation to the next higher dose level cohort will occur. 
 
If 1 DLT is observed within the DLT window in the initial 3 subjects of a cohort, then 
the cohort will be expanded to 6 subjects. If no further DLT(s) are observed in the 
6 subjects, then dose escalation to the next higher dose level cohort will occur.  
If  2 subjects experience a DLT in a cohort, then enrollment into this cohort will be 
stopped. 
 
see Section 3.4 for replacement of subjects. 
Dose escalation will occur at the planned dose levels until the MTD is determined or until 
the highest dose level is tested.  The MTD is defined as the highest dose level with an 
observed incidence of DLT in  33 of subjects enrolled in a cohort dose level.  At least 
6 evaluable subjects will be treated at the MTD or highest tested dose.   
For MRD AML (Group 2) and MDS (Group 3), dose exploration will be guided by 
prespecified monitoring rules (Appendix H), which is based on a modified toxicity 
probability interval algorithm (mTPI-2; Guo et al, 2017) with a target DLT rate of 25 and 
an acceptable toxicity probability interval of 20-30. Consistent with conventional 
oncology phase 1 study designs (eg, 3  3 design) and given the imprecision with 
making decisions using as few as 3 subjects, in the instance of 1 DLT in the initial 3 
subjects at a dose level then, as appropriate, the design allows expansion at the dose 
level beyond 3 subjects. 
The mTPI-2 algorithm employs a simple beta-binomial Bayesian model. Let 𝑝𝑇 be the 
target toxicity level and (𝑝𝑇 − ϵ1, 𝑝𝑇  ϵ2) be the equivalence toxicity interval denoted as EI. 
The unit toxicity interval (0, 1) is divided into subintervals with equal length given by 
(ϵ1  ϵ2). Let the under-dosing intervals (LI) denote for a set of intervals below EI, and the 
overdosing intervals (HI) for a set of intervals above EI. The 3 types of dosing intervals 
(EI, LI, HI) are associated with 3 different dose escalation decisions. The LI correspond 
to a dose escalation (E), the HI correspond to a dose de-escalation (D), and proper 


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dosing intervals (EI) correspond to staying at the current dose (S). This study design 
uses a target toxicity level, 𝑝𝑇 of 25, and EI of (20, 30). 
Decision rules are based on the unit probability mass (UPM) calculated on these 
equal-length intervals. Given an interval and a probability distribution, the UPM of that 
interval is defined as the probability of the interval divided by the length of the interval. If 
the interval with the largest UPM is from LI, EI or HI, then the corresponding dose 
decision would be E, S, or D, respectively. 
A dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95 or more probability of exceeding the target DLT rate 
𝑝𝑇 (ie, P [DLT  𝑝𝑇 | data]  95) with at least 3 evaluable subjects treated and 
evaluated at that dose level. 
After the escalation phase is completed, final DLT rates at each dose level will be 
estimated by isotonic regression (Ji et al, 2010).  The MTD will be determined as the 
dose level with the DLT estimate closest to the target toxicity level of 25.  In the case 
of dose levels with estimated toxicity of equal distance (tied dose levels) from the target 
toxicity of 25, the following approach will be used (Ji et al, 2010): among all tied dose 
levels the highest dose level with target toxicity  25 will be selected, unless all tied 
dose levels have estimated toxicity  25, in which case the lowest dose level will be 
selected. 
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 330.  The DLT 
window will be 4 weeks, regardless of the length of the treatment cycle.  The CTCAE will 
be used to assess toxicities/adverse events with the exception of cytokine release 
syndrome (see Table 7 for grading of cytokine release syndrome). 
DLT Evaluation 
A subject is not DLT-evaluable if he/she drops out before completion of the DLT window 
for reasons other than an adverse event related to study drug or the subject has not 
received IP treatment for at least 14 days at the target dose for a 3- or 4-week 
cycle or at least 7 days at a target dose for a 2-week cycle.  All available safety data 
for subjects who are not DLT evaluable will still be evaluated and considered in DLRM 
decisions.  No dose escalation will occur unless at least 3 subjects have been assessed 
as DLT evaluable.  Duration of a cycle might be extended and be different from the 
duration of the DLT window.  For all cohorts, the DLT window may also be extended 


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retrospectively to assess events starting or persisting outside the window in case the 
DLT definition is time dependent (eg, in case of neutropenia, see below). 
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. 
Events listed below are to be considered as DLTs and exceptions when occurring in a 
subject during the DLT window unless clearly attributable to causes other than AMG 330 
treatment: 
 
Any treatment-related death. 
 
Grade 4 neutropenia lasting  42 days from start of cycle in absence of evidence of 
active AML (in case of 3 or 4 weeks treatment cycles, the number of days would 
increase accordingly) 
 
Grade 3−5 non-hematologic toxicity not clearly resulting from the underlying 
leukemia EXCEPT: 
 
Alopecia 
 
Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
 
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, if successfully managed and which resolves within 
72 hours 
 
Grade 3 rash  
 
Grade 3 or 4 tumor lysis syndrome  if it is successfully managed clinically and 
resolves within 7 days without end-organ damage. 
 
Grade 3 or 4 isolated electrolyte abnormalities (ie, those occurring without clinical 
consequence) that resolve, with or without intervention, to  Grade 2 levels in 
 72 hours will not be considered DLT. 
 
Grade 3 or 4 asymptomatic enzyme elevations including AST, ALT (without bilirubin 
elevation), GGT (gamma-glutamyl transferase), lipase and amylase that resolve to 
 Grade 2, with or without intervention, within 7 days will not be considered a DLT. 
 
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 


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 
Grade 3 CRS reported at the initial dose (ie, at MTD1; applicable only after 
MTD1 has been defined) will be considered a DLT 
 
Grade 4 CRS occurring during AMG 330 treatment. 
 
Two separate grade 3 CRS events will be considered a DLT. 
6.2.1.5 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Criteria for Dose Delay or Dose Reduction 
Any clinically relevant (as determined by the investigator) grade 4 adverse event related 
to IP that does not meet the DLT criteria should lead to a dose delay and/or a dose 
reduction.  The decision if a dose delay or reduction will be performed is up to the 
investigator’s discretion.  The sponsor may be consulted. 
In case of grade 2 cytokine release syndrome, treatment can be continued on the 
currently tested dose level for 8 hours.  If symptoms do not improve to grade 1, the dose 
will be de-escalated by 50  for an additional 24 hours.  If CRS grade 2 resolves to 
grade 1, the dose can be re-escalated back to the level being tested.  If symptoms 
persist, AMG 330 will be interrupted until symptoms improve to grade 1.  If treatment is 
interrupted for  24 hours, the interrupted dose can be resumed and re-escalated back 
to the tested dose level.  If treatment is interrupted for  24 hours, restart or repeat rules 
apply (see below). 
In case of grade 3 cytokine release syndrome, treatment must be interrupted.  The 
Amgen medical monitor has to be consulted prior to a planned restart. 
In case of grade 4 cytokine release syndrome, treatment must be permanently 
discontinued. See Section 6.6 for specific instructions for the management of cytokine 
release syndrome. 
Dose delay:  treatment should be interrupted until the event is resolved to grade  1, and 
can then be resumed at the same dose unless the interruption lasted for more than 
24 hours, please see below.  (Note:  if the event needs  21 days to resolve, treatment 
has to be permanently discontinued, see also below).   
Dose reduction:  treatment may be resumed after the event is resolved to grade  1 or 
immediately at the investigator`s discretion at the previous (lower) dose level.  
Re-escalation to the target dose can be considered if the event has resolved to 
 grade 1 if applicable.   


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In case of re-appearance of the same grade 4 adverse event, IP should be permanently 
discontinued.   
For persistent or re-occurring clinically relevant grade 3 adverse event related to IP, a 
dose delay or a dose reduction should be considered. 
Infusion Interruption 
Significant events requiring a change in treatment will be managed by immediate 
infusion interruption:  
 
The subject experiences a DLT as defined in Section 6.2.1.4 
 
The subject experiences a clinically relevant grade 4 adverse event related to IP 
(see above)  
 
The subject experiences a grade  2 cytokine release syndrome that does not 
respond to medical management as described in Table 7 
 
The subject meets criteria for discontinuation of IP as described in Section 8.3 
 
Technical problem with the infusion pump 
 
The investigational product is incorrectly prepared or administered (eg, overdose) 
Restarting the Infusion 
Treatment may resume if the interruption is  21 days and if: 
 
The interruption occurred due to other reasons than toxicity (disease-related events, 
technical or logistic reasons; eg, diagnostic measurements).  The infusion can be 
restarted at the same dose and without additional measures. 
 
The toxicity has resolved to CTCAE grade  1 (in case of dose reduction, infusion 
may be restarted without prior resolution of the toxicity to CTCAE grade  1 at the 
investigator`s discretion) 
Please also refer to specific guidance on restart after cytokine release syndrome in 
Section 6.6.  Restarting the infusion after a treatment interruption requires care.  The 
start should be performed in the hospital, under supervision of the investigator, if the 
reason for the interruption was other than a technical issue or the interruption exceeded 
4 hours independent of reason.  Assessments should be performed after infusion restart 
depending on the length of the interruption and the visit day on which the interruption 
occurred as described in the table below.  The subject should be hospitalized for at least 
48 hours after restart of the infusion. 


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Table 6.  Assessments to be Performed After Infusion Interruption and Restart 
Length of 
Cycle 
Length of 
Infusion 
Interruption 
Dose level at 
which interruption 
occurred 
Assessments to be performed 
2 weeks 
 24 hours 
Run-in dose, dose 
step or target dose 
Continue following schedule of assessments 
per protocol 
 24 hours 
Run-in dose, dose 
step or target dose 
Repeat the cycle and schedule of 
assessments (Table 8 or Table 9) starting at 
day 1, perform dose step assessments as 
needed per Table 14 
3 or 4 weeks 
 24 hours 
Run-in dose, dose 
step or target dose 
Continue following schedule of assessments 
per protocol 
 24 hours 
 7 days 
Run-in dose or step 
dose  
Repeat the cycle and schedule of 
assessments (Table 9 – Table 23) starting at 
day 1, perform dose step assessments as 
needed per Table 14 
 24 hours but 
 7 days 
Target dose 
Consult with Sponsor regarding which visit 
days should be performed (Table 9 –
Table 23), perform dose step assessments as 
needed per Table 14ᵃ 
 7 days 
Run-in dose, dose 
step or target dose 
Repeat the cycle and schedule of 
assessments (Table 9 – Table 23) starting at 
day 1, perform dose step assessments as 
needed per Table 14 
ᵃ If treatment is interrupted towards the end of cycle 1 after the target dose is reached, and the decision is 
made to not restart the infusion prior to day 29, only perform EOI assessments on Cycle 1 Day 29 
In case of an infusion interruption of  24 hours, regardless of the reason for interruption, 
restart of the infusion should be performed at the initial MTD (run in dose) and dose 
steps should be performed prior to administering the target dose.  The dose level for 
each step and number of steps should be determined in consultation with the Sponsor 
prior to re-initiation of the infusion. 
After two unsuccessful restarts, the subject will be considered as not DLT evaluable (if 
no DLT has been observed during treatment) and can be replaced.  The subject may 
remain on the study and continue treatment with a previously tested target dose that has 
been well tolerated.  
Dexamethasone (8 mg IV) should be administered within 1 hour prior to restart and 
within 1 hour prior to the dose step(s).  The subject should be hospitalized starting from 
restart of infusion until 72 hours after the dose step.  After the dose step, assessments of 
vital signs, pulse oximetry and clinical evaluation should be performed as per the 
schedule of assessments for dose steps (Table 14). 
The number of days of infusion at the target dose before and after an interruption should 
sum up to the planned duration, ie, minimum 10 days at the target dose for a 14 day 


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cycle, and minimum 14 days at the target dose for a  21 or 28 day cycle.  In this case, 
the subject would still be DLT-evaluable.  However, if the cycle was interrupted for more 
than 7 days, a new cycle should be started and the interrupted cycle would not be 
evaluable for DLT, unless the event that lead to the interruption was a DLT. 
Please refer to the table below to determine the minimum duration of treatment for a 
subject to be counted as DLT evaluable. 
Note: In case a treatment cycle is considered complete but lasted less than the planned 
number of days (14, 21, or 28, as applicable), the EOI bone marrow assessment should 
be performed once it was confirmed that the cycle will not be resumed in order to assess 
treatment response and determine the infusion-free interval prior to start of the next 
cycle, if applicable.  Bone marrow and blood samples (for 
, immune cells, and 
plasma biomarker testing) should also be sent to the applicable central laboratories. 
Planned Treatment Duration 
Minimum Duration of Treatment at Target Dose to be 
Counted as DLT evaluable 
2 weeks 
7 days at target dose 
3 weeks 
14 days at target dose 
4 weeks 
14 days at target dose 
Permanent Discontinuation 
A subject will permanently discontinue treatment with investigational product in the event 
of:  
 
Dose-limiting or other unmanageable toxicity.  Exception: If a DLT occurs in a subject 
with a clear clinical benefit from treatment a restart at a lower dose and / or 
implementation of a dose step can be considered if the toxicity has resolved and 
after consultation with the sponsor 
 
Grade 4 CRS 
 
Grade 3 CRS occurring at the initial run-in dose for a cycle (ie, at the MTD1)  
 
Grade 2 or 3 CRS meeting any of the criteria listed below: 
 
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  
 
If a subject experiences 2 separate grade 3 CRS events  
 
Disease progression as defined by revised IWG response criteria (Appendix E for 
R/R AML, Section 7.6 for MRD AML and Appendix K for MDS). 
 
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 


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 
Hematological or extramedullary relapse subsequent to CR/CRh/CRi/morphologic 
leukemia-free state on protocol treatment for R/R AML.  Exception:  a blast count 
 5 at the pre-dose assessment (after the infusion-free interval) would not lead to 
permanent treatment discontinuation even if the count had been  5 directly after 
the previous treatment cycle.   
 
An infusion interruption of more than 21 days due to an adverse event not clearly 
related to the underlying disease.  
 
Occurrence of CNS-related adverse event considered related to AMG 330 by the 
investigator and meeting one or more of the following criteria: 
 
More than one seizure 
 
A CNS-related adverse event CTCAE Grade 4 
 
A CNS-related adverse event leading to treatment interruption that needed more 
than one week to resolve to CTCAE Grade  1 
 
Non-manageable Graft versus host disease 
 
Investigator’s decision that a change of therapy (including immediate HSCT) is in the 
subject’s best interest 
 
Administration of relevant non-permitted concomitant medications 
Women who become pregnant while on study through 1 week 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. 
Men with pregnant partners or whose partners become pregnant while the subject is on 
study will receive subsequent scheduled doses and must practice sexual abstinence or 
use a condom while on study through 12 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 EOS 
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. 
6.2.2 
Marketed Investigational Products – 
 
Two marketed products, 
, will be used prophylactically to 
mitigate incidence and severity of CRS related to AMG 330 administration.  The use of 


Product:  AMG 330 
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 for CRS prophylaxis will be investigational in Groups 4 and 5 
only and in US only (ie, investigational use of marketed products).  Guidance and 
information on preparation, handling, storage, accountability, destruction, or return of the 
investigational products, other protocol-required therapies and/or devices during the 
study are provided in the Investigational Product Instruction Manual (IPIM), a document 
external to this protocol, and are in accordance with the respective FDA-approved 
product inserts.  Safety information can be found on the 
 US 
prescription information document.  
 is not FDA-approved for the disease/condition being studied.  
 will be manufactured and packaged by Amgen Inc. and distributed 
using Amgen clinical study drug distribution procedures.  For information on 
, please refer to the AMG 330 IPIM. 
6.2.2.1 
 
Only for Groups 4 and 5 (Section 3.1), 
 will be used prophylactically as a 
single agent to mitigate incidence/severity of CRS (see Section 3.1.6.1 for guidance on 
the use of 
 as a double-agent in combination with dexamethasone). In 
Group 4, Arm 1, subjects will receive AMG 330 at a dose of 
 g/day for  days, 
 g/day for  days and 
 g/day for  days for a total cycle of 
 days.  
 
will be administered 
. 
If the best outcome from Group 4 indicates that CRS incidence/severity with 
 
is similar to that observed with dexamethasone premedication alone, then 
 
premedication in combination with an alternative dose step schedule approach will be 
tested to improve CRS onset dynamics in Group 5.  For the mini-step approach, 
AMG 330 will administered using daily dose steps to reach a target dose of 
 g/day.  
 will be administered on day 
 of the study.  For the maxi-step 
approach, a single dose step of AMG 330 at 
 g/day will be administered prior to the 
target dose of 
g/day, and 
 will be administered on day 
 of the 
study. 
 can be provided in different marketed presentations including but not limited 
to 
.  Additional details regarding this therapy are provided in 
the IPIM. 


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6.2.2.2 
 
Only for Groups 4 and 5 (Section 3.1), 
 will be used prophylactically as a 
single agent to mitigate incidence/severity of CRS (see Section 3.1.6.1 for guidance on 
the use of 
 as a double-agent in combination with dexamethasone).  For 
subjects in Group 4, Arm 1, 
 will be used prophylactically to mitigate 
incidence/severity of CRS.  In Group 4, Arm 2, subjects will receive AMG 330 at a dose 
of 
 g/day for  days, 
 g/day for  days and 
 g/day for  days for a total cycle 
of 
 days.  
 will be administered IV at a dose of 8mg/kg one hour prior to 
the initiation of AMG 330 dosing on cycle 1, day 1. 
If the best outcome from Group 4 indicates that CRS incidence/severity with 
 
is similar to that observed with dexamethasone premedication alone, then 
 
premedication in combination with an alternative dose step schedule approach will be 
tested to improve CRS onset dynamics In Group 5.  For the mini-step approach, 
AMG 330 will be administered using daily dose steps to reach a target dose of 
 g/day.  For the maxi-step approach, a single dose step of AMG 330 at 
 g/day 
will be administered prior to the target dose of 
g/day.  
 will be 
administered one hour prior to initiation of AMG 330 dosing during each cycle. Additional 
details regarding this therapy are provided in the IPIM. 
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.  Please also refer to Section 6.5. 
Dexamethasone: Premedication with dexamethasone is required prior to each 
AMG 330 treatment cycle and prior to each dose step for the prevention of CRS 
(Exception: see instructions for dexamethasone use in Groups 4 and 5).  
Dexamethasone should be administered as a single IV dose (8 mg) within 1 hour of start 
of infusion or dose step, respectively.  
In the case of restart of infusion after an infusion interruption of  24 hours,  
dexamethasone (8 mg IV) should be administered within 1 hour prior to restart and 
within 1 hour prior to the dose step.  
For administration of dexamethasone after occurrence of CRS, follow guidance in 
Section 6.6 below. 


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6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, ALT, total bilirubin 
[TBL], and/or international normalized ratio [INR]) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies as specified in the 
FDA, 2009. 
6.4.1 
Criteria for Permanent Withholding of Amgen Investigational 
Product 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: 
ALT or AST  3.0 ULN; TBL  2.0 ULN or INR  1.5, ALP  2.0 ULN; and no other 
confounding factors including preexisting or acute liver disease (FDA, 2009). 
 
Important alternative causes for elevated AST/ALT and/or TBL values include, but 
are not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
 
Right sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir)  
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic Fatty Liver Disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product due to Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 


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underlying liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational product:  
 
Elevation of either AST or ALT according to the following schedule: 
 
Baseline AST or ALT value: Any AST or ALT elevation:   8 x ULN at any time 
 
Baseline AST or ALT value: Any AST or ALT elevation:   5 x ULN but 
 8 x ULN for  2 weeks 
 
Baseline AST or ALT value: Any AST or ALT elevation:   5 x ULN but 
 8 x ULN and unable to adhere to enhanced monitoring schedule 
 
Baseline AST or ALT value: 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:  TBL  3 x ULN at any time 
 
OR:  ALP  8 x ULN at any time 
AMG 330 can be withheld pending investigation into alternative causes of DILI.  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 TBL is 
discovered and the laboratory abnormalities resolve to normal or baseline 
(Section 6.4.3). 
6.4.3 
Criteria for Rechallenge of Amgen Investigational Product After 
Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then the investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.4.1) should never 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.  Concomitant therapies are to be collected from informed consent, 
through the EOS.  For all concomitant therapies collect therapy name, indication, dose, 
unit, frequency, route, start date, and stop date.   
Oxygen administration as supportive measure is permitted during study treatment.   


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Hydroxyurea for 7 days at a dose of 
 g / day is recommended prior to the first 
cycle of IP treatment for subjects with high WBC ( 15,000 cells/mcL).  Administration of 
hydroxyurea after start of IP may be permitted after discussion with the Amgen medical 
monitor.  
COVID-19 vaccines are allowed per local standard of care for cancer patients.  
Vaccination procedure should be avoided during DLT period.  COVID-19 
vaccination should be documented as concomitant medication and 
vaccination-related adverse events should be recorded in the eCRF.  
Tocilizumab:  Tocilizumab may be used to treat CRS as clinically relevant and 
described in Table 7 below. 
6.6 
Specific Recommendations for Cytokine Release Syndrome, Tumor 
Lysis Syndrome and Infection Prophylaxis 
Cytokine Release Syndrome 
CRS is clinically defined and may have various manifestations.  There are no 
established diagnostic criteria.  Signs and symptoms of Cytokine release syndrome 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 
Subjects may be at an increased risk for cytokine release syndrome during the first few 
days following the initial infusion of AMG 330. Cytokine release syndrome may be 
life-threatening or fatal.  Infusion reactions may be clinically indistinguishable from 
manifestations of cytokine release syndrome. Throughout the infusion with AMG 330, 
monitor subjects for clinical signs (eg, fever, tachycardia, dyspnea, tremors) and 
laboratory changes (eg, transaminase increase) which may be related to cytokine 
release syndrome. 


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Grading and management of cytokine release syndrome should be performed according 
to the guidelines provided in Table 7 (based on the adopted grading system referenced 
in Lee et al [Blood 2014]). 
 


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Table 7.  Grading and Management of Cytokine Release Syndrome 
CRS Grade 
Description of Severitya 
Minimum Expected Interventionc 
Instructions for Interruption of AMG 330 
1 
Symptoms are not life threatening and 
require symptomatic treatment only, 
eg, fever, nausea, fatigue, headache, 
myalgias, malaise 
 
Administer symptomatic treatment (eg, 
paracetamol/ acetaminophen for fever, fluids for 
hypotension). 
 
Monitor for CRS symptoms including vital signs and 
pulse oximetry at least Q2 hours for 12 hours or 
until resolution, whichever is earlier. 
N/A 
2 
Symptoms require and respond to 
moderate intervention 
Oxygen requirement  40, OR  
Hypotension responsive to fluids or low 
dose of one vasopressor, OR 
Grade 2 organ toxicity or grade 3 
transaminitis per CTCAE criteria 
Administer:  
 Symptomatic treatment (eg, paracetamol/ 
acetaminophen for fever; vasopressors for 
hypotension) 
 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. 
 Consider use of tocilizumab 8 mg/kg iv. Up to 
3 additional doses can be given 8 hours apart, if 
needed.   
Monitor for CRS symptoms including vital signs and 
pulse oximetry at least Q2 hours for 12 hours or until 
resolution to CRS grade  1, whichever is earlier. 
For subjects with extensive co-morbidities or poor 
performance status, manage per grade 3 CRS guidance 
below. 
Institute medical management. If 
hypotension  persists 8 hours after 
adequate medical management, 
de-escalate AMG 330 to 50 of the current 
dose for 24 hours. If symptoms persist, 
interrupt AMG 330. Refer Section 6.2.1.5 
for dose interruption guidelines. If 
symptoms improve to  Grade 1, 
re-escalate to the dose at which the CRS 
event previously occurred. If symptoms 
progress to grade 3 criteria, see row below. 
Permanently discontinue AMG 330 if there 
is no improvement to CRS  grade 1 within 
7 days. 
Page 1 of 2 
Footnotes defined on next page of table 


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Table 7.  Grading and Management of Cytokine Release Syndrome 
CRS Grade 
Description of Severitya 
Minimum Expected Intervention 
Instructions for Interruption of AMG 330 
3 
Symptoms require and respond to 
aggressive intervention 
 Oxygen requirement 40, OR 
 Hypotension requiring high doseb 
or multiple vasopressors, OR 
 Grade 3 organ toxicity or grade 4 
transaminitis per CTCAE criteria 
Admit to intensive care unit for close clinical and vital 
sign monitoring per institutional guidelines. 
Administer tocilizumab 8 mg/kg iv. Up to 3 additional 
doses of 8 mg/kg of tocilizumab can be given 8 hours 
apart, if needed. 
Administer dexamethasone (or equivalent) IV at a dose 
maximum of 3 doses of 8 mg (24 mg/day). The dose 
should then be reduced step-wise. 
Immediately interrupt AMG 330 until event 
resolves to CRS grade  1 
Permanently discontinue AMG 330 if there 
is no improvement to CRS  grade 2 within 
5 days or CRS  grade 1 within 7 days. 
Permanently discontinue AMG 330 if CRS 
grade 3 occurs at the initial run in dose (ie, 
at MTD1).  
4 
Life-threatening symptoms 
 Requirement for ventilator support 
OR 
 Grade 4 organ toxicity (excluding 
transaminitis) per CTCAE criteria 
Admit to intensive care unit for close clinical and vital 
sign monitoring per institutional guidelines. 
Administer dexamethasone (or equivalent) IV at a dose 
maximum of 3 doses of 8 mg (24 mg/day). Further 
corticosteroid use should be discussed with the Amgen 
medical monitor. 
Additionally, tocilizumab should be administered at a 
dose of 8 mg/kg. Up to 3 additional doses can be given 
8 hours apart, if needed. 
Immediately stop the infusion and 
permanently discontinue AMG 330 therapy. 
Page 2 of 2 
CRS, Cytokine Release Syndrome; CTCAE, Common Terminology Criteria for Adverse Events; IV, Intravenous 
a Revised grading system for cytokine release syndrome (Lee et al, 2014) 
b High dose vasopressors (all doses are required for 3 hours): Norepinephrine monotherapy 20 g/min; Dopamine monotherapy 10 g/kg/min, Phenylephrine 
monotherapy 200 g/min, Epinephrine monotherapy 10 g/min; If on vasopressin, vasopressin  norepinephrine equivalent of 10 g/min; If on combination 
vasopressors (not vasopressin), norepinephrine equivalent of 20 g/min 
c Investigators may also consider additional therapy, based on clinical judgment. 
 


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Restart of Treatment after Infusion Interruption due to Cytokine Release 
Syndrome: 
After interruption of AMG 330 infusion due to Grade  3 cytokine release syndrome, the 
infusion may be restarted if all of the following criteria are met: 
 
The Amgen medical monitor must be consulted prior to restarting treatment 
 
The event has resolved to grade  1 prior to restarting treatment 
If the target dose is 
 g/day, AMG 330 therapy should be restarted at the MTD1 
(
 g/day) for 4 days before step up to an intermediate dose level of 
 g/day.  If 
AMG 330 therapy at 
 g/day is well tolerated for 4 days (ie, absence of grade 
 2 CRS) then a dose step up to a target dose of 
 g/day can occur. 
If the target dose is greater than 
 g/day, AMG 330 therapy should be restarted as 
described in Section 6.2.1.5. In case of an infusion interruption of  24 hours, regardless 
of the reason for interruption, restart of the infusion should be performed at the initial 
MTD (run in dose) and dose steps should be performed prior to administering the target 
dose.  The dose level for each step and number of steps should be determined in 
consultation with the Sponsor prior to re-initiation of the infusion. 
If a subject experiences 2 separate grade 3 CRS events, AMG 330 must be permanently 
discontinued. 
Please also refer to the general guidance for restart of infusion after interruptions in 
Section 6.2.1.5. 
For Grade 3 and 4 cytokine release syndrome, please see Section 6.2.1.4 for DLT 
considerations. 
Tumor Lysis Syndrome 
Subjects with AML and WBC  10,000/mcl are considered to be at low risk for tumor 
lysis syndrome.  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.  
Additional high risk features include baseline uric acid  450 mcg/L (7.5 mg/dl), serum 
creatinine  1.4 mg/dL, and lactate dehydrogenase (LDH) greater than the ULN. 
Patients with intermediate risk WBC count and elevated baseline uric acid 
( 450 mcg/L), serum creatinine 1.4 mg/dl, or LDH greater than ULN will be 


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CONFIDENTIAL 
 
 
recommended to receive allopurinol prophylaxis.  Typical dosing is 600-800 mg/day 
administered bid or qid and should begin 3 days before the first dose of study drug.  
Patients should be well hydrated and supplemented with intravenous fluid as clinically 
indicated. 
For grade 3 and 4 tumor lysis syndrome, please see Section 6.2.1.4 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, fluoroquinalones), 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 
The investigational product must be administered using infusion pumps approved for use 
by the appropriate regulatory authorities for the country in which the subject is 
undergoing treatment in both the inpatient and outpatient setting.  Investigational product 
infusion for solution will be prepared in bags for IV infusion and delivered through 
infusion lines with a 0.2 μm in-line filter that are both compatible with the investigational 
product as described in the IPIM. 
Additional details for the use of the above mentioned medical devices and specific set of 
device specifications are provided in the IPIM. 
Additional medical devices (eg, syringes, sterile needles, alcohol prep pads), that are 
commercially available are not provided or reimbursed by Amgen (except, if required by 
local regulation).  The investigator overseeing the conduct of the study at each 
respective institution will be responsible for obtaining these supplies. 
6.8 
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) provisioned and/or repackaged 
/modified by Amgen.  Drug(s) or device(s) includes investigational product. 


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Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.9 
Excluded Treatments 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 blasts as described in Section 6.5. 
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the sponsor’s 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. 
The following procedures should also not be undertaken within the timeframes 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 long line 
insertion) 
 
Treatment with another investigational drug or device. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 


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Table 8.  Schedule of Assessments for Cohorts With 14 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML) Only 
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 
11 
15g 
16 
22 g 
Hours 
Pre-dose 
Relative to start of infusion 
Relative to end of infusion 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
EOI 
0.5 
2 
4 
8 
24 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
Hospitalization 
Xc 
Concomitant Medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious adverse events 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-related events 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurementi 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
Hepatitis Serology 
X 
Anti-AMG 330-antibody 
X 
Page 1 of 2 
Footnotes defined on last page of this table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 89 of 193 
CONFIDENTIAL 
 
 
Table 8.  Schedule of Assessments for Cohorts With 14 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML) Only 
  
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 
11 
15g 
16 
22 g 
Hours 
Pre-dose 
Relative to start of infusion 
Relative to end of infusion 
0.5 1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
EOI 
0.5 
2 
4 
8 
24 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
  
  
X 
  
  
  
  
  
  
BIOMARKER ASSESSMENTS 
 
X 
X 
  
  
 
  
  
 
  
  
  
  
X 
X   
  
X 
  
X 
  
  
  
  
  
  
Serum markersj 
  
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
  
  
  
  
  
  
  
Immune cellsj 
X 
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
X 
  
  
  
  
  
  
Plasma biomarkersj 
X 
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
X 
  
  
  
  
  
  
Bone marrow for biomarker assessments  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xf 
  
X  
  
  
  
  
  
Xf 
PK ASSESSMENTS 
AMG 330 PK Collectionj 
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
  
DISEASE ASSESSMENTS 
Bone marrow aspirate/ biopsy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xf 
  
X  
  
  
  
  
  
Xf 
Treatment response 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xf 
  
X 
  
  
  
  
  
Xf 
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; PBMCs  peripheral blood mononuclear cells; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
c Hospitalization at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours.  At the start of infusion in the 
first cycle, a hospitalization of 9 days is recommended. 
d Obtained at cycle 3 only. 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.  
f Bone marrow assessment at D8 is optional.  Bone marrow assessments on D22 and D29 only if blasts are higher than 5 at prior assessment (see Section 6.2.1.1). 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D22.  In case the infusion-free period between two cycles will only last 
one week, D22 assessments do not apply and will be replaced by D1 assessments of the following cycle. 
i Schedule for ECGs during cycle 1 also applies in case of intra-subject dose escalation. 
j If sample processing / shipment is not logistically feasible for a certain time point (eg, in case it this sample time point is not mandatory. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 90 of 193 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Cohorts With 14 Day Infusion Duration Treatment Cycle 2 and Following to End of Study 
Group 1 (R/R AML) Only 
  
 
 
Treatment Period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT 
EOS 
Cycle Day 
1 
1 
2 
3 
4 8 11 15 22 g 
1 
1 
2 
3 
8 11 15 22 g 
Hours 
Pre-dose 
 
Relative to start of infusion 
Pre-
dose 
 
Relative to start of infusion 
0 
24 
48 
0 
24 
48 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalization 
 
Xc 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serious adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Disease-related events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Evaluationa 
X 
 
X 
X 
X X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
 
X 
X 
X X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
X 
 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
 
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
  
X  
Coagulation 
X 
 
X 
X  
X X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry 
X 
 
X 
X 
X X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
  
X 
  X 
  
X 
X 
X 
 
  
X 
X 
  
X 
X 
X 
X 
Anti-AMG 330-antibody 
X 
 
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
  
 
X 
  
  
 
X 
  
  
  
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 91 of 193 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Cohorts With 14 Day Infusion Duration Treatment Cycle 2 and Following to End of Study 
Group 1 (R/R AML) Only 
  
 
 
Treatment Period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT 
EOS 
Cycle Day 
1 
1 
2 
3 
4 
8 
11 
15 
22 g 
1 
1 
2 
3 
8 
11 
15 
22 g 
Hours 
Pre-dose 
 
Relative to start of infusion 
Pre-
dose 
 
Relative to start of infusion 
0 
24 
48 
0 
24 
48 
BIOMARKER ASSESSMENTS 
h 
X 
 
X 
X 
 
X 
  
X 
 
Xd 
 
Xd 
Xd Xd 
  
Xd 
  
  
  
Serum markersh 
X 
 
X 
X 
 
X 
  
  
  
Xd 
 
Xd 
Xd Xd 
  
  
  
  
  
Immune cellsh 
X 
 
X 
X  
 
X 
  
X 
  
Xd 
 
Xd 
Xd Xd 
  
Xd 
  
X 
X 
Plasma biomarkersh 
X 
 
X 
X  
 
X 
  
X 
  
Xd 
 
Xd 
Xd Xd 
  
Xd 
  
X 
X 
Bone marrow for biomarker assessments  
X 
 
  
  
 
  
  
Xf 
Xf 
X 
 
  
  
  
  
Xf 
Xf 
  
X 
PK ASSESSMENTS 
AMG 330 PK Collectionh 
X 
 
X 
X 
 
X 
  
X 
  
Xd 
 
Xd 
Xd Xd 
  
Xd 
  
  
  
DISEASE ASSESSMENTS 
Bone marrow aspirate / biopsy  
X 
 
  
  
  
  
  
Xf 
Xf 
X 
 
  
  
  
  
Xf 
Xf 
  
X 
Treatment response 
X 
 
  
  
  
  
  
Xf 
Xf 
X 
 
  
  
  
  
Xf 
Xf 
  
X 
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
c Hospitalization at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours. 
d Obtained at cycle 3 only. 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
f  Bone marrow should be assessed at D29.  Bone marrow assessments on D15 or D22 only in case of clinical signs of disease progression (see Section 6.2.1.1). 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D22.  In case the infusion-free period between two cycles will only last 
one week, D22 assessments do not apply and will be replaced by D1 assessments of the following cycle. 
h 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. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 92 of 193 
CONFIDENTIAL 
 
 
Table 10.  Schedule of Assessments for Cohorts With 21 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML) Only 
  
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 
11 
15 
18 
22 
23 
29g 
Hours 
Pre-
dose 
Relative to start of infusion 
Relative to end of infusion 
0.5 
1 
2 3 4 6 8 12 
16 
20 24 
48 
EOI 
0.5 
2 
4 
8 
24 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
Hospitalization 
Xc 
Concomitant Medications 
X 
X 
  
Serious adverse events 
X 
X 
  
Adverse events 
X 
  
Disease-related events 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurementi 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Hepatitis Serology 
X 
Anti-AMG 330-antibody 
X 
Page 1 of 2 
Footnotes defined on last page of this table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 93 of 193 
CONFIDENTIAL 
 
 
Table 10.  Schedule of Assessments for Cohorts With 21 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML) Only 
  
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 8 
11 15 18 22 
23 
29g 
Hours 
Pre-
dose 
Relative to start of infusion 
Relative to end of infusion 
0.5 1 2 3 4 
6 
8 
12 16 20 24 48 
EOI 
0.5 
2 
4 
8 
24 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
  
 
X 
 
 
 
 
 
 
BIOMARKER ASSESSMENTS 
 
X 
X 
  
  
X     
X   
  
  
  
X 
X 
  
X 
  
X 
  
X 
  
  
    
  
  
Serum markersj 
  
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
Immune cellsj 
X 
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
  
  
  
Plasma biomarkersj 
X 
X 
  
  
  
  
  
X 
  
  
  
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
  
  
  
Bone marrow for biomarker assessments 
X 
  
  
  
  
  
  
  
  
  
  
  
  
    
Xf 
  
  
  
X 
  
  
  
  
  
Xf 
PK ASSESSMENTS 
AMG 330 PK Collectionj 
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
X 
X 
  
X 
  
X 
  
X 
X 
X X X 
X   
DISEASE ASSESSMENTS 
Bone marrow aspirate / biopsy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
    
Xf 
  
  
  
X 
  
  
  
  
  
Xf 
Treatment response 
  
  
  
  
  
  
  
  
  
  
  
  
  
    
Xf 
  
  
  
X 
  
  
  
  
  
Xf 
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; PBMCs  peripheral blood mononuclear cells; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
c Hospitalization at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours.  At the start of infusion in the 
first cycle, a hospitalization of 9 days is recommended. 
d Obtained at cycle 3 only. 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
f Bone marrow assessment at D8 is optional.  Bone marrow assessments on D29 and D36 only if blasts are higher than 5 at prior assessment (see Section 6.2.1.1). 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D29.  In case the infusion-free period between two cycles will only last 
one week, D29 assessments do not apply and will be replaced by D1 assessments of the following cycle. 
I Schedule for ECGs during cycle 1 also applies in case of intra-subject dose escalation. 
j 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. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 94 of 193 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Cohorts With 21 Day Infusion Duration Treatment Cycle 2 and Following to End of 
Study 
Group 1 (R/R AML) Only 
  
 
 
Treatment period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT 
EOS 
Cycle Day 
1 
1 
2 
3 
4 8 11 15 18 22 29 g 
1 
1 
2 
3 
8 11 15 18 22 29 g 
Hours 
Pre-dose 
 
Relative to start of infusion 
Pre-dose 
 
Relative to start of infusion 
0 
24 
48 
0 
24 
48 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalization 
 
Xc 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serious adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
 
 
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
X 
X 
Disease-related events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Evaluationa 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
X 
 
X 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
 
  
  
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
  
  
  
X 
Coagulation 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
  
X 
X 
  
X 
  
X 
X 
X 
X 
Anti-AMG 330-antibody 
X 
 
  
  
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
  
  
X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
  
 
X 
  
  
 
X 
  
  
  
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 95 of 193 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Cohorts With 21 Day Infusion Duration Treatment Cycle 2 and Following to End of 
Study 
Group 1 (R/R AML) Only 
  
 
 
Treatment period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT EOS 
Cycle Day 
1 
1 
2 
3 
4 
8 11 15 18 22 
29 g 
1 
1 
2 
3 
8 
11 
15 18 22 
29 g 
Hours 
Pre-dose 
 
Relative to start of infusion 
Pre-
dose 
 
Relative to start of infusion 
0 
24 
48 
0 
24 
48 
BIOMARKER ASSESSMENTS 
h 
X 
 
X 
X 
X 
X 
X 
Xd 
 
Xd 
Xd 
Xd 
Xd 
Xd 
Serum markersh 
X 
 
X 
X 
X 
Xd 
 
Xd 
Xd 
Xd 
Immune cellsh 
X 
 
X 
X 
X 
X 
X 
Xd 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
Plasma biomarkersh 
X 
 
X 
X 
X 
X 
X 
Xd 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
Bone marrow for biomarker assessments 
X 
 
Xf 
Xf 
X 
 
Xf 
Xf 
X 
PK ASSESSMENTS 
AMG  330 PK Collectionh 
X 
 
X 
X 
X 
X 
X 
Xd 
 
Xd 
Xd 
Xd 
Xd 
Xd 
DISEASE ASSESSMENTS 
Bone marrow aspirate / biopsy  
X 
 
Xf 
Xf 
X 
 
Xf 
Xf 
X 
Treatment response 
X 
 
Xf 
Xf 
X 
 
Xf 
Xf 
X 
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal 
c Hospitalization at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours. 
d Obtained at cycle 3 only 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
f  Bone marrow should be assessed at D36.  Bone marrow assessments on D22 or D29 only in case of clinical signs of disease progression  (see section 6.2.1.1) 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D29.  In case the infusion-free period between two cycles will only last 
one week, D29 assessments do not apply and will be replaced by D1 assessments of the following cycle.   
h 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 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 96 of 193 
CONFIDENTIAL 
 
 
Table 12.  Schedule of Assessments for Cohorts With 28 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML), Group 2 (MRD AML) and Group 3 (MDS) Only 
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 8 11 15 18 22 25 
29 
30 
36 g 
Hours 
Pre-
dose 
Relative to start of infusion 
Relative to end of 
infusion 
0.5 
1 
2 3 4 6 
8 
12 16 20 24 48 
EOI 0.5 2 4 8 24 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
Hospitalization 
Xc 
Concomitant Medications 
X 
X 
  
Serious adverse events 
X 
X 
 
Adverse events 
X 
 
Disease-related events 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurementi 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis Serology 
X 
Anti-AMG 330-antibody 
X 
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 97 of 193 
CONFIDENTIAL 
 
 
Table 12.  Schedule of Assessments for Cohorts With 28 Day Infusion Duration Screening and Treatment Cycle 1 
Group 1 (R/R AML), Group 2 (MRD AML) and Group 3 (MDS) Only 
  
SCR 
Treatment Period 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 
11 15 18 22 25 
29 
30 36 g 
Hours 
Pre-
dose 
Relative to start of infusion 
Relative to end of 
infusion 
0.5 
1 
2 3 4 6 8 
12 
16 20 24 48 
EOI 0.5 2 4 8 24 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
X 
BIOMARKER ASSESSMENTS 
Pharmacogenetics (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Serum markersj 
X 
Xk 
X 
X 
Xk 
X 
Immune cellsj 
X 
X 
X 
 
 
 
X 
Plasma biomarkersj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow for biomarker 
assessments 
X 
Xf 
X 
Xf 
PBMCs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Whole blood MRD (Group 2 only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PK ASSESSMENTS 
AMG 330 PK Collectionj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
DISEASE ASSESSMENTS 
Bone marrow aspirate / biopsy f 
X 
Xf 
X 
Xf 
Treatment response 
Xf 
X 
Xf 
Page 2 of 2 
Footnotes defined on next page 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 98 of 193 
CONFIDENTIAL 
 
 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; PBMCs  peripheral blood mononuclear cells; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
c Hospitalization for R/R AML and MDS:  at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours.  At 
the start of infusion in the first cycle, a hospitalization of 9 to 12 days is recommended for Group 1, based on AMG 330 administration schedule.  Hospitalization for MRD AML:  at 
start of cycles 1 and 2 and after dose increase in cycle 1 (dose step or intra-subject dose escalation, if applicable) will be for a minimum of 48 hours.  
d Obtained at cycle 3 only. 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
ᶠ Bone marrow assessment at D8 is optional.  Bone marrow assessments on D36 and D43 only if blasts are higher than 5 at prior assessment (see section 6.2.1.1 ).  For subjects in 
Group 2, MRD assessment required using both local and central testing. See section 7.5.2 for a detailed description. 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D36.  In case the infusion-free period between two cycles will only last 
one week, D36 assessments do not apply and will be replaced by D1 assessments of the following cycle. 
i Schedule for ECGs during cycle 1 also applies in case of intra-subject dose escalation. 
j 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 Day 1 HR1 and HR12 collection only for Group 1 (do not collect for Group 2 or Group 3). 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 99 of 193 
CONFIDENTIAL 
 
 
Table 13.  Schedule of Assessments for Cohorts With 28 Day Infusion Duration Treatment Cycle 2 and Following to End of 
Study 
Group 1 (R/R AML), Group 2 (MRD AML), Group 3 (MDS) and Group 4 (R/R AML, Cycles 2) Only 
  
 
 
Treatment Period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT 
EOS 
Cycle Day 
1 
1 
2 
3 
4 
8 
11 15 18 22 25 29 
36 g 
1 
1 
2 
3 
8 
11 15 18 22 25 29 
36 g 
Hours 
Pre-
dose 
 
Relative to start of infusion 
Pre-
dose 
 
Relative to start of infusion 
0 
24 
48 
0 
24 
48 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalization 
 
Xc 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serious adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Disease-related events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Evaluationa 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
X 
 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
X 
 
  
  
  
  
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
  
  
  
  
  
X 
Coagulation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
  
X 
X 
  
X 
  
X 
  
X 
X 
X 
X 
Anti-AMG 330-antibody 
X 
 
  
  
  
  
  
  
  
  
  
    
X 
 
  
  
  
  
  
  
  
  
    
X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
  
 
X 
  
  
 
X 
  
  
  
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 100 of 193 
CONFIDENTIAL 
 
 
Table 13.  Schedule of Assessments for Cohorts With 28 Day Infusion Duration Treatment Cycle 2 and Following to End of 
Study 
Group 1 (R/R AML), Group 2 (MRD AML), Group 3 (MDS) and Group 4 (R/R AML, Cycles 2) Only 
  
 
 
Treatment Period 
Cycle 
 
2 
 
3 and all subsequent cycles 
EOT 
EOS 
Cycle Day 
1 
1 
2 
3 
4 
8 
11 15 18 22 25 29 36 g 
1 
1 
 
2 
3 
8 
11 15 18 22 25 29 36 g 
Hours 
Pre-
dose 
 
Relative to start of infusion 
Pre-
dose 
 
Relative to start of infusion 
0 6 24 48 
0 
6 
24 48 
BIOMARKER ASSESSMENTS 
h 
 X 
 
 
X 
 
  
  
  
 X 
  
 X 
  
 X   
Xd  
 
 
Xd 
 
  
  
 Xd 
  
 Xd 
  
 Xd   
  
  
Serum markersh 
X 
 
X 
X 
 
  
 
  
  
  
  
  
  
  
Xd 
 
Xd Xd 
 
 
  
  
  
  
  
  
  
  
  
Immune cellsh 
X 
 
X 
X 
 
  
 
  
 
  
 
  
X 
  
Xd 
 
Xd Xd 
 
 
  
 
  
 
  
Xd 
  
X 
 
Bone marrow for biomarker assessments  
Xi 
 
 
  
  
  
  
  
  
  
  
  
Xf  
Xi 
 
 
  
  
  
  
  
  
  
  
Xf 
 
  
X 
PBMCsh, j 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
X 
 
Whole blood MRD (Group 2 only) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
PK ASSESSMENTS 
AMG  330 PK Collectionh 
X 
 
 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
Xd 
 
 
Xd Xd Xd 
  
Xd 
  
Xd 
  
Xd 
  
 X 
X 
DISEASE ASSESSMENTS 
Bone marrow aspirate / biopsy  
Xi 
 
 
  
  
  
  
  
  
  
  
  
Xf 
 
Xi 
 
 
  
  
  
  
  
  
  
  
Xf 
 
  
X 
Treatment response 
Xi 
 
 
  
  
  
  
  
  
  
  
  
Xf 
 
Xi 
 
 
  
  
  
  
  
  
  
  
Xf 
 
  
X 
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal 
c Hospitalization for R/R AML and MDS:  at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours.  
Hospitalization for MRD AML:  at start of cycles 1 and 2 and after dose increase in cycle 1 (dose step or intra-subject dose escalation, if applicable) will be for a minimum of 
48 hours. 
d Obtained at cycle 3 only 
e Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
f  Bone marrow should be assessed at D29 
g In case of extended infusion-free interval, there will be weekly visits at site, assessments will be performed as on D36  (see section 6.2.1.1).  In case the infusion-free period between 
two cycles will only last one week, D36 assessments do not apply and will be replaced by D1 assessments of the following cycle. 
h 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 If bone marrow was assessed 14 days prior to C2D1 or C3D1, this sample is optional 
j Collections not required for Group 4 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 101 of 193 
CONFIDENTIAL 
 
 
Table 14.  Additional Assessments Applicable in Case of Dose Step (Regardless of Treatment Cycle) 
All Groups EXCEPT Group 5, Mini Steps 
Day (relative to dose step) 
1 
2 
3 
4 
Hours 
prior to 
step 
relative to start of dose step 
0.5 
1 
2 
4 
6 
8 
12 
16 
20 
24 
48 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalization 
Xc 
Clinical Evaluationa 
X 
  
  
  
  
  
  
  
  
 
X 
X 
X 
Vital signs, pulse oximetrye 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
X 
  
  
  
  
  
  
  
  
 
X 
  
  
LABORATORY ASSESSMENTS 
Coagulation 
X 
  
  
  
  
  
 X 
  
  
 
X 
X 
X 
Hematology, Chemistry 
X 
  
  
  
  
  
 X 
  
  
 
X 
X 
X 
Urinalysis 
X 
  
  
  
  
  
  
  
  
 
  
X 
  
BIOMARKER ASSESSMENTS 
 , g,  
X h 
  
  
 
 
 
  
  
  
 
X h 
X 
  
Serum markersd, g 
X 
  
 X i 
X  
  
X 
  
 X i 
  
 
X 
 
  
Immune cellsd, g 
X 
  
  
  
  
X 
  
  
  
 
X 
X 
  
PK ASSESSMENTS 
AMG  330 PK Collection e 
X 
X 
  
X 
X 
  
X 
  
  
 
X  
X 
  
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal 
c Hospitalization for R/R AML and MDS at start of cycles 1 and 2 and after dose increase (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 72 hours.  
Hospitalization for MRD AML:  at start of cycles 1 and 2 and after dose increase in cycle 1 (dose step, or intra-subject dose escalation, if applicable) will be for a minimum of 48 hours. 
 
  
e PK only obtained in Cycle 1.  
f Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
g 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 
h For Group 4, Cycle 1, do not collect CD33 at the following time points: pre step dose 2 and 24 hours post dose step 2 
i Collections only required for Group 1 and Group 4 during Cycle 1 (do not collect for Groups 2, 3, and 5) 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 102 of 193 
CONFIDENTIAL 
 
 
Table 15.  Schedule of Assessments for Group 4, Arm 1 (
 Premedication) – Cycle 1 
  
SCR 
Treatment Period 
EOT 
EOS 
Cycle 
  
1 
  
  
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 11 
15 
16 22ᶠ 
  
Relative to start of infusion 
Relative to end of infusion 
Hours 
Pre-
Dose 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
EOI 
0.5 
2 
4 
8 
2
4 
GENERAL AND SAFETY 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
X 
  
  
  
  
  
  
  
  
  
        X 
Serious adverse events 
X  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events 
 Xⁱ 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Disease-related events 
Xⁱ 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
X 
X X 
X 
X 
  
  
  
  
X 
X 
X 
X 
Vital signs, pulse oximetryd 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
  
  
  
  
X 
X 
X 
X 
ECG triplicate measurement 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
  
  
X 
LABORATORY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum pregnancy testb 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation 
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X X 
X 
X 
  
  
  
  
  
X 
X 
X 
Hematology, Chemistry  
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X X 
X 
X 
  
  
  
  
  
X 
X 
X 
Urinalysis  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
  
  
  
  
X 
X 
X 
Hepatitis Serology 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibody 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of this table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 103 of 193 
CONFIDENTIAL 
 
 
Table 15.  Schedule of Assessments for Group 4, Arm 1 (
 Premedication) – Cycle 1 
  
SCR 
Treatment Period 
EOT 
EOS 
Cycle 
  
1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-14 to -1 
1 
  
  
  
  
  
  
  
  
  
  
2 
3 
4 
8 
11 
15 
16 
22ᶠ 
  
  
  
  
  
Relative to start of infusion 
Relative to end of 
infusion 
  
  
  
  
  
Hours 
  
Pre-
Dose 
0.
5 
1 
2 
3 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
  
  
  
  
EOI 
0.5 
2 
4 
8 
24 
 
  
  
BIOMARKER 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ᶢ  
  
X 
  
 
 
 
 
 
 
  
  
  
X 
 
 
 
  
X 
  
  
  
  
  
X 
  
  
Serum markersᶢ  
  
X 
  
X 
X 
  
  
X 
  
X 
  
  
X 
 
 
 
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ  
  
X 
  
  
  
  
  
X 
  
  
  
  
X 
 
 
 
  
X 
  
  
  
  
  
  
X 
 
Bone marrow for biomarker 
assessmentsᵉ 
X 
  
  
  
  
 
 
 
 
 
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
PK ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 PK Collection 
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
 
 
 
DISEASE ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone marrow aspirate/biopsyᵉ 
X 
  
  
  
  
  
 
 
 
 
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
Treatment Responseᵉ 
X 
  
  
  
  
  
 
 
 
 
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
DOSING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 
  
  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
a Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
b Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal 
c Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours.  .   
d Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions  
e Bone marrow assessment at D8 is optional. 
f In case of extended infusion-free interval, there will be weekly visits at site.  
ᶢ If sample processing / shipment is not logistically feasible for a certain time point, this sample time point is not mandatory 
h 
. 
ⁱTo be recorded on day -1 (post start of 
 dosing) 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 104 of 193 
CONFIDENTIAL 
 
 
Table 16.  Schedule of Assessments for Group 4, Arm 2 (
 Predmedication) – Cycle 1 
  
SCR 
Treatment Period 
EOT 
EOS 
Cycle 
  
 
 
  
  
  
  
  
  
  
  
1  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-14 to -1 
  
  
 1 
  
  
  
  
  
  
2 
3 
4 
8 
11 
15 
  
  
  
  
16 
22ᶠ 
  
  
  
  
  
Relative to start of infusion 
Relative to end of infusion 
  
  
  
Hours  
  
Pre-Dose 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
  
  
  
  
EOI 
0.5 
2 
4 
8 
24 
  
  
  
GENERAL AND SAFETY ASSESSMENTS 
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Serious adverse events 
X  
Adverse events 
  
X 
X  
Disease-related events 
 
X 
X 
Clinical Evaluationa 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
Vital signs, pulse oximetryd 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
ECG triplicate measurement 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
  
  
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testᵇ 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation 
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
X 
X 
X 
Hematology, Chemistry  
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
X 
X 
X 
Urinalysis  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
  
  
  
  
X 
X 
X 
Hepatitis Serology 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibodyʰ 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 105 of 193 
CONFIDENTIAL 
 
 
Table 16.  Schedule of Assessments for Group 4, Arm 2 (
 Predmedication) – Cycle 1 
  
SCR 
Treatment Period 
EOT 
EOS 
Cycle 
1 
Cycle Day 
-14 to -1 
1 
2 
3 
4 
8 
11 
15 
16 
22ᶠ 
  
  
  
Relative to start of infusion 
Relative to end of infusion 
  
  
  
Hours  
  
Pre-Dose 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
  
  
  
  
EOI 
0.5 
2 
4 
8 
24 
  
  
  
BIOMARKER ASSESSMENTS 
ᶢ  
  
X 
  
 
 
 
 
 
  
  
  
  
X 
 
 
 
  
X 
  
  
  
  
  
X 
  
  
Serum markersᶢ  
  
X 
  
X 
X 
  
  
X 
  
X 
  
  
X 
 
 
 
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ  
  
X 
  
  
  
  
  
X 
  
  
  
  
X 
 
 
 
  
X 
  
  
  
  
  
  
X 
 
Bone marrow for biomarker 
assessmentsᵉ 
X 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
PK ASSESSMENTS 
AMG 330 PK Collection 
  
X 
X 
  
X 
  
X 
  
X 
  
  
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
 
 
 
DISEASE ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone marrow aspirate/biopsyᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
Treatment Responseᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
DOSING  
AMG 330 
  
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
ⁱ 
. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 106 of 193 
CONFIDENTIAL 
 
 
Table 17.  Schedule of Assessments for Group 5, Arm 1 (
and Mini-step Dosing Approach) Cycle 1 
  
SCR 
Treatment Period 
  
Cycle 
  
1 
Cycle Day 
-14 to 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
11 
12 
15 18 22 25 
29 
30 36ᶠ 
  
  
  
Relative to start of infusion 
Relative to end of 
infusion 
  
Hours 
  
Pre 
0.5 
1 
2 
3 
4 
6 
8 12 16 20 24 
  
  
  
  
  
  
  
  
 
  
  
  
  EOI 0.5 2 
4 
8 24 
  
GENERAL AND SAFETY ASSESSMENTS 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationᶜ  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
Serious adverse 
events 
X 
X 
Adverse events 
Xⁿ 
X 
X 
Disease-related 
events 
Xⁿ 
X 
X 
Clinical Evaluationa 
X 
X 
 
 
 
 
 
 
 
 
 
 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
Vital signs, pulse 
oximetryd 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
ECG triplicate 
measurement 
X 
X 
 
 
 
 
 
 
 
 
 
 
Xᵏ 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Hematology, 
Chemistry  
X 
X 
 
 
 
 
 
 
X 
 
 
 
Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ Xᵐ 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X
ᵏ 
 
 
 
 
X
ᵏ 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 330-
antibodyʰ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 107 of 193 
CONFIDENTIAL 
 
 
Table 17.  Schedule of Assessments for Group 5, Arm 1 (
 and Mini-step Dosing Approach) Cycle 1 
  
SCR 
Treatment Period 
Cycle 
  
1 
Cycle Day 
-14 to 
-1 
1 
  
  
  
  
  
  
  
  
  
  
2 
3 
4 
5 
6 
7 
8 
9 
1
1 
12 
15 
18 
22 
25 
29 
30 
36
ᶠ 
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
Hours 
  
Pre-
Dose 
0.
5 
1 
2 
3 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
  
  
  
  
  
  
  
  
 
  
  
  
  
EOI 
0.
5 
2 
4 
8 
24 
  
BIOMARKER 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ᶢ  
  
X 
  
  
 
 
 
 
  
  
  
  
X
ᵏ 
X
ᵏ 
  
  
  
  
Xᵏ 
  
  
 
X 
  
X 
  
X   
  
  
  
  
  
Serum markers 
 
Refer to Table 18 for Serum Marker Collection Schedule 
Immune cells 
 
Refer to Table 18 for Immune Cell Collection Schedule 
PBMCs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
Bone marrow for 
biomarker 
assessmentsᵉ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
  
  
  
X   
  
  
  
  
 
PK ASSESSMENTS 
AMG 330 PK 
Collection 
  
Refer to Table 18 for AMG 330 PK Collection Schedule 
DISEASE 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Bone marrow 
aspirate/biopsyᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
  
  
  
X   
  
  
  
  
  
Treatment 
Responseᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
  
  
  
X   
  
  
  
  
  
DOSING  
AMG 330 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
Footnotes defined on next page 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 108 of 193 
CONFIDENTIAL 
 
 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained.  
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
ᵏ Taken pre dose step.  
ᶥ For each dose step, take vital signs and pulse oximetry pre dose, 1HR, 2HR, 4HR, 6HR, 8HR, 12HR, 16HR and 20H post dose step.  
ᵐ For each dose step, take coagulation, hematology and chemistry pre dose and 8HR post dose step. 
ⁿ Adverse Events and Disease-Related Events to be recorded starting at day -1 if 
 is administered. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 109 of 193 
CONFIDENTIAL 
 
 
Table 18.  Biomarker Collection Schedule for Group 5, Arm 1, Cycle 1 
AMG 330 Dose 
level (CIV) 
AMG 330 Days 
administered 
Biomarker time points (Serum Markers and 
Immune Cells) 
PK time points 
g/day 
D1 
PRE, 2HRa, 6HR 
PRE, 2HR, 6HR 
g/day 
D2 
PRE, 6HRa 
g/day 
D3 
PRE, 6HR 
PRE, 6HR 
g/day 
D4 
PRE, 6HRa 
  
g/day 
D5 
PRE, 6HR 
PRE, 6HR  
g/day 
D6 
PRE, 6HRa 
  
g/day 
D7 
PREa, 6HRa 
PRE, 6HR 
g/day 
D8 
PREa, 6HRa 
g/day 
D9-D29 
D9 PRE, D9 2HRa, D9 6HR, D11b, D29 EOIb 
D9 PRE, D9 2HR, D9 6HR, D29 EOI, , 2HR,  6HR, D30 
a D1HR2, D2HR6, D4HR6, D6HR6, D7PRE, D7HR6, D8PRE, D8HR6, and D9HR2 time points for serum biomarker only, not included in Immune Cells. 
b D11 and EOI time points for Immune Cell biomarker asssessment only, not included in Serum Markers. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 110 of 193 
CONFIDENTIAL 
 
 
Table 19.  Schedule of Assessments for Group 5, Arm 1 (
and Mini-step Dosing Approach) Cycle 2 
  
AMG 330 Treatment Period 
Cycle 
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-1 
1 
1 
  
2 
3 
4 
5 
6 
7 
8 
9 
11 
12 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours 
  
Pre-Dose 
0 
6 
24 
48 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Hours relative to dose step 
  
  
  
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
GENERAL AND SAFETY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
 
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
  
  
Serious adverse events 
 
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events 
 
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
  
  
Disease-related events 
 
 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
  
X 
  
  
Xʲ 
Xʲ 
Xʲ 
Xʲ 
Xʲ 
Xʲ 
X 
  
Xʲ 
X 
  
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetryd 
  
X 
  
  
Xᵏ 
Xᵏ 
Xᵏ 
Xᵏ 
Xᵏ 
Xᵏ 
Xᵏ 
  
Xᵏ 
X 
  
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
  
X 
  
  
Xʲ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
LABORATORY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum pregnancy testb 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation 
  
X 
  
  
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ  
Xᶥ 
  
Xᶥ  
X 
  
X 
X 
X 
X 
X 
X 
Hematology, Chemistry  
  
X 
  
  
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
Xᶥ 
  
Xᶥ 
X 
  
X 
X 
X 
X 
X 
X 
Urinalysis  
  
X 
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
X 
  
X 
X 
X 
Hepatitis Serology 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibodyg 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Page 1 of 2 
Footnotes defined on last page of this table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 111 of 193 
CONFIDENTIAL 
 
 
Table 19.  Schedule of Assessments for Group 5, Arm 1 (
and Mini-step Dosing Approach) Cycle 2 
  
AMG 330 Treatment Period 
Cycle 
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-1 
1 
1 
  
  
  
  
  
  
  
  
2 
3 
4 
5 
6 
7 
8 
9 
11 
12 
15 
18 
22 
25 
29 36ᵉ 
  
  
  
Relative to start of 
infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours 
  
Pre-
Dose 
0 
1 
2 
4 
6 
8 
12 
16 
20 24 
48 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Hours relative to dose step 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
BIOMARKER ASSESSMENTS 
  
  
X 
  
  
  
  
  
  
  
  
  
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 X 
  
Serum markersᶠ  
  
X 
  
  
  
  
X 
  
  
  
  
X 
 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
Immune cellsᶠ  
  
X 
  
  
  
  
X 
  
  
  
  
X 
X 
  
  
  
  
 
 
 
  
  
  
  
  
  
  
  
PBMCs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bone marrow for biomarker 
assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
PK ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
AMG 330 PK Collection 
X 
  
  
  
  
  
  
  
  
Xj 
Xj 
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
 
DISEASE ASSESSMENTS 
Bone marrow 
aspirate/biopsy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Treatment Response 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
DOSING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained.  
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ In case of extended infusion-free interval, there will be weekly visits at site.(See Section 6.2.1.1) 
ᶠ 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. 
ᶢ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
ʲ Taken pre dose step.  
ᵏ For each dose step, take vital signs and pulse oximetry pre dose, 1HR, 2HR, 4HR, 6HR, 8HR, 12HR, 16HR and 20H post dose step. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 112 of 193 
CONFIDENTIAL 
 
 
ᶥ For each dose step, take coagulation, hematology and chemistry pre dose and 8HR post dose step.  
Table 20.  Schedule of Assessments for Group 5, Arm 1 (
 and Mini-step Dosing Approach) Cycle 3 and 
Following to End of Study 
  
AMG 330 Treatment Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
3 and all subsequent cycles 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT EOS 
Cycle Day 
-1 
1 
1 
  
  
  
  
  
  
  
  
2 
3 
4 
5 
6 
7 
8 
9 
11 
12 
15 
18 
22 25 
29 36ᶠ 
  
  
  
  
  
Relative to start of 
infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours 
  
Pre-
Dose 
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Hours relative to dose step 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalizationᶜ  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
 
       X 
X 
X 
Serious adverse events 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Adverse events 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Disease -related events 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
  
X 
  
  
  
  
  
  
  
  
  
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X
ᵏ 
X 
  
Xᵏ 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetryd 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X
ᶩ 
X
ᶩ 
X
ᶩ 
X
ᶩ 
X
ᶩ 
X
ᶩ 
X
ᶩ 
  
Xᶩ 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
X 
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Coagulation 
  
X 
  
  
  
  
  
  
  
  
  
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
  
 X
ᵐ 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry  
  
X 
  
  
  
  
  
  
  
  
  
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
X
ᵐ 
  
 X
ᵐ 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
X 
  
X 
X 
X 
X 
X 
Hepatitis Serology 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibodyʰ 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 113 of 193 
CONFIDENTIAL 
 
 
Page 1 of 2 
Footnotes defined on last page of this table 
Table 20.  Schedule of Assessments for Group 5, Arm 1 (
 and Mini-step Dosing Approach) Cycle 3 and 
Following to End of Study 
  
AMG 330 Treatment Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
3 and all subsequent cycles 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT EOS 
Cycle Day 
-1 
1 
1 
  
  
  
  
  
  
  
  
2 
3 
4 
5 
6 
7 
8 
9 
11 
12 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
  
  
Relative to start of infusion  
  
  
  
  
Hours 
 
Pre-
Dose 
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
Hours relative to dose 
step 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
 
 
BIOMARKER ASSESSMENTS 
ᶢ, ⁿ  
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 X 
  
  
  
Serum markersᶢ, ⁿ  
  
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ, ⁿ  
  
X 
  
  
  
  
X 
  
  
  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PBMCsg, n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Bone marrow for 
biomarker assessmentsᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
 
PK ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 PK Collection 
  
X 
  
  
  
  
  
  
  
  
X 
X 
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
DISEASE ASSESSMENTS  
Bone marrow 
aspirate/biopsyᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 X 
Treatment Response 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 X 
DOSING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 
  
  
X  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
Footnotes defined on next page 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 114 of 193 
CONFIDENTIAL 
 
 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained.  
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. (see Section 6.2.1.1) 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
 
ᵏ Taken pre dose step 
ᶥ For each dose step, take vital signs and pulse oximetry pre dose, 1HR, 2HR, 4HR, 6HR, 8HR, 12HR, 16HR and 20H post dose step 
ᵐ For each dose step, take coagulation, hematology and chemistry pre dose and 8HR post dose step 
ⁿ Obtained Cycle 3 only 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 115 of 193 
CONFIDENTIAL 
 
 
Table 21.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 1 
  
SCR 
Treatment Period 
Cycle 
  
1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-14 to 
-1 
1 
2 
3 
4 
  
  
5 
6 
8 
11 
15 
18 
22 
25 
29 
30 
36ᶠ 
  
  
  
Relative to start of infusion 
Relative to end of infusion 
Hours 
  
Pre-
Dose 
0.
5 
1 
2 
3 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
  
  
  
  
  
E
OI 
0.
5 
2 
4 
8 
24 
  
Hours relative to dose 
step 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PR
E 
2 
6 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant 
Medications 
X 
X 
Serious adverse events 
 X 
X 
Adverse events 
 Xᵏ 
X 
X 
Disease-related events 
Xᵏ 
X 
X 
Clinical Evaluationa 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
X 
Vital signs, pulse 
oximetryd 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
X 
ECG triplicate 
measurement 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
LABORATORY 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum pregnancy testb 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation 
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
X 
Hematology, 
Chemistry  
X 
X 
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
X 
Urinalysis  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
X 
X 
  
  
  
  
  
X 
Hepatitis Serology 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-
antibodyʰ 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Page 1 of 2 
Footnotes defined on last page of this table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 116 of 193 
CONFIDENTIAL 
 
 
Table 21.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 1 
  
SCR 
Treatment 
Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
  
1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-14 to 
-1 
1 
2 
3 
4 
  
  
5 6 
8 11 15 18 22 25 
29 
  
  
  
  
3
0 
36
ᶠ 
  
  
  
Relative to start of 
infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Relative to end of infusion 
Hours 
  
Pre-Dose 
0.5 
1 
2 
3 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
  
  
  
  
  
EOI 
0.
5 
2 
4 
8 
24
 
Hours relative to dose step 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PR
E 
2 6   
  
  
  
  
  
  
  
  
  
  
  
  
 
BIOMARKER 
ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ᶢ  
  
X 
  
  
  
  
  
  
  
  
X 
 
 
 
 
 
 
 
  
X 
  
X 
  
X 
  
  
  
  
  
  
Serum markersᶢ  
  
X 
  
  
X 
  
  
X   
  
  
  
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ  
  
X 
  
  
  
  
  
X   
  
  
  
X 
 
 
 
 
 
 
 
 
 
 
  
  
X 
  
  
  
  
  
  
PBMCs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Bone marrow for biomarker 
assessmentsᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
PK ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 PK Collection 
  
X 
X 
  
X 
  
X   
X   
  
  
X 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
X X X X 
DISEASE ASSESSMENTS 
Bone marrow 
aspirate/biopsyᵉ 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
Treatment Response 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
DOSING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
Footnotes defined on next page 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 117 of 193 
CONFIDENTIAL 
 
 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
ᵏAdverse Events and Disease-Related Events to be recorded starting at day -2 if 
 is administered 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 118 of 193 
CONFIDENTIAL 
 
 
Table 22.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 2 
  
  
AMG 330 Treatment Period 
Cycle 
  
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-2 
-1 
1 
1 
  
2 
3 
4 
  
5 
8 
11 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
  
  
  
  
Hours 
  
  
Pre-Dose 
0 
6 
24 
48 
  
  
  
  
  
  
  
  
  
  
  
Hours relative to dose step 
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
GENERAL AND SAFETY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
  
X 
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
  
                   X 
  
Serious adverse events 
  
X 
Adverse events 
  
X 
Disease-related events 
X 
Clinical Evaluationa 
  
  
X 
  
  
X 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetryd 
  
  
X 
  
  
X 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
LABORATORY ASSESSMENTS 
Serum pregnancy testb 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation 
  
  
X 
  
  
X 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry  
  
  
X 
  
  
X 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
X 
X 
X 
Hepatitis Serology 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibodyʰ 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Page 1 of 2 
Footnotes defined on next page of table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 119 of 193 
CONFIDENTIAL 
 
 
Table 22.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 2 
  
  
AMG 330 Treatment Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
  
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle Day 
-2 
-1 
1 
1 
  
2 
3 
4 
  
5 
8 
11 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
  
  
  
  
Hours 
  
  
Pre-Dose 
0 
6 
24 
48 
  
  
  
  
  
  
  
  
  
  
  
Hours relative to dose step 
  
  
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
BIOMARKER ASSESSMENTS 
ᶢ  
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
 X 
  
Serum markersᶢ  
  
  
X 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ  
  
  
X 
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
PBMCs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bone marrow for biomarker 
assessmentsᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
PK ASSESSMENTS 
AMG 330 PK Collection 
X 
  
X 
X 
  
  
  
X 
  
  
  
  
  
X 
 
DISEASE ASSESSMENTS 
Bone marrow aspirate/biopsyᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Treatment Response 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
DOSING 
AMG 330 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. (See Section 6.2.1.1) 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 120 of 193 
CONFIDENTIAL 
 
 
Table 23.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 3 and 
Following to End of Study 
  
  
AMG 330 Treatment Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
3 and all subsequent cycles 
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
EOS 
Cycle Day 
-1 
1 
1 
  
2 
3 
4 
  
5 
8 
11 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours 
  
Pre-Dose 
0 
6 
24 
48 
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours relative to dose step 
 
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalizationᶜ  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
  
X 
X 
Serious adverse events 
  
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
  
X 
X 
Adverse events 
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
X 
X 
Disease-related events 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationa 
  
X 
  
  
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, pulse oximetryd 
  
X 
  
  
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
X 
X 
LABORATORY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum pregnancy testb 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Coagulation 
  
X 
  
  
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry  
  
X 
  
  
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
X 
X 
X 
X 
X 
Hepatitis Serology 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-AMG 330-antibodyʰ 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of the table 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 121 of 193 
CONFIDENTIAL 
 
 
Table 23.  Schedule of Assessments for Group 5, Arm 2 (
 and Maxi-step Dosing Approach) Cycle 3 and 
Following to End of Study 
  
  
AMG 330 Treatment Period 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cycle 
3 and all subsequent cycles 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
EOS 
Cycle Day 
-1 
1 
1 
  
2 
3 
4 
  
5 
8 
11 
15 
18 
22 
25 
29 
36ᶠ 
  
  
  
  
  
Relative to start of infusion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours 
  
Pre-Dose 
0 
6 
24 
48 
  
  
  
  
  
  
  
  
  
  
  
  
  
Hours relative to dose step 
 
  
  
  
  
  
PRE 
6 
  
  
  
  
  
  
  
  
 
 
 
BIOMARKER ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ᶢ  
  
Xk 
  
  
Xk 
  
  
  
  
  
  
  
  
  
 Xk 
  
  
  
Serum markersᶢ  
  
Xk 
  
Xk 
Xk 
 
 
 
  
  
  
  
  
  
  
  
  
  
Immune cellsᶢ  
  
Xk 
  
Xk 
Xk 
Xk 
 
 
 
  
  
  
  
  
  
  
  
  
  
PBMCs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
X 
 
Bone marrow for biomarker assessmentsᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
PK ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 PK Collection 
  
X 
  
X 
X 
  
  
  
X 
  
  
  
  
  
X 
DISEASE ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone marrow aspirate/biopsyᵉ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 X 
Treatment Response 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 X 
DOSING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AMG 330 
  
  
X 
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
Page 2 of 2 
Footnotes defined on next page 


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EOI  End of Infusion; EOS  End of Study; EOT  End of Treatment; SCR  Screening 
ᵃ Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. 
ᵇ Serum pregnancy test will be performed for all females unless surgically sterile or  2 years postmenopausal. 
ᶜ Hospitalization at start of cycle 1 and after dose increase (dose step) will be for a minimum of 72 hours. 
ᵈ Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
ᵉ Bone marrow assessment at D8 is optional. 
ᶠ In case of extended infusion-free interval, there will be weekly visits at site. (See Section 6.2.1.1) 
ᶢ 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. 
ʰ Anti-AMG 330-antibody sample will be collected before both 
 and AMG 330 administrations on D1-Predose. 
K Obtained Cycle 3 only 
 


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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.  All screening procedures must be performed within 14 days 
of day 1, unless otherwise noted.  Subjects who meet the inclusion and exclusion criteria 
will be eligible to be enrolled in the study. 
A subject may be rescreened up to 3 additional times during the study at the discretion 
of the investigator. 
During the study, every effort should be made to perform the study procedures as 
indicated on the Schedules of Assessments (Table 8 – Table 23).  In case a dose step/ 
dose steps are performed, assessments indicated in the schedule of assessments for 
dose steps (Table 14) apply in addition to assessments described for the respective 
study day in the schedule of assessments applicable for a given cycle 
(Table 8 – Table 23).  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 330 
infusion.  If a permanent central line with more than one lumen is used, blood draws can 
be done via the lumen that is not used for drug administration (see also Section 7.3.12).  
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).  If blood 
samples will be collected on the same day that the infusion bag is being changed, the 
blood samples must be collected before the infusion bag is changed. 
The study specific manuals provide additional details regarding the requirements for 
these procedures. 
Acceptable deviation windows are as follows: 
 
ECGs, biomarker blood draws (cycles 1 – 3), vital signs (incl. pulse oximetry) and 
clinical evaluation:   
 
 15 minute window if collected within the first 24 hours (excluding the 24 hour 
sample) after the start of an infusion (or dose step, if applicable). 
 
 2 hour window if collected between 24 hours and 3 days after the start of an 
infusion (or dose step, if applicable).   
 
Assessments after day 3 should be performed on the indicated study day, but not 
at a certain hour of the day.   
 
 1 day window if collected at D8 or later, or at the EOI.   


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 
Bone marrow assessments post treatment start:  /- 3 days 
 
PK blood draws in cycles 1 - 3:  
 
within two hours prior to treatment start / dose step (if applicable ) 
 
 15 minute window for samples taken within the first 24 hours after start of 
infusion and within 24 hours after EOI.  In case of a dose step, the  15 minute 
window also applies to the samples taken within the first 24 hours after dose 
step.   
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 plasma 
concentrations of AMG 330 and anti-AMG 330 antibodies, as well as blood and bone 
marrow samples for biomarker assessment and biomarker development.  Refer to the 
laboratory manual for detailed collection, processing, and shipping procedures. 
7.2.1 
Screening 
After written informed consent has been obtained, subjects will be screened in order to 
assess eligibility for study participation.  The total screening window is up to 14 days and 
starts on the day that informed consent is obtained.  If a subject has not met all eligibility 
criteria at the end of the 14-day window, the subject will be registered as a screen 
failure.  Subjects who screen fail may be eligible to re-screen per the investigator’s 
discretion.  Laboratory assessments used to determine subject eligibility may be 
repeated once for confirmation during each 14-day screening period before the subject 
is considered a screen failure.  The subject must be re-consented if a re-screening 
attempt occurs outside the 14-day screening period.  The following procedures are to be 
completed during the screening period at the time points designated in the Schedules of 
Assessments (Table 8 – 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 330 can be used as screening assessments and do not need to be repeated 
to confirm subject eligibility. Bone marrow aspirate/biopsies and MRD assessment 
performed as standard of care prior to signature can be used to determine eligibility if 
taken within 21 days prior to start of treatment and after consultation with the Sponsor. 
For subjects enrolling in Group 2, bone marrow aspirate samples are required for  
central MRD testing at screening in addition to local assessment (see Section 7.5.2 
below for further details).  


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If laboratory assessments are repeated during the screening period, the result of the last 
sample taken prior to start of treatment with AMG 330 will be taken into account for 
determination of subject eligibility.   
 
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 measurement 
 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test (females only), and hepatitis serology 
 
Biomarker assessments: 
, immune cell subsets and markers of immune 
system activation, tumor mutation and phenotype analysis, and serum marker 
analysis  
 
Bone marrow aspirate and biopsy (phenotyping and genotyping of AML blasts is 
required for Group 1, and MRD assessment is required for Group 2) 
 
Serious adverse event reporting 
 
Documentation of concomitant and rescue medications.  All prior cancer treatment 
therapies will be collected, and other prior therapies that were being taken as of 
signature of the informed consent should be collected.  Concomitant medications for 
which washout periods have to be observed (refer to Section 4.2) are to be collected 
starting two weeks prior to start of study treatment. For prior therapies, collect 
therapy name, indication, dose, unit, frequency, start date, and stop date. 
7.2.2 
Treatment 
Subjects will be hospitalized for a minimum of 72 hours (R/R AML Group 1 and MDS 
Group 3) or 48 hours (MRD AML Group 2) under the following circumstances: 
 
at the start of the first 2 infusion cycles  
 
at each dose step in cycle 1 
 
at dose increase in case of intra-subject dose escalation 
In addition, subjects will be hospitalized for a minimum of 48 hours after treatment 
interruption requiring restart of treatment in the hospital.  At the start of infusion in the 
first cycle, a hospitalization of 9 to 12 days is recommended for R/R AML subjects in 
Group 1, based on AMG 330 administration schedule.  Starting from cycle 3 and 


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higher, hospitalization is at the discretion of an investigator for all groups.  
Subjects can be hospitalized for a longer time period at the discretion of the investigator.  
If required for logistical reasons (eg, long travel times), subjects may be hospitalized the 
day before dosing (day -1) of any cycle and at the EOI for cycle 1 for required PK 
samples. 
See Section 6.2.1.1 for duration of infusion cycles and infusion-free interval.   
In the second week of cycle 1, subjects will return to the clinic for two visits.  In case of 
21- or 28-day treatment cycles twice weekly visits at the clinic will also be required in the 
third and fourth week (as applicable) week of infusion.  Weekly visits will apply during the 
infusion-free interval.   
Treatment begins on day 1 (cycle 1 day 1) when the first cIV infusion of investigational 
product is administered to a subject.   
The following procedures will be completed during the treatment period at the times 
designated in the Schedules of Assessments (Table 8 – Table 23).   
Note: After each dose step, the assessments described in Table 14 have to be 
performed.  
Investigational product is to be administered after all other protocol-required pre-dose 
assessments have been performed on D1 of each cycle.   
The results of the D1 laboratory tests taken prior to infusion start will not have to be 
available before starting treatment with AMG 330.  Laboratory assessments that were 
done within 24 hours prior to treatment start do not need to be repeated at D1 prior to 
infusion. 
 
Hospitalization 
 
Clinical evaluation 
 
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 
 
Laboratory assessments:  hematology, chemistry, coagulation, urinalysis, and serum 
pregnancy test (females only) 


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 
Biomarker assessments:  
, immune cell subsets and markers of immune 
system activation, MRD, LSCs, tumor mutation and phenotype analysis, and serum 
and plasma marker analysis  
 
AMG 330 PK sample collection 
 
Anti-AMG 330 antibody sample collection 
 
Bone marrow aspirate / biopsy 
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Disease-related event reporting 
 
Documentation of concomitant and rescue medications 
 
MRI (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 
 
For subjects to whom intra-subject dose escalation (see Section 3.1) applies: 
 
Subjects need to be hospitalized for at least 72 hours (R/R AML) or 48 hours 
(MRD AML) at the start of treatment in cycles 1 and 2 
 
ECG assessments should be performed as in cycle 1, 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 
The EOT visit will occur upon documented confirmed disease progression, intolerable 
adverse event, or withdrawal of consent.  See Section 6.2.1.5 for a complete list of 
reasons for permanent treatment discontinuation.  For subjects who choose to 
discontinue investigational product treatment, the EOT visit should occur as soon as 
possible after the last dose of investigational product is administered.  Medically 
significant adverse events, considered related to the investigational product by the 
investigator or the sponsor, will be followed until resolved or considered stable.  The 
following procedures will be completed during the EOT visit as designated in the 
Schedules of Assessments (Table 8 – Table 23) 
 
Clinical evaluation 
 
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 


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 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis 
 
Biomarker assessments: immune cell subsets and markers of immune system 
activation, plasma biomarkers  
 
Anti-AMG 330 antibody sample collection 
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Disease-related event reporting 
 
Documentation of concomitant and rescue medications 
7.2.4 
End of Study Visit 
The EOS visit is a safety follow-up visit that is to be performed at least 4 weeks (or up to 
7 days thereafter) after the last dose of AMG 330 or prior to the initiation of other AML  
therapy whichever occurs earlier.  All efforts should be made to conduct this visit.  If it is 
not possible to conduct the EOS visit, documentation of the efforts to complete the visit 
should be provided in the source documents and noted as not done in the eCRF.   
The following procedures will be completed at the EOS visit as designated in the 
Schedules of Assessments (Table 8 – Table 23). 
 
Clinical evaluation 
 
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 
 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis 
 
Biomarker assessments: immune cell subsets and markers of immune system 
activation, plasma biomarkers  
 
Bone marrow aspirate / biopsy 
 
Anti-AMG 330 antibody sample collection 
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Disease-related event reporting 
 
Documentation of concomitant and rescue medications 


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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 through 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 previous chemotherapy or radiotherapy, 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. Exception: no toxicity 
grade should be recorded for ongoing AML history. 
7.3.4 
Concomitant Medications 
Concomitant therapies 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 two weeks prior to start of study treatment), concomitant medications for which 
washout periods have to be observed (refer to Section 4.2) are to be collected starting 
two weeks prior to start of study treatment. Collect therapy name, indication, dose, unit, 
frequency, route, start date, and stop date.   
7.3.5 
Clinical Evaluation 
7.3.5.1 
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 


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time points specified in the Schedules of Assessments (Table 8 – 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 received investigational product will be 
reported on the Event eCRF. 
7.3.5.2 
ECOG Performance Status 
Subjects will be graded according to the ECOG Performance Status (see Appendix F). 
7.3.5.3 
Height Measurements 
Height in centimeters should be measured without shoes at screening. 
7.3.5.4 
Weight Measurements 
Weight in kilograms should be measured without shoes. 
7.3.6 
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. 
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. 
7.3.7 
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. 


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7.3.8 
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. 
Electrocardiograms should be performed in a standardized method, in triplicate, and 
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: 
 
Three baseline ECGs will be collected  30 minutes apart, with each baseline ECG 
in triplicate run consecutively (ie,  30 seconds apart; 2 sets collected at screening, 
and 1 set collected pre-dose on day 1 [ie, total  9 ECGs]) 
 
Triplicate ECGs at time points after dosing 
Baseline is defined as predose assessments from cycle 1 day 1.  The investigator or 
designated site physician will review all ECGs.  Electrocardiograms will be transferred 
electronically to an ECG central reader for analysis 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. 
7.3.9 
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 8 – 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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Table 24.  List of Analytes 
Chemistry 
Hematology 
Urinalysis 
Coagulation 
Other Labs 
Sodium 
Potassium 
Bicarbonate 
Or  
Total CO2  
Chloride 
Total protein 
Albumin 
Adjusted 
Calcium 
Magnesium 
Phosphorus 
Glucose 
Creatinine 
Total bilirubin 
ALP 
AST 
ALT 
GGT 
Amylase 
Lipase 
CRP 
LDH 
Uric Acid 
Ferritin 
Erythrocytes 
Hemoglobin 
Hematocrit 
MCV 
Platelets 
WBC Differential 
Total Neutrophils 
Seg. Neutrophils 
Lymphocytes 
Atypical Lymphocytes 
Monocytes 
Bands/Stabs 
Eosinophils 
Basophils 
Blasts 
Myeloblasts 
Monoblasts 
Megakaryoblasts 
Promyelocytes 
Myelocytes 
Metamyelocytes 
Nucleated RBC 
Immature 
Granulocytes 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
Ketones 
Microscopic 
exam 
(performed at 
the discretion of 
the investigator) 
PT 
PTT 
INR 
Fibrinogen 
AT III 
Pregnancy testa 
Serology (HepB, 
HepC) 
MRD (for subjects 
with 5 blasts in 
bone marrow; 
Groups 1 and 2) 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; anti-HBc  Hepatitis B core antibody; 
AST  aspartate aminotransferase; AT III  Antithrombin III; CRP  C-reactive protein; 
GGT  gamma-glutamyl transferase; HepBsAg  hepatitis B surface antigen; HepCAb  hepatitis 
C antibody; INR  international normalize ratio; LDH  lactate dehydrogenase; MCV  mean corpuscular 
volume; PT  prothrombin time; PTT  partial thromboplastin time; WBC  white blood cell 
a Serum pregnancy test will be performed for all females unless surgically sterile or  2 years 
postmenopausal. 
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. 
7.3.9.1 
Serum Pregnancy Test 
A serum pregnancy test will be performed locally at each site on all women unless they 
are surgically sterile or  2 years postmenopausal.  On visits where required, the serum 
pregnancy test must be performed prior to dosing with investigational product.  If the 
pregnancy test is positive at day 1 of cycle 1, the subject should not be given 
investigational product.   


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7.3.10 
Events 
Adverse event and serious adverse event  as well as disease-related 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 Section 9.1.1 and Section 9.2.2, 
respectively.  The severity of all events will be graded according to CTCAE, version 4.0 
(Appendix A) unless specified otherwise. Exception: cytokine release syndrome will be 
graded according to the adopted grading system referenced in Lee et al (Blood 2014, 
see Table 7). 
7.3.11 
MRI Cranial 
A contrast-enhanced magnetic resonance imaging (MRI) of the head should be 
considered for subjects who experienced a CNS event Grade 3 or higher, particularly in 
cases of confusion, disorientation or seizures. 
7.3.12 
Pharmacokinetic Blood Sampling 
Blood samples will be obtained for determination of serum concentrations of AMG 330 at 
the time points specified in the Schedules of Assessments (Table 8 – Table 23).  Blood 
must not be drawn from the port catheter.  If a permanent central line with more than one 
lumen is used, blood draws can be done via the lumen that is not used for drug 
administration.  However, the preference is for PK samples to be drawn peripherally.  If 
the PK sample must be drawn through the central line, AMG 330 administration should 
be interrupted during sample withdrawal.   
Sample collection, processing, storage, and shipping instructions are provided in a 
separate laboratory manual. 
7.4 
Antibody Testing Procedures 
Blood samples for antibody testing are to be collected at the time points outlined in the 
Schedules of Assessments (Table 8– Table 23) for the measurement of 
anti-AMG 330 binding antibodies.  Anti-AMG 330 antibodies in serum will be evaluated 
using pre-dose and confirmatory assays.  Samples that are confirmed positive for 
anti-drug antibodies will be tittered to determine the relative levels of anti-drug antibodies 
in the samples.  Additional blood samples may be obtained to rule out 
anti-AMG 330 antibodies during the study. 
Please see the laboratory manual for detailed blood sample collection and handling 
instructions. 


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7.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to investigational product(s) or protocol-required therapies. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 330. 
Peripheral blood, plasma and serum, as well as bone marrow samples will be collected 
from subjects for biomarker analyses at time points specified in the Schedule of 
Assessments (Table 8 – Table 23).  Potential analyses that may be performed include, 
but are not limited to serum and plasma markers, 
, evaluation of immune cell 
subsets and activation status, MRD assessment, and LSCs as described below. 
7.5.1 
Bone Marrow Aspirate and Biopsy Assessments 
Bone marrow aspirate / biopsy samples (20 mL) will be collected for biomarker analyses 
at time points specified in the Schedule of Assessments (Table 8 – Table 23).  At 
screening, aspirate and biopsy samples should be obtained.  If aspirate is fully 
evaluable, aspirate can be used for all further assessments. 
Bone marrow aspirate/biopsy will be performed for the following: 
 
Cytology and cytochemistry to establish WHO subtype of AML – at screening only 
 
Immunological phenotyping to verify myeloid leukemia and assessments of MRD (for 
subjects with 5 blasts in bone marrow) and LSCs. 
 
Standard cytogenetics (gene expressions, gene mutations, cell culture and banding 
analysis) – mandatory at screening only.   
 
Tumor mutational analyses and T cell receptor analyses (peripheral blood 
mononuclear cells [PBMCs] will be used as control). 
Previous bone marrow aspirate/biopsy samples obtained prior to ICF signature but 
within 21 days of day 1 may be used to determine eligibility provided the subject has not 
received treatment for their leukemia (excluding hydroxyurea to control blast counts) 
since the aspirate/biopsy was obtained. 
A bone marrow biopsy and aspirate for central laboratory assessments will still be 
required during screening for all subjects including those for whom a historical result was 
used to determine eligibility.   


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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 
Phenotyping and Genotyping of AML Blasts and 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 PCR based techniques for molecular markers is applicable 
only in a minority of cases.  Immunophenotypical detection of MRD is analyzed in one 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), the asynchronic 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 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 approximately 1 malignant cell among 1,000 to 10,000 normal cells by flow 
cytometry, 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.   


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In this study, MRD assessments 
 
. For subjects enrolling in Group 1, 
bone marrow sample for phenotyping and genotyping of AML blasts at baseline is only 
required for central testing; local testing is optional. 
 
. 
For subjects enrolling in Group 4 and 5, central testing is not required; local testing is 
optional. 
7.5.2.1 
MRD Testing for Screening/Eligibility for Subjects in Group 2  
For subjects to be eligible for study participation in Group 2, bone marrow aspirate is 
required prior to enrollment to establish MRD status. 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 with a 
minimum 10-3 sensitivity at a CLIA certified laboratory (for US only) agreed upon by the 
Sponsor as listed in Table 15 (Section 7.3.9); local testing is sufficient for the enrollment 
decision, if the test result is from  21 days from the start of treatment. Additional bone 
marrow aspirate from the first bone marrow pull is required to be sent for testing at 
central lab and retrospective analysis for all subjects enrolled in Group 2. Timing of 
sample collection is described in in the Schedule of Activities. 
7.5.2.2 
MRD Testing During Treatment  
After treatment initiation, subsequent MRD sample collections for central lab testing may 
be taken at the same time as the bone marrow aspirate collections for disease response 
assessment as indicated in the Schedule of Assessments, which is based on the 
following guidelines:  
 
Group 1: For subjects that achieve peripheral blood blast counts during hematology 
assessment after completion of the first and/or second cycle of AMG 330, or when PI 
suspects a CR, bone marrow aspirates will be collected for MRD status 
determination alongside disease assessment prior to initiation of the subsequent 
cycle. For patients who achieve CRi, additional bone marrow samples will be taken 
upon count recovery for MRD[-]CR status determination.  For patients with confirmed 
CR, additional bone marrow aspirates for MRD status determination will be collected 
every cycle thereafter or when clinically indicated, until blast counts in whole blood 
rise above 0 and/or subject shows signs of clinical progression. 
 
Group 2: Bone marrow aspirates for MRD status determination will be collected after 
completion of every cycle or when clinically indicated, until blast counts in whole 
blood rise above 0 and/or subject shows signs of clinical progression. 


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Exploratory MRD assessments 
In addition to immunophenotypical detection of minimal residual disease (MRD), this trial 
will also utilize next-generation sequencing (NGS) to detect the persistence of 
AML-associated mutations with a targeted-gene approach. 
 
 
 
 
 
7.6 
Disease Response 
For R/R AML (Group 1 and Group 4 in Phase 1a), disease response assessments will 
be based upon review of cytogenetics, bone marrow aspirates/biopsies, and peripheral 
blood count.  In subjects refusing bone marrow aspirates/biopsies collection after 
completing treatment, lack of disease response may be documented by the presence of 
blasts in peripheral blood or in other tissues or fluids (eg, in cerebrospinal fluid collected 
by lumbar puncture).  
Response categories are defined as follows (Appendix E and Topp et al., 2015): 
CR: 
 
less than 5 blasts in the bone marrow 
 
absence of blasts with Auer rods 
 
absence of extramedullary disease 
 
absolute neutrophil count (ANC)  1,000/l  
 
platelet count  100,000/l  
 
independence of red cell transfusions 
CRi 
 
all CR criteria except for incomplete recovery of peripheral blood counts (residual 
neutropenia [ 1,000/l] or thrombocytopenia [100,000/l])  
Morphologic leukemia-free state 
 
less than 5 blasts in the bone marrow  
 
absence of blasts with Auer rods 
 
absence of extramedullary disease 
 
no hematologic recovery required 


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CRh 
 
less than 5 blasts in the bone marrow 
 
no evidence of disease 
 
partial recovery of peripheral blood counts: platelet count  50,000/l, and 
ANC  500/l 
 
no extramedullary disease 
Partial Remission (PR) 
 
relevant in the setting of phase I and II clinical trials only 
 
all hematologic criteria of CR 
 
decrease of bone marrow blast percentage to 5 to 25 
 
decrease of pretreatment bone marrow blast percentage by at least 50 
Response must be established from a bone marrow sample supplemented with 
neutrophil and platelet counts.   
For R/R AML subjects enrolled in Group 5 (Phase 1a) and all R/R AML Groups in 
Phase 1b, disease response assessment will be based on ELN recommendations from 
an international expert panel and FDA guidance (Appendix E, Dohner et al, 2017).  
Response: 
 
CR without minimal residual disease (CRMRD-) 
 
Complete remission (CR) 
 
CR with partial hematological recovery (CRh) 
 
CR with incomplete hematological recovery (CRi) 
 
Morphologic leukemia-free state (MLFS) 
 
Partial remission (PR) 
Treatment failure: 
 
Primary refractory disease 
 
Death in aplasia 
 
Death from indeterminate cause 
Response criteria for clinical trials only: 
 
Stable disease 
 
Progressive disease (PD) 


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Relapse: 
 
Hematologic relapse (after CRMRD–, CR, CRi) 
 
Molecular relapse (after CRMRD–) 
For MRD AML subjects who enroll in Group 2, the conversion from MRD-positive status 
to MRD negative, is defined as MRD threshold below 0.1 as per ELN 
recommendations (Schuurhuis et al., 2018). In addition,
Response categories are defined as below: 
 
MRD conversion (MRD positive change to MRD negative) 
 
No MRD response (MRD remains positive) 
 
Molecular relapse (previous MRD negative response changes to MRD positive 
status) 
For MDS subjects (Group 3), disease response assessments will be based upon review 
of cytogenetics ( Appendix L, Appendix M), bone marrow aspirates/biopsies, and 
peripheral blood count.  Response categories are defined as follows (Appendix K and 
Cheson, Blood 2006): 
Complete remission  
 
Bone marrow: 5 myeloblasts with normal maturation of all cell lines 
 
Persistent dysplasia will be noted 
 
Peripheral blood 
 
Hgb 11 g/dL 
 
Platelets 100 x 109/L 
 
Neutrophils 1.0 x 109/L 
 
Blasts 0 
Partial remission  
 
All CR criteria if abnormal before treatment except: 
 
Bone marrow blasts decreased by 50 over pretreatment but still 5 
 
Cellularity and morphology not relevant 
Marrow CR 
 
Bone marrow: 5 myeloblasts and decrease by 50 over pretreatment 
 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR 
Stable disease  
 
Failure to achieve at least PR, but no evidence of progression for 8 wks 


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Relapse after CR or PR  
 
At least 1 of the following: 
 
Return to pretreatment bone marrow blast percentage 
 
Decrement of 50 from maximum remission/response levels in granulocytes or 
platelets 
 
Reduction in Hgb concentration by  1.5 g/dL or transfusion dependence 
Cytogenetic response  
 
Complete 
 
Disappearance of the chromosomal abnormality without appearance of new ones 
 
Partial 
 
At least 50 reduction of the chromosomal abnormality 
Disease progression  
 
For patients with: 
 
Less than 5 blasts: 50 increase in blasts to 5 blasts 
 
5-10 blasts: 50 increase to 10 blasts 
 
10-20 blasts: 50 increase to 20 blasts 
 
20-30 blasts: 50 increase to 30 blasts 
 
Any of the following: 
 
At least 50 decrement from maximum remission/response in granulocytes or 
platelets 
 
Reduction in Hgb by 2 g/dL 
 
Transfusion dependence 
 
Death 
7.7 
Blood and Bone Marrow Samples 
Blood and bone marrow samples are to be collected for biomarker development, and 
safety and response assessments at time points specified in the Schedule of 
Assessments (Table 8 – Table 23).   
Samples will be investigated by local and central laboratories as follows: 
Assessments of chemistry, hematology, and coagulation, urinalysis, pregnancy tests, 
serology, bone marrow cytology and cytochemistry to establish WHO subtype of AML, 
as well as bone marrow standard cytogenetics and assessments to determine treatment 
response will be performed by local laboratories.   


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The following assessments will be performed by central laboratories:  
anti-AMG 330 antibody, PK, biomarkers, bone marrow and blood immunological 
phenotyping (incl. immune cell subsets, MRD, LSCs), bone marrow mutational analyses, 
and pharmacogenetics (optional). 
Refer to the laboratory manual for detailed collection and handling procedures for all 
blood samples. 
7.8 
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 330.  For subjects who 
consent to this/these analysis/analyses, DNA may be extracted from a saliva sample. 
7.9 
Sample Storage and Destruction 
Any blood, biomarker, PK, cytogenetic, and bone marrow aspirate and biopsy samples 
collected according to the Schedule of Assessments (Table 8 – 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 330, characterize antibody 
response, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained, but are 
not necessarily reported as part of this study.  Samples can be retained for up to 
20 years. 


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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 or other protocol required therapies and must discuss with 
the subject the options for continuation of the Schedules of Assessments 
(Table 8 – Table 23)  including different options of follow-up (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
treating physicians, from the review of medical records) and collection of data, including 


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endpoints, adverse events, disease related events, and device related events, as 
applicable.  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, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) include any of the 
following: 
 
Subject request 
 
Safety concern (eg, due to an adverse event, non-compliance, requirement for 
alternative therapy, or pregnancy) 
 
Death 
 
Lost to follow-up 
 
Confirmed disease progression as defined by revised IWG response criteria and 
ELN response criteria (Appendix E, Appendix K and Appendix M) or disease 
progression accompanied by worsening of symptoms or deterioration of the subject’s 
general condition 
 
Protocol specified criteria: 


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 
Proceeding to HSCT 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
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 
Disease-related Events 
Disease-Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease (see Appendix G for a list of expected 
disease-related events).   
Disease-Related Events that do not qualify as Serious Adverse Events: 
 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease-Related Event. 
Disease-Related Events that would qualify as an Adverse Event or Serious Adverse 
Event:  
 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator for the subject`s condition, or if the investigator believes there is a 
causal relationship between the investigational product(s)/study treatment/protocol 
required therapies and disease worsening must be reported as an Adverse Event or 
Serious Adverse Event. 
 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease (eg, 
diabetes, migraine headaches, or gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 


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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.   
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).  If a new primary malignancy appears, it will be considered an adverse event. 
Note:  The adverse event term “disease progression” should not be used to describe the 
disease-related event or adverse event.  
The investigator’s clinical judgment is used to determine whether a subject is to 
be removed from treatment due to an adverse event.  In the event a subject, or 
subject’s legally acceptable representative requests to withdraw from 
protocol-required therapies or the study due to an adverse event, refer to 
Section 8.1 for additional instructions on the procedures recommended for safe 
withdrawal from protocol-required therapies or the study. 
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.   
9.1.3 
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.  
Product complaints are described in Section 6.8.   


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9.1.4 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease-Related Event as 
defined in Section 9.1.1): 
 
Fatal 
 
Life threatening (places the subject at immediate risk of death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect 
 
Other medically important serious event 
A Disease-Related event (eg, related to disease progression) is to be reported as a 
serious adverse event if: 
 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
 
if the investigator believes a causal relationship exists between the investigational 
product(s)/protocol-required therapies and the event, 
 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Reporting Procedures for Disease-related Events 
The investigator is responsible for ensuring that all Disease-Related Events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product through the EOS are recorded on the Event CRF as a Disease-Related Event.  
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious 
disease-related event data to the sponsor within 24 hours of it being available. 


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Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product, and determined to be serious, must be 
recorded on the Event CRF as Serious Adverse Event. 
Additionally, the investigator is required to report a fatal Disease-Related Event on the 
Event CRF as a Disease-Related Event.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
product through the EOS are reported using the applicable eCRF (eg, EventCRF). 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity (and/or toxicity per protocol), 
 
Assessment of relatedness to investigational product, medical devices, or other 
protocol-required therapy, 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.  The investigator must assess 
whether the adverse event is possibly related to the investigational product or medical 
device(s).  This relationship is indicated by a “yes” or “no” response to the question:  Is 
there a reasonable possibility that the event may have been caused by the 
investigational product or medical device(s)?   
The investigator must assess whether the adverse event is possibly related to any study 
mandated activity or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by a study activity/procedure?  The investigator is responsible for reviewing 
laboratory test results and determining whether an abnormal value in an individual study 
subject represents a clinically significant change from the subject’s baseline values.  In 
general, abnormal laboratory findings without clinical significance (based on the 
investigator's judgment) are not to be recorded as adverse events.  However, laboratory 
value changes that require treatment or adjustment in current therapy are considered 


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adverse events.  Where applicable, clinical sequelae (not the laboratory abnormality) are 
to be recorded as the adverse events. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.   
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last dose of investigational product or the EOS visit 
(whichever is 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 knowledge of the event via the Event CRF. 
Expected disease related serious events (see Appendix G) will be entered into the Event 
eCRF.  However, disease related events will not be reported to Amgen individually in an 
expedited manner (within 24 hours of awareness of these events) as they are 
anticipated to occur in the study population at some frequency independent of the 
protocol required therapy.  The DLRT will monitor for these events at their regular 
meetings. 
After the protocol-required adverse event reporting period defined above, the 
investigator does not need to actively monitor subjects for serious adverse events.  
However, these serious adverse events should be reported to Amgen.  In some 
countries (eg, European Union [EU] member states), investigators are required to report 
serious adverse events that they become aware of after end of study.  If serious adverse 
events are reported, the investigator is to report them to Amgen within 24 hours following 
the investigator’s knowledge of the event. Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting. 
The serious adverse event must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the applicable CRF.  If the electronic data 
capture (EDC) system is unavailable to the site staff to report the serious adverse event, 
the information is to be reported to Amgen via an electronic Serious Adverse Event 
(eSAE) Contingency Report Form within 24 hours of the investigator’s knowledge of the 
event.  See Appendix B for a sample of the eSAE Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 


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the eSAE Contingency Report Form, the data must be entered into the EDC system 
when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
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? 
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure? 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product/activity/procedure 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 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable eCRF (eg,  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 GCP.   
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is 
required to proactively follow each subject at subsequent visits/contacts.  All 


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adverse events and serious adverse events will be followed until resolution, 
stabilization, until the event is otherwise explained, or the subject is lost to 
follow-up. 
All new information for previously reported serious adverse events must be sent 
to 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. 
9.2.2.4 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety 
surveillance and signal management process.  
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies 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 30 days after the last dose of protocol-required 
therapies.   
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C). Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If 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 lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below. 


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In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 30 days after the last dose of protocol-required 
therapies. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
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: subject incidence and grade of adverse events and DLTs  
Secondary Endpoints:   
 
PK parameters:  half-life, steady state concentration, volume of distribution and 
clearance of AMG 330 
 
Incidence of anti-AMG 330 antibody formation 
 
Efficacy parameters for R/R AML:  response rate (response defined as 
CR/CRi/morphologic leukemia-free state [per modified IWG criteria] or CRh), 
duration of response, time to progression, time to response  
 
Efficacy parameters for MRD-positive AML: response rate (response defined as 
conversion from MRD status with 0.1 threshold to MRD-), duration of response, 
time to response 
 
Efficacy parameters for MDS: response rate (response defined as CR or marrow 
complete remission [per International Working Group (IWG) standardized response 
criteria]), duration of response, time to progression, time to response 
Exploratory Endpoints:   
 
Depletion of LSCs 
 
MRD response  
 
Lymphocyte counts, CD33 monocytes and T cells, as well as T cell activation 
(including T cell subsets).  Other immune subsets may also be examined.   
 
 


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 
Changes in serum cytokine levels  
 
Frequency and severity of CRS and other AEs given alternative CRS prophylaxis in 
combination with optimized dose step approaches of AMG330 
 
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 330. 
The analysis of DLT will be restricted to DLT-evaluable subjects (see Section 6.2.1.4 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. 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses.  The analyses of biomarkers may be performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints. 
10.2 
Sample Size Considerations 
It is anticipated that approximately 256 subjects will be enrolled in this study. For the 
dose escalation cohorts, approximately 70 subjects will be enrolled in Group 1 
(R/R AML), up to 36 subjects will be enrolled in Group 2 (MRD) and up to 36 subjects 
will be enrolled in Group 3 (MDS).  Up to 30 additional subjects will be enrolled in a dose 
expansion cohort for each group (up to 90 additional subjects total).  Approximately 
24 subjects will be enrolled in the Groups 4 and 5 , 6 subjects for each arm in Group 4 
and 6-12 subjects in Group 5. 
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.  


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With 3 subjects per cohort, there is a 27-70 probability of observing at least one DLT if 
the true DLT rate is 10-33 and with 6 subjects per cohort, there is a 47-91 probability. 
In the dose expansion cohorts, a subject number of 10 will provide a 65 probability of 
observing at least one adverse event with10 incidence rate and 89 probability of 
observing at least one adverse event with 20 incidence rate. 
Assuming a response rate of less than 5 and at least one subject having a response in 
the first 10 subjects for the enrollment to continue in the expansion cohort, there is 
greater than 59 chance of stopping the expansion cohort.  
Assuming a response rate of greater than 20 and at least one subject having a 
response in the first 10 subjects for the enrollment to continue in the expansion cohort, 
there is less than 11 chance of stopping the expansion cohort.  A sample of 
30 subjects would provide a 96 probability of observing at least one adverse event, 
when the incidence of the adverse event is 10.  A sample of 30 subjects would provide 
a 100 probability of observing at least one adverse event, when the incidence of the 
adverse event is 20.  An exact 80 binomial confidence interval (CI) will be provided 
for overall response rate.  With the 10 subjects and 20 overall response rate, the 
expected 80 CI would be 5.5 to 45.0 with the half-width 19.8. 
Assuming a sample of 30 subjects and 20 overall response rate, the expected 80 CI 
would be 10.9 to 32.5 with the half-width 10.8. 
10.3 
Planned Analyses 
The following data analyses are planned:  (1) dose decision analyses in the 
dose-escalation cohorts, (2) interim analyses for safety and preliminary efficacy updates, 
(3) data analysis prior to public disclosures (eg, scientific meetings), (4) the primary 
analysis after all dose-escalation and dose-expansion subjects have completed 
6 months of treatment, and (5) the final analysis after all subjects have ended the study. 
10.3.1 
Interim Analysis and Early Stopping Guidelines 
Interim analyses are planned after all subjects in each indication and each phase 
have ended the study eg, for R/R AML:  all subjects enrolled in Group 1 phase 1a, 
Groups 4 and 5 have ended the study.  Interim analyses may be combined if the 
analysis timing is close or if the number of subjects in each indication or phase is 
small.   


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Ad-hoc interim analyses for safety and preliminary efficacy updates will be performed.  
Data analysis prior to public disclosures (eg, scientific meetings) will also be performed.  
Safety data will be reviewed on an ongoing basis.  Amgen, in consultation with the site 
investigators, will review in DLRMs all available cumulative data by indication prior to 
making dose escalation decisions.  Adverse events and DLTs observed in all subjects 
will be evaluated continually by indication and fully integrated into all DLRMs and 
considered in all enrollment and dosing decisions. 
Enrollment of a cohort can be suspended at any time based on safety findings at any 
dose level and in the expansion cohort, if at any time  33 of subjects treated at the 
MTD (including those treated at the MTD in the expansion phase) or RP2D experience a 
DLT within the DLT window, and a DLRM will be convened.  In addition, the study may 
be discontinued or modified at any time due to documented safety findings. 
10.3.2 
Dose Level Review Team (DLRT) 
For each group, DLRMs will be held to review data, monitor safety, and make 
recommendations on dose escalation / change, or changes in pre-medication.  The 
DLRT will be composed of the investigators or designees, and the following Amgen 
representatives: early development leader, medical monitor, global safety officer or 
designee, clinical study manager, biostatistician, PK scientist (optional), and other 
functional area representatives as appropriate.  A quorum as defined below must be in 
attendance for the DLRM.  The quorum is defined as  50 of the participating 
investigators 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 required voting members of the DLRT include: investigators, Amgen medical 
monitor, early development leader, and global safety officer or designee. 
The following recommendations can be made by the DLRT: 
 
dose escalation / de-escalation decisions  
 
expansion of a cohort 
 
continuation, delay or termination of dosing 
 
implementation of dose step(s) 
 
extension of the run-in phase in case of dose step(s) 


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 
extension of the duration of treatment cycles 
 
implementation of mandatory steroid pre-treatment in case of cytokine release 
syndrome-related adverse events 
 
enrollment of additional subjects in the expansion cohort 
 
duration of the DLT period based on emergent safety data 
 
level and duration of dose steps (schedule) adjustment based on available safety, 
PK, and PD data 
All available study data, including demographics, IP 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.  Data 
will not need to be source data verified and queries will not need to be resolved prior to 
the DLRM. 
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 the first 5 subjects have at least completed their first 
treatment cycle plus two weeks or dropped out of treatment / study, whichever occurs 
earlier. Once the first 10 subjects have at least completed their first treatment cycle plus 
two weeks or dropped out of study, all available study data will be reviewed by the DLRT 
to determine if additional (up to 20) subjects may be enrolled.  If additional subjects are 
enrolled after the first 10 subjects, all available study data will be reviewed (with 
recruitment ongoing) by the DLRT after every 5 subjects have at least completed their 
first treatment cycle plus two weeks or dropped out of treatment / study.  Ad hoc 
meetings may be convened any time in case of important safety events (see also 
Section 10.3.1). 
10.3.3 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or terminated the study early. 
10.3.4 
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 approximately 6 months after enrollment of the last study subject. 


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10.4 
Planned Methods of Analysis 
10.4.1 
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. All analyses will be conducted by Group. 
10.4.2 
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 330. 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  The number and percentage of subjects reporting 
adverse events will be evaluated overall and by Group and by dose level.  Adverse 
events will also be tabulated by relationship to study drug. 
Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required therapies, and 
treatment-emergent adverse events will also be provided.  All summary of adverse 
events will include disease-related events. 
Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be listed 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 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 listed 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. 


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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 group will be 
summarized. 
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized. 
All on-study ECG data will be listed, and select parameters of interest may be plotted. 
10.4.3 
Secondary Endpoints 
10.4.3.1 
Pharmacokinetics Data Analysis 
For AMG 330, pharmacokinetic parameters half-life, steady-state concentration, volume 
of distribution, and clearance) 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 330 exposure and either pharmacodynamic effect and/or 
clinical outcome may also be performed. 
10.4.3.2 
Efficacy Endpoint Analyses 
Listings will be produced for all subjects in the dose-escalation cohorts and the 
dose-expansion cohorts indicating the time to progression, time to response, and 
duration of response for each Group.  The proportion of subjects with a response with 
corresponding exact 80 CI will be calculated using the Clopper-Pearson method 
(Clopper and Pearson, 1934) and tabulated for subjects treated at the MTD.  The 
proportion of subjects that are progression free at 6 months with corresponding exact 
80 CI will be calculated using the Clopper-Pearson method.  Kaplan Meier curve may 
be presented for time to progression with estimates for rates and 80 CI at selected 
weeks.  Statistical analyses of efficacy endpoints will be considered exploratory. 
10.4.3.3 
Anti-AMG 330 Antibodies 
The incidence and percentage of subjects who develop anti-AMG 330 antibodies 
(binding) at any time will be tabulated by Group and dose level. 
Positive anti-AMG 330 antibody data will be listed and reviewed for each subject.  
Summaries of positive anti-AMG 330 antibody test results over time may be provided.  


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The impact of immunogenicity on safety will also be reviewed by assessing adverse 
events and serious adverse events.   
10.4.4 
Exploratory Endpoints 
The following statistical analyses will be considered exploratory and will be performed 
only when deemed appropriate.  Relationships between changes in tumor dynamics and 
above biomarkers of interest listed as exploratory endpoints will be explored.  Changes 
in expression levels of biomarkers and their relationship to dose may also be explored.  
Summary statistics over time will be provided and graphical presentations may be used.  
The relationship between AMG 330 exposure and PD effects and related biomarkers in 
blood, or tumor specimens and/or AMG 330 exposure and clinical outcomes (eg, tumor 
response) will be also explored if deemed appropriate.  Frequency and severity of CRS 
will be tabulated by Group (and by Arm if applicable). Details of analysis will be provided 
in a supplemental analysis plan for exploratory biomarker analysis. 
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 Clinical Study Manager to the investigator.  The 
written informed consent document is to be prepared in the language(s) of the potential 
subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/are 
administered. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  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 


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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 ICF 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 / Amgen (as applicable according to local laws and regulations)must 
submit and, where necessary, obtain approval from the IRB/IEC for all subsequent 
protocol amendments and changes to the informed consent document.  The 
investigator / Amgen is to notify the IRB/IEC of deviations from the protocol or serious 
adverse events occurring at the site and other adverse event reports received from 
Amgen, in accordance with local procedures. 
The investigator / Amgen (as applicable according to local laws and regulations) 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 if applicable. 
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, age 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.   


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 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and age (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 regulations/International Conference on Harmonisation (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. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  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 to Amgen, if applicable. 
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 study contract.  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, if 
applicable. 
Subjects may be eligible for continued treatment with Amgen IP by an extension protocol 
or as provided for by the local country’s regulatory mechanism.  However, Amgen 


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reserves the unilateral right, at its sole discretion, to determine whether to supply Amgen 
IP(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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed eCRFs, ICFs, and subject identification list   
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen   
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable.  
 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable.   
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 


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The Amgen clinical monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The clinical monitor is to have access to subject medical records and other 
study related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, or laboratories) and review of study related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available.   
 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”.   
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer.   
 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the eCRF, and 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 
Schedules of Assessments (Table 8 –Table 23), the investigator can search publically 
available records (where permitted) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible. 


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12.5 
Language 
Electronic CRFs must be completed in English.  TRADENAMES (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
12.6 
Publication Policy 
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, 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 
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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13. 
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Dohner H, Estey E, Grimwade D, et al.  Diagnosis and management of AML in adults: 
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Estey E, de Lima M, Tibes R, et al.  Prospective feasibility analysis of reduced-intensity 
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Freeman SD, Virgo P, Couzens S, et al.  Prognostic relevance of treatment response 
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Gil-Perez A, Montalban-Bravo G.  Management of myelodysplastic syndromes after 
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Greenberg PL, Tuechler H, Schanz J, et al.  Revised international prognostic scoring 
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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. 
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by real-time quantitative PCR in acute myeloid leukemia with CBFB-MYH11 
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addressing Ockham's razor: mTPI-2. Contemporary Clinical Trials. 2017; 58, 23-33. 
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syndrome and failure of therapy with hypomethylating agents:  an emerging entity with a 
poor prognosis.  Clin Lymphoma Myeloma Leuk.  2014;14:93-97. 
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mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from 
myelodysplastic syndrome after azanucleoside failure.  Leuk Res.  2014;38:443-446. 
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management of cytokine release syndrome. Blood 2014;124(2):188-195 
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etanercept and thrice weekly rituximab in relapsed CLL/SLL:  clinical activity in the 
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Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: A historical perspective. 
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Topp MS, Gökbuget N, Zugmaier G, et al. Phase II Trial of the Anti-CD19 Bispecific 
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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events Version, version 4 (CTCAE V 4) 
is available at the following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.   
Drug-induced Liver Injury Reporting & Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT, 
ALP and TBL 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 eCRF (eg, Event eCRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen.   
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.4.1 and 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 TBL  2 x ULN or INR  1.5, retesting of liver tests, bilirubin (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. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count with differential to assess for eosinophilia 


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


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Appendix B.  Electronic Serious Adverse Event Contingency Form 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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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, 2010) 
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 t(15;17)(q22;q12); PML-RARA* 
AML with t(9;11)(p22;q23); MLLT3-MLL† 
AML with t(6;9)(p23;q34); DEK-NUP214 
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 
Provisional entity:  AML with mutated NPM1 
Provisional entity:  AML with mutated CEBPA 
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 
Acute erythroid leukemia 
Pure erythroid leukemia 
Erythroleukemia, erythroid/myeloid 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis (syn.: acute myelofibrosis; acute myelosclerosis) 
Page 1 of 2 
Footnote defined on next page of table 


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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); MLL rearranged 
Mixed phenotype acute leukemia, B/myeloid, NOS 
Mixed phenotype acute leukemia, T/myeloid, NOS 
Provisional entity: NK–cell lymphoblastic leukemia/lymphoma 
Page 2 of 2 
Adopted from Dohner et al, 2010; 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;AMLwith 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 for AML 
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 partial 
hematological 
recovery (CRh)a 
All CR criteria, except for abosulute neutrophil count 
 0.5 x 109/L and platelet count  50 x 109/L but the count 
recovery criteria for CR are not met 
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 I and II 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 II/III trials), or 
failure to achieve CR, CRi, or PR (phase I 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 
aSource:  FDA Guidelines, 2020 
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 I 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. 


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Progressive Diseasea 
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. 
a Patients may remain on study treatment if the investigator believes the patient is deriving some benefit. 
Relapse Criteria 
Relapse after complete remission 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 2009 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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CONFIDENTIAL 
 
 
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.  Expected Disease-related Events by System Organ Class (SOC) 
System Organ Class (SOC)  
Disease-related Events  
Blood and lymphatic system disorders  
Febrile neutropenia, anaemia, neutropenia, 
thrombocytopenia, leukopenia, leukocytosis, 
disseminated intravascular coagulation  
Cardiac disorders  
Palpitations, tachycardia  
Ear and labyrinth disorders  
Ear pain, tinnitus  
Eye disorders  
Blurred vision, photophobia  
Gastrointestinal disorders  
Abdominal distention, abdominal pain, 
constipation, diarrhoea, gingival pain, nausea 
General disorders and administration site 
conditions  
Fatigue, pyrexia, malaise, pain, chest pain  
Infections and infestations  
Infections1, sepsis  
Investigations  
Alanine aminotransferase increased, aspartate 
aminotransferase increased, alkaline 
phosphatase increased, white blood cell count 
decreased, haemoglobin decreased, platelet 
count decreased  
Metabolism and nutrition disorders  
Decreased appetite, hypokalaemia, 
hyponatraemia, hypomagnesaemia, 
hypophosphataemia, hypocalcaemia, 
hyperuricaemia 
Musculoskeletal and connective tissue 
disorders  
Skeletal pain, muscular pain, arthralgia, 
generalized muscle weakness, neck pain  
Nervous system disorders  
Cranial nerve disorder, dizziness, headache, 
lethargy, meningismus, syncope  
Respiratory, thoracic and mediastinal 
disorders  
Cough, dyspnea, epistaxis, pleuritic pain  
Other  
Haemorrhage2 
1 Represents preferred terms under Infections and infestations SOC 
2 Represents haemorrhage HLGT preferred terms contained within multiple SOCs 
Coded:  MedDRA v17.0  


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Appendix H.  mTPI-2 Guidelines for Dose Escalation/De-escalation 


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Appendix I.  2016 WHO Myelodysplastic Syndrome Subtypes 
Name  
Dysplastic 
Lineages 
Cytopenias* 
Ring 
sideroblasts 
as  of 
marrow 
erythroid 
elements 
BM 
and 
PB blasts 
Cytogenetics 
by 
conventional 
karyotype analysis 
MDS with 
single 
lineage 
dysplasia 
(MDS-SLD) 
1 
1 or 2 
15/5 ¶ 
BM 5, 
PB 1, 
no Auer 
rods 
Any, unless 
fulfills all criteria 
for MDS with 
isolated del(5q) 
MDS with 
multilineage 
dysplasia 
(MDS-MLD) 
2 or 3 
1 or 3 
15/5 ¶ 
BM 5, 
PB 
1, no 
Auer rods 
Any, unless fulfills 
all criteria for MDS 
with isolated 
del(5q) 
MDS with ring sideroblasts (MDS-RS) 
MDS-RS 
with 
single 
lineage 
dysplasia 
(MDS-
RSSLD) 
1 
1 or 2  
15/5 ¶ 
BM 5, 
PB 
1, no 
Auer rods 
Any, unless 
fulfills all criteria 
for MDS with 
isolated del(5q) 
MDS-RS 
with 
multilineage 
dysplasia 
(MDS-
RSMLD) 
2 or 3 
1 to 3 
15/5 ¶ 
BM 5, 
PB 
1, no 
Auer rods 
Any, unless 
fulfills all criteria 
for MDS with 
isolated del(5q) 
MDS with 
isolated del 
(5q) 
1 to 3 
1 to 2 
None or any 
BM 5, 
PB 
1, no 
Auer rods 
del(5q) alone or 
with 1 additional 
abnormality except 
–7 or del (7q) 
MDS with excess blasts (MDS-EB) 
MDS-EB-1 
0 to 3 
1 to 3 
None or any  
BM 5 to 
9 or PB 2 
to 
4, no 
Auer 
rods 
Any  
MDS-EB-2 
0 to 3 
1 to 3 
None or any 
BM 10 to 
19 or PB 
5 to 19 
or Auer 
rods 
Any  
Page 1 of 2 
Footnotes defined on next page of table 


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Appendix I.  2016 WHO Myelodysplastic Syndrome Subtypes 
Name  
Dysplastic 
Lineages 
Cytopenias* 
Ring 
sideroblasts 
as  of 
marrow 
erythroid 
elements 
BM 
and 
PB blasts 
Cytogenetics 
by 
conventional 
karyotype analysis 
MDS, unclassifiable (MDS-U) 
With 1 
blood blasts 
1 to 3 
1 to 3 
None or any 
BM 5, 
PB  1, Δ 
no Auer 
rods 
Any 
With single 
lineage 
dysplasia 
and 
pancytopenia 
1 
3 
None or any 
BM 5, 
PB 1, 
no Auer 
rods 
Any  
Based on 
defining 
cytogenetic 
abnormality 
0 
1 to 3 
15 ◊ 
BM 5, 
PB 1, 
no Auer 
rods 
MDS-defining 
abnormality 
Refractory 
cytopenia of 
childhood 
1 to 3 
1 to 3 
None 
BM 5, 
PB 2 
Any 
Page 2 of 2 
BM: bone marrow; PB: peripheral blood; MDS: myelodysplastic syndrome 
* Cytopenias defined as: hemoglobin, 10 g/dL; platelet count, 100 x 10 /L; and absolute neutrophil count, 
1.8 x 10 /L. Rarely, MDS may present with mild anemia or thrombocytopenia above these levels. 
Peripheral blood monocytes must be 1 x 10 /L.  If SF3B1 mutation is present. 
Δ One percent peripheral blood blasts must be recorded on at least 2 separate occasions. 
◊ Cases with 15 ring sideroblasts by definition have significant erythroid dysplasia, and are classified as 
MDS-RS-SLD. 


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Appendix J.  Revised International Prognostic Scoring System (IPSS-R) in MDS 
 
Score 
Prognostic 
variable 
0 
0.5 
1.0 
1.5 
2.0 
3.0 
4.0 
Cytogenetics* 
Very good 
 
Good 
 
Intermediate 
Poor 
Very poor 
Bone marrow 
blast (percent) 
2 
 
2 to 5 
 
5 to 10 
10 
 
Hemoglobin 
(g/dL) 
10 
 
8 to 10 
8 
 
 
 
Platelets 
(cells/microL) 
100 
 
50 
 
 
 
 
Absolute 
neutrophil count 
(cells/microL) 
0.8 
 
 
 
 
 
 
This scoring system was applied to an initial group of 7012 patients with primary MDS by 
the French American-British classification who had at least two months of stable blood 
counts, 30 percent bone marrow blasts and 19 percent peripheral blood blasts, and 
who were observed until progression to AML transformation or death (did not receive 
disease-modifying agents for MDS). Patients could be stratified into five groups with the 
following estimated overall survival and progression to AML. 
Risk Group  
IPSS-R Score 
Median Overall Survival 
(years) 
Median time to 25 percent 
AML evolution (years) 
Very low 
1.5 
8.8 
14.5 
Low 
1,5 to 3.0 
5.3 
10.8 
Intermediate 
3 to 4.5 
3.0 
3.2 
High 
4.5 to 6 
1.6 
1.4 
Very High 
6 
0.8 
0.7 
The prognostic value of the IPSS-R was validated in an external cohort of 200 patients with MDS 
AML: acute myeloid leukemia; MDS: myelodysplastic syndromes. 
* Cytogenetic definitions: 
Very good: –Y, del(11q) 
Good: Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate: del(7q), 8, 19, i(17q), any other single, double not including del(5q) or –7/del(7q), 
or independent clones 
Poor: –7, inv(3)/t(3q)/del(3q), double including –7/del(7q), complex: 3 abnormalities. 
Very poor: Complex: 3 abnormalities 
This research was originally published in Blood. Greenberg PL, Tuechler H, Schanz J, et al. Revised 
International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 2012. Copyright 
 2012 the American Society of Hematology. 


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Appendix K.  Modified International Working Group Response Criteria for MDS 
Category 
Response criteria (responses must last at least 4 wk) 
Complete 
Remission 
Bone marrow:  5 myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡ 
 
Hgb  11 g/dL 
 
Platelets  100 x 10⁹/L 
 
Neutrophils  1.0 x 10⁹/L† 
 
Blasts 0 
Partial remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by  50 over pretreatment but still  5 
Cellularity and morphology not relevant 
Marrow CR† 
Bone marrow:  5 myeloblasts and decrease by  50 over pretreatment† 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR† 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for  8 wks 
Relapse after CR 
or PR 
At least 1 of the following: 
 
Return to pretreatment bone marrow blast percentage 
 
Decrement of  50 from maximum remission/response levels in 
granulocytes or platelets 
 
Reduction in Hgb concentration by  1.5 g/dL or transfusion dependence 
Cytogenetic 
response 
Complete 
 
Disappearance of the chromosomal abnormality without appearance of new 
ones 
Partial 
 
At least 50 reduction of the chromosomal abnormality 
Disease 
progression 
For patients with: 
 
Less than 5 blasts:  50 increase in blasts to  5 blasts 
 
5-10 blasts:  50 increase to  10 blasts 
 
10-20 blasts:  50 increase to  20 blasts 
 
20-30 blasts:  50 increase to  30 blasts 
Any of the following: 
 
At least 50 decrement from maximum remission/response in granulocytes 
or platelets 
 
Reduction in Hgb by  2 g/dL 
 
Transfusion dependence 
 
Death during treatment or disease progression characterized by worsening 
of cytopenias, increase in percentage of bone marrow blasts, or progression 
to a more advanced MDS FAB subtype than pretreatment 
Deletions to IWG response criteria are not shown. 
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10. 
MDS indicates myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic 
improvement; PR, partial remission; FAB, French-American- British; AML, acute myeloid leukemia; PFS, 
progression-free survival; DFS, disease-free survival. 
* Dysplastic changes should consider the normal range of dysplastic changes (modification). 
† Modification to IWG response criteria. 
‡ In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into 
which they fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy 
courses should not be considered as interrupting durability of response, as long as they recover to the 
improved counts of the previous course. 


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Appendix L.  MDS Cytogenetic Scoring System: International Prognostic Scoring 
System, Revised 
Prognostic 
subgroups  
Cytogenetic 
abnormalities 
Percent 
of 
patients 
Survival 
(years, 
median) 
AML 
evolution, 
25 pecent 
(years, 
median) 
Hazard 
ratio OS 
Hazard 
ration 
AML 
Very good 
-Y, del(11q) 
4 
5.4 
NR 
0.7 
0.4 
Good 
Normal, del(5q), 
del(12p), del(20q), 
double including 
del(5q) 
72 
4.8 
9.4 
1 
1 
Intermediate 
del(7q), _8, _19, 
i(17q), any other 
single or double 
independent 
clones 
13 
2.7 
2.5 
1.5 
1.8 
Poor 
-7, 
inv(3)/t(3q)/del(3q), 
double including -
7/del(7q), 
complex: 3 
abnormalities 
4 
1.5 
1.7 
2.3 
2.3 
Very poor 
Complex:  3 
abnormalities 
7 
0.7 
0.7 
3.8 
3.6 
AML: acute myeloid leukemia; OS: overall survival 
This research was originally published in Blood. Modified from: Greenberg PL, Teuchler H, Schanz J, et al. 
Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454-65. 
Copyright  2012 American Society of Hematology.  


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Appendix M.  Recurring Chromosomal Abnormalities in Adults With MDS 
Disease 
Chromosome 
abnormality 
Frequency 
Involved genes* 
Consequence 
MDS 
Unbalanced 
8 
10 
 
 
 
-7/del(7q) 
10 
 
 
 
del(5q) 
10 
 
 
 
del(20q) 
5 to 8 
 
 
 
-Y 
5 
 
 
 
i(17p) 
3 to 5 
TP53 
 
Loss of function 
-13/del(13q) 
3 
 
 
 
del(11q) 
3 
 
 
 
del(12p)/t(12p) 
3 
 
 
 
del(9q) 
1 to 2 
 
 
 
idic(X)(q13) 
1 to 2 
 
 
 
Balanced 
t(1:3)(p36.3;q21.3) 
1 
PRDM16 
MECOM 
Deregulation of PRDM16 – 
transcriptional activation? 
t(2;11) 
(p21;q23.3)/t 
(11q23.3) 
1 
 
KMT2A 
KMT2A fusion protein – 
altered transcriptional 
regulation 
inv(3)(q21.3q26.2) 
1 
 
MECOM 
Overexpression of MECOM 
– altered transcriptional 
regulation 
t(6;9)(p23.3;q34.1) 
1 
DEK 
NUP214 
Fusion protein – nuclear 
pore protein 
Therapy-
related MDS 
-7/del(7q) 
50 
 
 
 
del(5q) 
40 to 45 
 
 
 
dic(5;17) 
(q11.1-13;p11.1-
13) 
5 
 
TP53 
Loss of function, DNA 
damage response 
der(1;7)(q10;p10) 
3 
 
 
 
t(3;21) 
q(26.2;q22.1) 
2 
MECOM 
RUNX1 
Loss of RUNX1, 
overexpression of MECOM 
– altered transcriptional 
regulation 
t(11;16) 
(q23.3;p13.3)/t 
(11q23) 
3 
KMT2A 
CREBBP 
KMT2A fusion protein – 
altered transcriptional 
regulation 
* Genes are listed in order of citation in the karyotype, eg, for the t(11;16), KMT2A is at the 11q23.2 and 
CREBBP at 16p13.3. 
Source: Vardiman, JW, Brunning, RD, Arber, DA et al. Introduction and overview of the classification of the 
myeloid neoplasms. In: WHO classification of tumors of hematopoietic and lymphoid tissues, Swerdlow, 
SH 
Campo, E, Harris, NL, et al. (Eds), WHO Press, 2008. 
Modified with additional data from: Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World 
Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.  


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Appendix N.  2017 ELN Risk Stratification by Genetics for AML 
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)  
−5 or del(5q); −7; −17/abn(17p)  
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. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 1 of 42 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 9 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Myeloid Malignancies 
 
Amgen Protocol Number:  AMG 330 20120252 
 
Amendment Date: 
15 February 2021 
 
Rationale: 
The protocol was amended to add language that selected target dose levels that have 
been deemed safe in subjects with relapsed/refractory acute myeloid leukemia 
(R/R AML) (Group 1) could be skipped in Groups 2 and 3 phase 1a of the study based 
on available safety, pharmacokinetics, and pharmacodynamics data if recommended by 
the Dose Level Review Team.  Reduced hospitalization was also added to the protocol 
for the minimal residual disease positive (MRD) AML group only.  The protocol was 
also amended to add language regarding COVID-19 vaccine to the concomitant 
medication section of the protocol.   
The following changes were incorporated into the study protocol:  
 
Added language that selected target dose levels that  have been deemed safe in 
subjects with R/R AML (Group 1) could be skipped in Groups 2 and 3 phase 1a of the 
study based on available safety, pharmacokinetics, and pharmacodynamics data if 
recommended by the Dose Level Review Team.   
 
Reduced hospitalization for the MRD AML group only. 
 
Clarified in the study schema per group that additional cohorts may be added if 
recommended by the Dose Level Review Team.  
 
Added aminotransferase elevation to the table of identified risks of AMG 330.  
 
Modified language to clarify the minimum duration at target dose to be dose-limiting 
toxicity evaluable.  
 
Added language regarding COVID-19 vaccination to the concomitant medications 
section.  
 
Included 
 United States (US) Prescribing Information in the 
marketed investigational products section and clarified that 
 
 may be used.  
 
Added language to clarify the use of 
 as clinically relevant.  
 
Minor correction in Schedule of Activities Table 19 footnote cross-referencing. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  15 February 2021 
Page 2 of 42 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Added partial remission to the list of response categories for R/R AML (Group 1 and 
Group 4 phase 1a) 
 
Added gamma glutamyl-transferase to the list of analytes (previously erroneously 
omitted).  
 
Added language to clarify the interim analysis plan for the study.  
 
Updated safety language to align with language from updated protocol template.  
 
Added complete remission with partial hematologic recovery (CRh) to the International 
Working Group Criteria for AML in Appendix E. 
 
Updated electronic Serious Adverse Event Contingency form in Appendix B to align 
with most recent version.  
 
Administrative and editorial updates.  


Product:  AMG 330 
Protocol Number:  20120252 
Date:  04 June 2020 
Page 1 of 52 
CONFIDENTIAL 
 
 
Amendment 8 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Myeloid Malignancies 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND-125 331 
EudraCT number 2014-004462-20 
 
Amendment Date: 
04 June 2020 
 
Rationale: 
The protocol was updated in amendment 8 in order to: 
• 
Clarify the dosing schedule for dexamethasone for Group 5, mini steps, if 
 
 are used in combination with dexamethasone. 
• 
Correct language describing the modified toxicity probability interval algorithm 
(mTPI-2), which will guide dosing decisions for Groups 2 and 3.  
• 
Make administrative, typographical and formatting changes throughout the protocol 
where applicable. 
• 
Correct errors in the schedules of assessments. The following corrections were 
made: 
Table Number 
Corrections  
15-23 
• 
Added disease-related events to remain consistent with other SoAs 
 
 
13 
Groups 1, 2, 3 and 
4 Cycles 2+ 
• 
Edited arrows on safety assessments to clarify they are taken through Day 36 
• 
Removed plasma biomarkers 
• 
Removed D36 bone marrow assessments and treatment response 
• 
Footnote f: removed language regarding D36 bone marrow 
• 
Footnote g: Added reference to section 6.2.1.1 for extended infusion free 
interval 
• 
Footnote j: Added that collections are not required for Group 4 (applies to 
PBMCs) 
 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  04 June 2020 
Page 2 of 52 
CONFIDENTIAL 
 
 
Table Number 
Corrections  
14 
Additional 
Assessments in 
Case of Dose 
Step 
• 
Footnote d: 
, Immune Cells, and Serum markers only 
obtained in Cycle 1.  
• 
Footnote e: PK only obtained in Cycle 1. (Kept as a separate footnote 
so lettering wouldn’t have to change for remaining footnotes) 
• 
Placed footnote h next to CD33 PRE and 24HR timepoints (h. For 
Group 4, Cycle 1, do not collect CD33 at the following time points: pre 
step dose 2 and 24 hours post dose step 2) 
• 
Placed footnote i next to 1HR and 12HR serum markers only (i. 
Collections only required for Group 1 and Group 4 during Cycle 1 (do 
not collect for Groups 2, 3, and 5)) 
15 
Group 4, Arm 1 
(
 
Premedication) 
– Cycle 1 
• 
Footnote d: 
, Immune Cells, and Serum markers only 
obtained in Cycle 1.  
• 
Footnote e: PK only obtained in Cycle 1. (Kept as a separate footnote 
so lettering wouldn’t have to change for remaining footnotes) 
• 
Placed footnote h next to CD33 PRE and 24HR timepoints (h. For 
Group 4, Cycle 1, do not collect CD33 at the following time points: pre 
step dose 2 and 24 hours post dose step 2) 
• 
Placed footnote i next to 1HR and 12HR serum markers only (i. 
Collections only required for Group 1 and Group 4 during Cycle 1 (do 
not collect for Groups 2, 3, and 5)) 
16 
Group 4, Arm 2 
(
 
Predmedication) 
– Cycle 1 
• 
Updated conmeds to be taken through EOS 
• 
Added AEs and DREs to pre-dose column (
 
pre-dose, AE monitoring to start at that time) 
17 
Group 5, Mini 
Step Dosing, 
Cycle 1 
• 
Updated conmeds to go through D36 
• 
Added SAE, AE and disease-related events to day -1  
• 
Added footnote n (n. Adverse Events and Disease-Related Events to 
be assessed on day -1 if 
 is administered). Applied to AEs 
and DREs on day -1 
• 
PBMCs added 
• 
Removed footnote k (k. taken pre-dose step) from biomarker 
assessments (except 
), bone marrow assessments and 
 dosing. 
19 
Group 5, Mini 
Step Dosing, 
Cycle 2 
• 
PBMCs added 
• 
Removed D36 bone marrow assessment and treatment response 
• 
Removed footnote e (Bone marrow assessment at D36 is optional) 
• 
Removed footnote k (take pre-dose step) from biomarker assessments 
(except on Days 2 and 3) 
• 
Updated lettering for footnotes f-m after removal of footnote e 
 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  04 June 2020 
Page 3 of 52 
CONFIDENTIAL 
 
 
Table Number 
Corrections  
20 
Group 5, Mini 
Step Dosing, 
Cycle 3+ 
• 
PBMCs added 
• 
Removed day 8 serum collections 
• 
Removed day 3 
  
• 
Removed bone marrow assessments and treatment response from 
D36 and EOT. Added BM and treatment response to EOS.  
• 
Added footnote n (n. Obtained Cycle 3 only) 
• 
Added footnote n to PBMCs to group name 
• 
Removed footnote k (taken pre-dose) from biomarker collections 
(except day 2 and 3 biomarker collections) 
• 
Added footnote n (obtained Cycle 3 only) to biomarkers 
21 
Group 5, Maxi 
Step Dosing, 
Cycle 1 
• 
Added SAEs, AE and disease-related events to day -2 
• 
Added footnote k (k. Adverse Events and Disease-Related Events to 
be assessed starting at day -2 if 
 is administered). Applied 
to AEs and DREs  
• 
Added PBMCs 
• 
Removed 
 from 2 and 6 Hour timepoints on Day 1 
22 
Group 5, Maxi 
Step Dosing, 
Cycle 2 
• 
Corrected conmeds, SAEs, AEs and disease-related assessments to 
be taken throughout Cycle 2 (originally marked as starting post AMG 
330 dose in error) 
• 
Added PBMCs 
• 
Removed 
 from Day 3  
• 
Added
 to D29 
• 
Removed bone marrow assessments and treatment response from 
D36 
23 
Group 5, Maxi 
Step Dosing, 
Cycle 3+ 
• 
Corrected conmeds, SAEs, AEs and disease-related assessments to 
be taken throughout Cycle 3 (originally marked as starting post AMG 
330 dose in error) 
• 
Removed 
 from Day 3 
• 
Added 
 to D29 
• 
Removed Serum markers for D3, D4 and D5 
• 
Removed immune cells for D4 and D5 
• 
Added PBMCs 
• 
Removed bone marrow assessments and treatment response from 
D36 and EOT. Added to EOS 
 
 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  10 April 2020 
Page 1 of 101 
CONFIDENTIAL 
 
 
Amendment 7 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Myeloid Malignancies 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND-125 331 
EudraCT number 2014-004462-20 
 
Amendment Date: 
10 April 2020 
 
Rationale: 
Changes incorporated in Protocol Amendment #7 are the following: 
• 
Treatment indication is updated to Myeloid malignancies including subjects with 
Minimal Residual Disease Positive (MRD+) AML, Myelodysplastic Syndrome (MDS) 
along with Relapsed/Refractory Acute Myeloid Leukemia (AML). 
• 
Incorporation of 2 additional groups in study to include subjects with AML who have 
achieved CR/CRi but are MRD+ (Group 2) and subjects with MDS (Group 3) 
• 
The current dose escalation group, which consists of subjects with R/R AML, will 
hereafter be designated as group 1.  All 3 groups will be included in both the 
phase 1a dose escalation and phase 1b dose expansion portions of the study.  
Enrollment in the MRD+ and MDS groups will occur simultaneously and will progress 
from dose escalation to dose expansion independently 
• 
The addition of a substudy to assess a novel approach for the prophylaxis of CRS in 
subjects with R/R AML.  The substudy will be conducted in 2 sequential groups: 
• 
Group 4 will evaluate whether premedication with either
or 
 (Group 4 and Group 5, respectively) can be used for CRS 
prophylaxis instead of dexamethasone. 
• 
Group 5 will evaluate an optimized AMG 330 step-dosing approach (ie, mini-step 
or maxi-step dosing).  Both the dosing approach and CRS premedication will be 
selected based on the outcomes from Group 4 of the substudy. 
• 
Addition of objectives specific to Group 2, 3, 4, and 5 subjects. 
• 
Design for subjects enrolling into Group 2, 3, 4, and 5 are described. 
• 
Clarified that sites that do not enroll subjects into an open cohort within 6 months of 
site initiation or during last 12 months of the study may be closed or replaced. 
• 
Disease background for MRD, MDS and prophylaxis of cytokine release syndrome 
included. 
• 
Study hypotheses is updated to demonstrate evidence of anti-leukemic activity at a 
well-tolerated AMG 330 dose in subjects with MDS in addition to subjects with AML  
• 
Efficacy parameters for MRD-positive AML and for MDS are included. 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  28 August 2019 
Page 1 of 3 
CONFIDENTIAL 
 
 
Amendment 6 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
AMG 330 
Amgen Protocol Number AMG 330 20120252 
 
Amendment Date: 
28 August 2019 
 
Rationale:  
In response to FDA feedback for protocol amendment 5 received on 26 August 2019, 
the protocol was revised to include a DLT window of at least 4 weeks in length for all 
cohorts. To implement these recommendations, additional edits have been added to 
clarify that the length of the infusion free period between cycles is dependent upon the 
duration of the treatment cycle as well as lab assessments. Per the Agency’s 
recommendation, the proposed intervention for Grade 1 CRS with 4 mg/kg IV of 
tocilizumab has been deleted. In addition to these changes, the Dose Limiting Toxicity 
(DLT) definition has been updated to account for acceptable enzyme elevations and for 
clearance of enzymes with long half-lives. Also, language regarding self-evident data 
corrections was removed to align with current Amgen process, and typographical errors 
were corrected throughout. Table numbers have been updated as needed.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  06 May 2019 
Page 1 of 35 
CONFIDENTIAL 
 
 
Amendment #5 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 330 20120252  
 
Amendment Date: 
06 May 2019 
Summary of Key Changes and Rationale: 
Changes in the protocol have been made to implement new guidelines for Cytokine 
Release Syndrome (CRS) mitigation. The guidelines have been updated to allow for 
early management of symptoms, to avoid drug interruptions, and to improve drug 
exposure. In addition, the Inclusion/Exclusion criteria have been updated (eg, to allow for 
the inclusion of R/R AML patients with prior MDS). The Dose Limiting Toxicity (DLT) 
definition has been updated to allow for effective assessment of safety signals. Changes 
have been made to allow for optimization of the dose level and treatment schedule, 
including additional step dosing and updates to the requirements for off-drug intervals. 
Multiple edits have been introduced to clarify existing guidelines and procedures. 
Administrative, typographical and formatting changes were made throughout the 
protocol where applicable. 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  06 May 2019 
Page 2 of 35 
CONFIDENTIAL 
 
 
Section 
Summary of Key Changes 
Rationale 
Section 1.3 
Exploratory 
Exploratory endpoint of 
Section 2.3 Risk 
Assessment, Table 1.  
Potential Risks of 
AMG 330 
Added rash to Table 1, 
“Potential Risks of AMG 330”  
Rash identified as a common risk 
based on emergent safety data. 
Section 3.2 Number of 
Sites 
Increased number of sites from 
7 to 10 
To reflect addition of sites in 
Japan.  
3.1 Study  
Design – Target MTD 
Estimation 
Language regarding target 
MTD estimation was updated to 
allow for more than one dose 
step after the 1st dose step.  
It is anticipated that three dose 
steps may be needed to allow for 
further escalation to an efficacious 
dose.  
3.1 Study  
Design – Multiple 
Subject Cohorts  
(3 + 3 Dose Level 
Decision Rules) 
The requirement for a 96-hour 
interval between the start of 
treatment of the second subject 
and all subsequent subjects in 
each cohort was removed.   
The sentinel period between the 
first and second subjects is 
adequate to review any safety 
signals prior to enrolling additional 
subjects into the cohort.  
Section 3.3 Number of 
Subjects 
Increased number of subjects 
enrolled from 70 to 100 
(approximately 70 in the dose 
escalation cohorts and up to 
30 in the dose expansion 
cohort). 
CRS has been identified as an 
on-target dose-dependent and 
dose-limiting toxicity. To ensure 
the safety of subjects and 
decrease the risk of CRS, 
intermediate dose levels will be 
assessed during the dose 
escalation phase requiring 
additional cohorts.  
3.4 Replacement of 
Subjects 
The definition of a DLT 
evaluable subject has been 
changed from a subject who 
has completed cycle 1-to a 
subject who has completed the 
DLT window. The minimum 
target dose exposure has been 
clarified: 10 days during a  
2-week cycle, and 14 days 
during a 3- or 4-week cycle. 
To reflect that the duration of a 
treatment cycle and a DLT window 
can be different, and to ensure 
adequate drug exposure within the 
DLT window timeframe.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  06 May 2019 
Page 3 of 35 
CONFIDENTIAL 
 
 
Section 
Summary of Key Changes 
Rationale 
4.1 Inclusion Criteria  
Inclusion criterion 4.1.3: 
Subjects with AML secondary 
to myelodysplastic syndrome 
(MDS) may be included into the 
study 
Pathogenesis of MDS 
transformation to AML, and the 
presence of a CD33 target suggest 
that AMG 330 may be effective in 
R/R AML subjects with prior MDS.  
4.2 Exclusion Criteria 
Exclusion 4.2.13: For antitumor 
therapy received within 14 days 
or 5 half-lives of day 1, 
‘whichever is longer’ has been 
changed to ‘whichever is 
shorter’.  
Corrected error; some biologics 
have a 21-day half-life and 
5 half-lives may take up to 
3 months, which is too long a 
waiting period for subjects with 
R/R AML.  
4.2 Exclusion Criteria 
Exclusion criteria 4.2.14: added 
exceptions for physiologic 
replacement steroids and 
hydrocortisone for treatment of 
transfusion reactions.  
To ensure safety of patients who 
require a use of physiological 
doses of hormones as a 
replacement therapy.  
4.2 Exclusion Criteria 
Removed exclusion 4.2.16: 
Ingestion of any food or drink 
containing grapefruit or Seville 
oranges, or St. John´s wort, 
within 7 days prior to receiving 
the first dose of AMG 330 
Grapefruit, Seville oranges and St. 
John’s Wort are CYP3A inhibitors. 
4.2 Exclusion Criteria 
Exclusion criterion 4.2.18: Prior 
participation in an 
investigational study (drug, 
procedure or device) within 
21 days of study day 1 was 
removed as an exclusion 
criterion 
Removed to ensure consistency 
with the exclusion 4.2.13 
(Antitumor therapy (chemotherapy, 
antibody therapy, 
molecular-targeted therapy, 
retinoid therapy, or investigational 
agent) within 14 days or 5 half 
lives (whichever is shorter) of 
day 1. 
6.2.1.1 Dosage, 
Administration, and 
Schedule 
Guidelines for the 
implementation of an infusion 
free period between cycles 
were updated.  
The length of the infusion free 
period between cycles will be 
optimized for subjects responding 
to AMG 330 treatment with the 
goal of providing an adequate 
exposure to control tumor 
re-growth.  An extended infusion 
free period (of 1 week or more) will 
be considered if peripheral blood 
counts have significantly worsened 
to allow time for recovery. 
6.2.1.4 Dose-cohort 
Study Escalation and 
Stopping Rules, 
Dose-limiting 
Toxicities (DLTs) 
Grade 3 rash will not be 
considered a DLT  
Rash has been identified as a 
common AE that may occur 
independently from CRS.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  06 May 2019 
Page 4 of 35 
CONFIDENTIAL 
 
 
Section 
Summary of Key Changes 
Rationale 
6.2.1.4 Dose-cohort 
Study Escalation and 
Stopping Rules, 
Dose-limiting 
Toxicities (DLTs) 
Asymptomatic elevation of 
enzymes that resolves within 
5 days will not be considered a 
DLT  
Clearance of elevated enzymes 
following a single release without 
associated tissue injury can 
require 5 days due the long 
half-life (eg, T1/2 of ALT is 2 days). 
6.2.1.4 Dose-cohort 
Study Escalation and 
Stopping Rules, 
Dose-limiting 
Toxicities (DLTs) 
The DLT window previously 
included a 2-week post cycle 
interval to monitor the dynamics 
of myelosuppression. This 
2-week interval has been 
removed from the DLT window.  
Review of data from cohorts 1-13 
shows that R/R AML patients 
experience various degrees of 
myelosuppression prior to 
AMG 330 treatment. 
Subsequently, the 2-week post 
cycle interval did not help to 
capture shifts of myeloid cell 
counts from baseline through the 
end of the DLT window.   
6.2.1.4 Dose-cohort 
Study Escalation and 
Stopping Rules, 
Dose-limiting 
Toxicities (DLTs) 
Clarification on when CRS 
qualifies as a DLT, depending 
on the frequency and severity, 
has been added. 
The maximum time required for 
CRS resolution based on the 
grade has been added to the DLT 
assessment for clarity. 
Section 6.2.1.5 
Dosage Adjustments, 
Delays, Rules for 
Withholding or 
Restarting, Permanent 
Discontinuation 
Table was added to clarify 
which assessments are to be 
performed after an infusion 
interruption and re-start, 
depending on the length of the 
interruption and the dose at 
which the interruption occurred 
(step or target dose).  
To reduce the likelihood of 
assessments being missed or 
repeated unnecessarily due to 
infusion interruptions.  
6.2.1.5 Dosage 
Adjustments, Delays, 
Rules for Withholding 
or Restarting, 
Permanent 
Discontinuation 
Added language to clarify that a 
subject will not be considered 
DLT evaluable 
after 2 unsuccessful drug 
re-starts. 
To reduce the number of repeat 
cycles and minimize patient 
burden.  
Table 8 CRS 
Management 
Guidelines 
The recommendations for 
management of CRS were 
modified to allow for dose 
reduction instead of drug 
interruption in cases of Grade 2 
CRS that do not resolve within 
8 hours.  
To reduce the probability of drug 
interruptions, leading to repeat of 
infusion cycles, decreased 
exposure and increased patient 
burden.   
9.2.1 Reporting 
Procedures for 
Disease-Related 
Events 
Instructions for sites to transmit 
Serious Disease-Related 
Events in the same manner as 
Serious Adverse Events and 
within same timelines. 
Updated to reflect current Amgen 
safety guidelines.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  28 June 2018 
Page 1 of 12 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 330 20120252 
Amendment Date:  
 
 
28 June 2018 
Rationale: 
Updates have been made to incorporate clarification and guidance to sites regarding the 
following: 
 
The recommendations for management of CRS were modified, including 
AMG 330 treatment interruption and restart due to adverse events of CRS. A 
separate supportive document is included to provide data to support this change. 
 
Schedule of Assessments were revised to include a column for cycle 2 Day 1 
time 0 to provide clarity for Tables 9, 11 & 13 
 
Increased number of subjects enrolled from 50 to 70 (approximately 40 in the 
dose escalation cohorts and up to 30 in the dose expansion cohort) 
 
The dosage, schedule and administration section 6.2.1.1 was updated to clarify 
rules for increasing duration of infusion from 14 days to 21 or 28 days, by the 
dose level review team (DLRT) 
 
Added Japan as a participating country 
 
Additional changes have been made for increased clarity throughout the protocol 
where applicable. 
 
Administrative, typographical and formatting changes were made throughout the 
protocol where applicable. 
 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 October 2016 
Page 1 of 35 
CONFIDENTIAL 
 
 
Amendment #3 
Protocol Title: A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND 125 331  
EudraCT number 2014-004462-20 
 
Amendment Date: 
19 October 2016 
Rationale: 
The main reasons for this protocol amendment were implementation of a mandatory 
dose step in each treatment cycle as well as addition of more detailed instructions for 
management of cytokine release syndrome (CRS), following the identification of CRS as 
an important risk of AMG 330 and a corresponding request by the US Food and Drug 
Administration (FDA) and the German Paul-Ehrlich Institute (PEI) and Munich Ethics 
Committee. Some additional required updates and corrections of errors were identified 
during study conduct. Finally, updates have been implemented to align with the current 
Amgen protocol template, most importantly some clarifications on the reporting of 
disease-related events. Detailed rationale for the individual changes is provided below.  
The following changes were added following the identification of CRS as an important 
risk of AMG 330: 
− 
CRS is now described as an identified risk, and was removed from the list of 
potential risks 
− 
Administration of steroids is now mandatory prior to start of treatment in each 
cycle.  
− 
A mandatory dose step in each treatment cycle (ie, starting infusion at a lower 
run in dose which is stepped up to the target dose after 4 [+/-1] days) including 
the requirement to administer a prophylactic steroid dose prior to each step was 
implemented as a mitigation measure for CRS.  
− 
A dose step will also be required in case of treatment re-start after an infusion 
interruption of more than 24 hours. In order to account for the mandatory dose 
steps and possible additional dose steps after infusion interruption and re-start, 
the definition of a complete cycle was changed to refer to the target dose rather 
than the total duration of days on treatment.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 October 2016 
Page 2 of 35 
CONFIDENTIAL 
 
 
− 
Additional specific guidance for management of CRS, including guidance for 
grading of CRS, instructions for infusion interruptions in case of CRS and restart, 
as well as criteria for permanent discontinuation after CRS were added 
(section 6.6) 
− 
The interval between start of treatment of the first and second subject in each 
cohort was extended to 6 days.  
The possibility to enroll additional subjects in a dose cohort in case exactly 2 DLTs were 
observed in 6 subjects of a cohort was removed. The following changes were 
implemented following experience in the first year of study conduct: 
− 
Prerequisites and requirements for intra-subject dose escalation were clarified.   
− 
HIV was removed from the list of mandatory screening tests, as it was not 
consistent with the wording of the exclusion criterion which reads “known positive 
test for HIV”  
− 
Updates to eligibility criteria: 
• 
Removal of the requirement for ALP to be  < 2 x ULN as increased ALP is 
often an isolated laboratory abnormality (ie it can be observed without 
abnormal ALT, AST or bilirubin levels)  in AML patients and ALT, AST, 
and bilirubin are more specifically indicative of hepatic and biliary function 
• 
Removal of the requirement to perform lumbar puncture to exclude AML 
in CNS in case of suspected CNS disease, as subclinical CNS 
involvement  is extremely rare in AML patients 
• 
The criterion for excluding subjects with hepatitis B or C was simplified in 
line with the current Amgen protocol template to improve clarity, and the 
list of hepatitis analytes was updated accordingly 
− 
The required time frame for recording concomitant medications for which a 
washout time is specified in the exclusion criteria in the CRF was extended to 
two weeks prior to start of IP treatment in order to allow documentation that these 
washout times were met.  
− 
Assessment of standard bone marrow cytogenetics is now only mandatory at 
screening which is in line with standard clinical practice. 
− 
Biomarker samples are no longer mandatory if it is not possible to process them 
at a given time point, because sample processing and/ or shipment to central 
laboratories at weekend days is not logistically feasible at the majority of sites.  
Other changes: 
− 
A section on handling of overdoses was added and overdose (defined as a daily 
dose of > 10 % higher than the protocol specified dose) now needs to be 
reported as SAE to be aligned with procedures followed in studies with the BiTE® 
molecule blinatumomab, to account for the complexity of preparation and 
administration inherent in these types of molecules.  
An exploratory laboratory test which had been planned in the expansion cohort to test 
renal elimination of AMG 330 is no longer planned and the corresponding 24 hour urine 
sample has been removed from the schedule of assessments.  
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 October 2016 
Page 3 of 35 
CONFIDENTIAL 
 
 
Changes related to updated Amgen protocol template: 
− 
Clarifications were added to the process for recording and reporting disease 
related events in section 9 and throughout the protocol as applicable 
− 
The section on product complaints was updated in line with current Amgen 
procedures 
− 
Clarifications were added to the options for follow up after subject`s withdrawal of 
consent  
− 
A clarification that SAEs that the investigator becomes aware of after end of 
study have to be reported in some countries (eg, EU) was added.  
− 
Follow up procedures in case of pregnancy or lactation were added 
− 
The section on data collection was updated to reflect Amgen`s current process 
with regards to self-evident corrections. 
− 
The publication policy was updated in line with the latest recommendations of the 
International Committee of Medical Journal Editors (ICMJE)   
− 
Reporting requirements for drug induced liver injury were slightly updated to align 
with current template 
Corrections of errors and clarifications: 
− 
Clarified definition of DLT-evaluable 
− 
The procedures to be performed in case of re-start of AMG 330 infusion after an 
interruption of more than 4 hours and more than 24 hours, respectively, were 
clarified 
− 
Criteria for permanent discontinuation of IP treatment were clarified and updated 
to be aligned with other protocol sections  
− 
A pre-dose blood sample for 
 genotyping for subjects in the expansion 
phase was added to the schedule of assessments as it had been missed in error 
before. In addition this sample was changed from a screening sample to a C1D1 
pre-dose sample; this way it will only be taken from enrolled subjects.  
− 
A time point for measurement of vital signs and pulse oximetry was added 16 
hours after the step to the schedule of assessments applicable after dose step, to 
be in line with safety assessments at the start of a cycle.  
− 
References to the separate schedule of assessments for dose steps were 
pointed out in the body of the protocol. 
− 
Hospitalization requirements were clarified 
− 
The end of study visit should occur earlier than 4 weeks (plus 7 days) after the 
end of infusion in case the subject moves to alternative therapy for AML. This is 
now consistent between the different protocol sections 
− 
The instruction to not record CTCAE grade of ongoing AML on the medical 
history form was added to align with CRF completion guidelines 
− 
The possibility to combine primary and final analysis in case both were triggered 
around the same time was added to the section on statistical considerations, as 
this is in line with standard practice   
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 October 2016 
Page 4 of 35 
CONFIDENTIAL 
 
 
Administrative changes, corrections of typographical and formatting errors were made 
throughout the protocol. 
Approved 
 
 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 August 2015 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment #2 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND 125 331 
EudraCT number 2014-004462-20 
 
Amendment Date: 
19 August 2015 
 
Rationale: 
The protocol was amended following comments received by the Paul-Ehrlich-Institute 
(German Competent Authority, PEI) on 23 June 2015 and the MD Anderson Cancer 
Center Centralized Review Committee (MDACC CRC) on 16 June 2015 and agreed to 
by Amgen. In addition, some typographical errors were corrected and clarifications 
added.  
The following changes were implemented as requested by the PEI: 
− 
Inclusion of a reference to a country-specific supplement for Germany (inclusion 
criterion #3 was changed to restrict the enrollment of refractory AML patients to 
those with refractory disease after at least 2 failed induction attempts) 
− 
An additional response assessment 4 weeks after the end of a treatment cycle in 
case of an extended treatment free interval due to insufficient recovery of 
peripheral blood counts 
− 
A tabulated list of potential adverse events was added to the background section 
− 
The requirement for an emergency room with resuscitation equipment during 
hospitalization  
− 
The requirement for a patient card to be handed to subjects in the outpatient 
setting 
− 
Removal of sponsor decision (other than safety related reasons) as reason for 
permanent discontinuation of individual subjects from treatment or from study. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  19 August 2015 
Page 2 of 11 
CONFIDENTIAL 
 
 
The following changes were implemented as requested by the MDACC CRC: 
− 
Addition of short description of rationale for potential implementation of dose step 
and clarification on process for estimating MTDs in case of dose step.  
− 
Implementation of an additional dose level review team meeting after 5 subjects 
have been enrolled in the expansion phase of the study 
The following additional corrections and clarifications were added: 
− 
In case a cycle ends early and will not be continued due to an interruption of 
more than 7 days, the end of infusion bone marrow and biomarker assessments 
should be done once feasible, e.g., in order to determine treatment response and 
the appropriate duration of the infusion-free interval.  
− 
Correction of an inconsistency concerning re-start of treatment after interruption 
due to adverse event 
− 
Time to progression was added to the secondary endpoints and secondary 
objectives to align with section 10.4.3.2, Efficacy Endpoint Analyses 
− 
Correction of a typographical error in the criteria for permanent treatment 
discontinuation due to DILI 
− 
Correction in the schedule of assessment footnote on vital sign assessments 
− 
Immunological phenotyping of bone marrow was removed from section 7.5.2 as 
this will not be done for this study 
− 
Correction of typographical error in Table 12, List of Analytes 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  21 May 2015  
Page 1 of 22 
CONFIDENTIAL 
 
 
Amendment #1 
Protocol Title:  A Phase 1 First-in-human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 330 Administered as 
Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number (AMG 330) 20120252 
IND number BB-IND 125 331 
EudraCT number 2014-004462-20 
 
Amendment Date: 
21 May 2015 
Rationale: 
The protocol was amended following comments received by the FDA on May 12th, 2015 
and on May 15th, 2015, and in line with the responses to questions submitted to the IND 
on May 19th, 2015.  
The following changes were implemented as requested by the FDA: 
− 
specific recommendations for infection prophylaxis (neutropenic subjects) as well 
as description of mitigation measures for cytokine release syndrome and tumor 
lysis syndrome, and provisions for identifying subjects at high risk of cytokine 
release syndrome and tumor lysis syndrome were added. 
− 
implementation of possibility for DLRM to introduce steroid pre-treatment for 
subsequent cohorts in case of observation of cytokine release syndrome  
− 
addition of recommendation for 9 days of hospitalization in first treatment cycle 
− 
DLT criteria were updated as per FDA request 
− 
rolling 6 design was replaced with 3+3 design 
− 
the dose escalation scheme was modified in accordance with FDA requests for 
slower escalation in the first dose cohorts.  
− 
a waiting period prior to dosing of the next subject was implemented for the first 
10 subjects receiving step dosing (if applicable) 
− 
an additional time point for coagulation and hematology safety labs was added 
(8 h post treatment start in the first cycle and after step if applicable) 
− 
the subject population that should receive pre-treatment with hydroxyurea prior to 
start of AMG 330 treatment was specified 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  21 May 2015  
Page 2 of 22 
CONFIDENTIAL 
 
 
In addition to changes requested by the FDA, the following administrative changes were 
made: 
− 
change of US study manager 
− 
adverse event CRF was replaced with event CRF following current DES 
standards 
− 
list of analytes for chemistry and hematology were updated to reflect eCRF 
contents 

SAP_001.pdf: 
Product:  AMG 330 
Protocol Number:  20120252 
Date:  29 October 2021 
Page 1 of 71 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1 First-in-Human Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and 
Efficacy of AMG 330 Administered as Continuous 
Intravenous Infusion in Subjects with Myeloid Malignancies 
Short Protocol Title: 
A Phase 1 First-in-Human Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and 
Efficacy of AMG 330 Administered as Continuous 
Intravenous Infusion in Subjects with Myeloid Malignancies 
Protocol Number: 
20120252 
NCT Number: 
2014-004462-20 
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 
Original (v1.0) 
22 July 2015 
Amendment [1 (v2.0)] 
29 October 2021 
NCT Number: NCT02520427
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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Page 2 of 71 
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Version 
Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original 
(v1.0) 
22Jul2015 
NA 
Amendment 
1 (v2.0) 
29 October 
2021 
 
Inclusion of design and analysis for new Groups 
to be consistent with protocol: MRDAML 
(Group 2), MDS (Group 3), alternative CRS 
prophylaxis for R/R AML (Group 4 and Group 5)  
 
Clarification of some definitions, such as 
treatment-emergent adverse event (TEAE), 
duration of response (DOR), time to response 
(TTR), event-free survival (EFS). Addition of 
overall survival endpoint. 
 
Clarification of analysis sets, such as Dose 
Limiting Toxicity Evaluable (DLT-Evaluable) 
Analysis Set   
 
Other administrative changes 
 
Detailed Summary of changes provided in the 
Appendix C. 
 


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Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 6 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 6 
2.1 
Objectives and Endpoints ............................................................................ 6 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size .............................................................................................. 13 
3.3 
Adaptive Design ........................................................................................ 13 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates ................................................................................... 15 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 15 
5.1 
General Definitions .................................................................................... 15 
5.2 
Study Points of Reference ......................................................................... 16 
5.3 
Study Dates .............................................................................................. 17 
5.4 
Endpoints .................................................................................................. 19 
6. 
Analysis Sets ........................................................................................................ 21 
6.1 
Safety Analysis Set ................................................................................... 21 
6.2 
Dose Limiting Toxicity Evaluable Analysis Set .......................................... 21 
6.3 
Pharmacokinetic (PK) Analysis Set ........................................................... 21 
7. 
Planned Analyses ................................................................................................. 22 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 22 
7.2 
Primary Analysis ....................................................................................... 24 
7.3 
Final Analysis ............................................................................................ 24 
8. 
Data Screening and Acceptance ........................................................................... 24 
8.1 
General Principles ..................................................................................... 24 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 25 
8.3 
Handling of Missing and Incomplete Data ................................................. 25 
8.4 
Detection of Bias ....................................................................................... 25 
8.5 
Outliers ..................................................................................................... 25 
8.6 
Distributional Characteristics ..................................................................... 26 
8.7 
Validation of Statistical Analyses ............................................................... 26 
9. 
Statistical Methods of Analysis.............................................................................. 26 
9.1 
General Considerations ............................................................................. 26 
9.2 
Subject Accountability ............................................................................... 27 
9.3 
Important Protocol Deviations ................................................................... 27 


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9.4 
Demographic and Baseline Characteristics ............................................... 27 
9.5 
Efficacy Analyses   .................................................................................... 29 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 29 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 29 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 29 
9.6 
Safety Analyses ........................................................................................ 30 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 30 
9.6.2 
Analyses of Dose Limiting Toxicities .......................................... 30 
9.6.3 
Adverse Events and Disease-related Events  ............................ 30 
9.6.4 
Laboratory Test Results  ........................................................... 31 
9.6.5 
Vital Signs  ................................................................................ 31 
9.6.6 
Physical Measurements  ........................................................... 31 
9.6.7 
Electrocardiogram  .................................................................... 31 
9.6.8 
Antibody Formation  .................................................................. 33 
9.6.9 
Exposure to Investigational Product  ......................................... 33 
9.6.10 
Exposure to Concomitant Medication ........................................ 33 
9.7 
Other Analyses ......................................................................................... 33 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 33 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 34 
9.7.3 
Analyses of Health Economic Endpoints ................................... 34 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 34 
10. 
Changes From Protocol-specified Analyses.......................................................... 35 
11. 
Literature Citations / References ........................................................................... 36 
12. 
Prioritization of Analyses....................................................................................... 36 
13. 
Data Not Covered by This Plan............................................................................. 36 
14. 
Appendices ........................................................................................................... 37 
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates ................. 37 
 
Appendix C. Summary of Changes  ...................................................................... 40 
 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLRM 
Dose-Level Review Meeting 
ECG 
Electrocardiogram 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
MTD 
Maximum tolerated dose 
QTcB 
QTcF 
Bazett-corrected QT Interval (QTcB) 
Fridericia-corrected QT Interval (QTcF) 
RP2D 
Recommended phase 2 dose  
R/R AML 
Relapsed or refractory AML 
Study Day 1 
Defined as the first day that investigational product(s) is 
administered to the subject 
μg 
Microgram 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within Protocol Amendment 9 (for study 20120252, AMG 
330 dated 15 February 2021). The scope of this plan includes the interim analysis, primary 
analysis, and final analysis that will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified. PK/PD and biomarker analyses will be 
provided by Clinical Pharmacology, Modeling and Simulation (CPMS) group and clinical 
biomarker group in Department of Translational Medicine. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Primary Objectives:   
 
Evaluate the safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory AML, MRD AML and MDS 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
[eg, recommended phase 2 dose (RP2D)] of AMG 330 in adult with 
relapsed/refractory AML, MRD+AML and MDS 
Secondary Objectives:   
 
Evaluate the pharmacokinetics (PK) of AMG 330 
 
Determine the formation of anti-AMG 330 antibodies 
 
Evaluate the anti-leukemia activity of AMG 330 by evaluating 
 
the number and proportion of subjects who respond to treatment with 
AMG 330.  Response is defined as any of the following: complete remission 
(CR), CR with incomplete recovery (CRi) or morphologic leukemia-free state 
(all according to Revised International Working Group [IWG] response 
criteria) or CR with partial hematologic recovery (CRh). 
 
the number and proportion of subjects with MDS who respond to treatment 
with AMG 330. Response is defined as any of the following: CR or marrow 
CR (all according to Revised IWG response criteria).  
 
the number and proportion of subjects with MRD-positive AML (Group 2) 
who respond to treatment with AMG 330. Response is defined as conversion 
from MRD status with 0.1 threshold to MRD- status 


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 
the duration of response, event-free survival, time to response, and overall 
survival 
Exploratory Objectives:   
 
Evaluate the protein, nucleic acid, and cellular biomarkers in blood and / or bone 
marrow, as applicable [eg, cytokines, lymphocyte subsets, minimal residual disease 
(MRD – Group 1 only), leukemic stem cells (LSCs)] 
 
Evaluate effects of genetic variations in and phenotype of cancer genes, including 
apoptotic markers, on adverse event profile and treatment response 
 
Evaluate mechanisms of resistance 
 
Evaluate potential measures of clinical benefit including number of blood products 
transfused and days of antibiotic treatment of infection 
 
Evaluate the relationship between AMG 330 exposure and response to treatment 
 
 
 
 
 
Explore the additional thresholds of conversions to MRD- status in MRD+ AML 
subjects as an efficacy measure for AMG 330 treatment 
Primary Endpoint:   
 
Safety:  subject incidence and grade of adverse events (AEs) and dose limiting 
toxicities (DLTs) 
Secondary Endpoints:   
 
Pharmacokinetic parameters:  half-life, steady state concentration, volume of 
distribution and clearance of AMG 330 
 
Incidence of anti-AMG 330 antibody formation 
 
Efficacy parameters for R/R AML: response rate (response defined as 
CR/CRi/morphologic leukemia-free state [per modified IWG criteria] or CRh), 
duration of response, time to response, event-free survival and overall survival 
(duration of response, event-free survival, and overall survival will only be measured 
in the expansion cohort)  
 
Efficacy parameters for MRD-positive AML: response rate (response defined as 
conversion from MRD+ status with 0.1% threshold to MRD-), time to response, 


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CONFIDENTIAL  
 
 
relapse-free survival, and overall survival (relapse-free survival and overall survival 
will only be measured in the expansion cohort)  
 
Efficacy parameters for MDS: response rate (response defined as CR or marrow 
complete remission [per International Working Group (IWG) standardized response 
criteria]), duration of response, time to response, event-free survival and overall 
survival (duration of response, event-free survival, and overall survival will only be 
measured in the expansion cohort) 
Exploratory Endpoints:   
 
Depletion of LSCs 
 
MRD response  
 
Lymphocyte counts, cluster of differentiation (CD) 33+ monocytes and T cells, as 
well as T cell activation (including T cell subsets).  Other immune subsets may also 
be examined 
 
 
 
 
 
 
 
Changes in serum cytokine levels 
 
Frequency and severity of cytokine release syndrome (CRS) and other AEs 
following 
 premedication, and alternative dose step 
schedules of AMG330  
 
  
2.2 
Hypotheses and/or Estimations 
AMG 330 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML and MDS. 
3. 
Study Overview 
3.1 
Study Design 
This is a first-in-human, open-label, phase 1 sequential dose escalation study.  AMG 330 
will be evaluated as a continuous intravenous (cIV) infusion in adult subjects with 
relapsed/refractory (R/R) AML (Group 1), MRD+ AML (Group 2) and MDS (Group 3).  The 
study will be conducted at approximately 17 sites in Germany, the Netherlands, Japan, 
Canada and the United States.  


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The dose-escalation cohorts will estimate the MTD/biologically active dose, safety, 
tolerability, PK, and pharmacodynamics (PD) of AMG 330.   
For R/R AML (Group 1), planned dose levels for the dose-escalation cohorts are as 
follows: 0.5, 
 and 960 µg/day. 
Intermediate and/or higher dose level(s) up to 1.6 mg of AMG 330 may be evaluated as 
necessary to reach MTD. The same dose level may be tested in multiple cohorts, but with 
different dose steps and/or different cycle lengths.   
For MRD+ AML (Group 2), planned target dose levels for the dose-escalation cohorts are 
as follows: 
 and 960 µg/day. Each target dose level will be preceded by dose 
steps. Intermediate dose steps and additional target dose level(s) up to 1.6 mg of AMG 
330 may be evaluated as necessary. Escalation can continue until the biologically active 
dose for MRD+ AML is established. Selected target dose levels, with the exception of the 
maximal tested dose, that have been deemed safe in subjects with R/R AML (Group 1) 
could be skipped in Group 2 phase 1a dose escalation cohorts based on available safety, 
PK, and PD data if recommended by the Dose Level Review Team (DLRT). 
For MDS (Group 3), planned target dose levels for dose-escalation cohorts are as follows: 
 and 960 µg/day. Each target dose will be preceded by dose steps. 
Intermediate dose steps and additional dose level(s) up to 1.6 mg of AMG 330 may be 
evaluated as necessary. Escalation can continue until MTD for MDS is established. 
Selected target dose levels, with the exception of the maximal tested dose, that have been 
deemed safe in subjects with R/R AML (Group 1) could be skipped in Group 3 phase 1a 
dose escalation cohorts based on available safety, PK, and PD data if recommended by 
the DLRT. 
It is anticipated that more than one MTD may be estimated, one for each dose step and 
one for the target dose. Should the initial dose be limited by adverse events related to first 
dose effects (eg, cytokine release syndrome [CRS]), the second MTD for the target dose 
will be estimated after giving the initial dose at MTD (dose step). Starting with cohort 6 
(R/R AML, Group 1), a dose step in each cycle is mandatory for all newly enrolled subjects. 
Administration of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 hour prior 
to the dose step for prevention of cytokine release is mandatory. The additional 
assessments described in the schedule of assessments for dose steps (in Protocol Table 
14) apply.  
 
  


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Product:  AMG 330 
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Dose Escalation: 
For Group 1 (R/R AML), dose escalation will be conducted in two stages.  In the single 
subject cohorts, single subjects will be enrolled at dose levels anticipated to be lower than 
those at which adverse events related to AMG 330 will be observed.  Once higher dose 
levels are open for enrollment or drug related safety or efficacy signals are observed, 
multiple subject cohorts of up to 6 subjects per dose level will open for enrollment (3+3 
design).  Subjects who complete the DLT period may proceed to a higher dose level for 
the following treatment cycle if no DLT has been reported for either this subject or any 
other subject in this dose cohort after completion of the DLT period, and once the next 
dose cohort is open for enrollment. (see Section 7.2.2 in protocol for details on 
assessments applicable in case of intra-subject dose escalation). 
In Group 1 (R/R AML), should the initial dose be limited by adverse events related to first 
dose effects (eg, CRS), dose steps will be implemented. An optimal dose step schedule 
and MTD for the target dose will be estimated following decision rules. 
For Groups 2 and 3 (MRD+ AML and MDS), each dose escalation cohort will enroll a 
minimum of 3 to a maximum of 9 evaluable subjects. Dose escalation will be guided by a 
modified toxicity probability interval approach (mTPI-2; Guo et al, 2017). The DLRT will 
review all available safety, laboratory, PK and PD data and provide dose-finding 
recommendations.  
For Groups 1, 2 and 3, enrollment will occur simultaneously, and each Group will progress 
from the dose escalation to the dose expansion independently. The total number of 
subjects to be enrolled for the dose escalation will depend on the toxicities observed as 
the study progresses. Additional subjects may be required if other dose levels or alternate 
treatment schedules are explored. 
Enrollment in Group 4 is independent from enrollment in Groups 1, 2 and 3. For Group 4, 
enrollment in Arm 1 will occur first. Once all subjects in Arm 1 have initiated treatment, 
enrollment into Arm 2 will begin. Once all Group 4 subjects have completed the DLT 
period, enrollment into Group 5 can commence. If there are 2 arms in Group 5, all subjects 
in Arm 1 must have initiated treatment before enrollment into Arm 2 can begin.   
Expansion Cohorts: 


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At completion of the dose escalation cohorts, additional subjects will be enrolled in dose 
expansion cohorts to gain further clinical experience, safety and efficacy data in subjects 
with AMG 330.  The dose to be evaluated will be at or below the MTD estimated in the 
dose escalation cohorts.  If there is at least 1 responding subject in the first 10 subjects 
enrolled in the expansion cohort, additional (up to 20) subjects will be enrolled after 
evaluating safety, tolerability and anti-leukemia activity of AMG 330 using all available 
cumulative data.  Additional expansion cohorts testing alternative dose levels or biologic 
subsets may be considered by amendment. 
For each Group, a final estimate of the MTD and/or RP2D will be evaluated and confirmed 
utilizing all DLT-evaluable subjects from the dose escalation and the dose expansion 
cohorts. 
Study Schema: 
The overall study design is described by a study schema at the end of the protocol 
synopsis and below (Figure 1). 
Figure 1. Study Design and Treatment Scheme 
 
 


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3.2 
Sample Size 
It is anticipated that approximately 256 subjects will be enrolled in this study. For the dose 
escalation cohorts, approximately 70 subjects will be enrolled in Group 1 (R/R AML), up 
to 36 subjects will be enrolled in Group 2 (MRD+) and up to 36 subjects will be enrolled in 
Group 3 (MDS).  Up to 30 additional subjects will be enrolled in a dose expansion cohort 
for each group (up to 90 additional subjects total). Approximately 24 subjects will be 
enrolled in the Groups 4 and 5, 6 subjects for each arm in Group 4 and 6-12 subjects in 
Group 5.    
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 3 subjects per cohort, there is a 27-70% probability of observing at least one DLT if 
the true DLT rate is 10-33% and with 6 subjects per cohort, there is a 47-91% probability. 
In the dose expansion cohorts, a subject number of 10 will provide a 65% probability of 
observing at least one adverse event with10% incidence rate and 89% probability of 
observing at least one adverse event with 20% incidence rate. 
Assuming a response rate of less than 5% and at least one subject having a response in 
the first 10 subjects for the enrollment to continue in the expansion cohort, there is greater 
than 59% chance of stopping the expansion cohort.  
Assuming a response rate of greater than 20% and at least one subject having a response 
in the first 10 subjects for the enrollment to continue in the expansion cohort, there is less 
than 11% chance of stopping the expansion cohort. A sample of 30 subjects would provide 
a 96% probability of observing at least one adverse event, when the incidence of the 
adverse event is 10%. A sample of 30 subjects would provide a 100% probability of 
observing at least one adverse event, when the incidence of the adverse event is 20%. 
An exact 80% binomial confidence interval (CI) will be provided for overall response rate.  
With the 10 subjects and 20% overall response rate, the expected 80% CI would be 5.5% 
to 45.0% with the half-width 19.8%.   
Assuming a sample of 30 subjects and 20% overall response rate, the expected 80% CI 
would be 10.9% to 32.5% with the half-width 10.8%. 
3.3 
Adaptive Design 
For MRD+ AML (Group 2) and MDS (Group 3), dose exploration will be guided by pre-
specified monitoring rules, which is based on a modified toxicity probability interval 
algorithm (mTPI-2; Guo et al, 2017) with a target DLT rate of 25% and an acceptable 


Product:  AMG 330 
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CONFIDENTIAL  
 
 
toxicity probability interval of 20%-30%. Consistent with conventional oncology phase 1 
study designs (eg, 3 + 3 design) and given the imprecision with making decisions using 
as few as 3 subjects, in the instance of 1 DLT in the initial 3 subjects at a dose level 
then, as appropriate, the design allows expansion at the dose level beyond 3 subjects. 
 
The mTPI-2 algorithm employs a simple beta-binomial Bayesian model. Let 𝑝𝑇 be the 
target toxicity level and (𝑝𝑇 − ϵ1, 𝑝𝑇 + ϵ2) be the equivalence toxicity interval denoted as EI. 
The unit toxicity interval (0, 1) is divided into subintervals with equal length given by (ϵ1 + 
ϵ2). Let the under-dosing intervals (LI) denote for a set of intervals below EI, and the 
overdosing intervals (HI) for a set of intervals above EI. The 3 types of dosing intervals 
(EI, LI, HI) are associated with 3 different dose escalation decisions. The LI correspond 
to a dose escalation (E), the HI correspond to a dose de-escalation (D), and proper 
dosing intervals (EI) correspond to staying at the current dose (S). This study design 
uses a target toxicity level, 𝑝𝑇 of 25%, and EI of (20%, 30%).  
 
Decision rules are based on the unit probability mass (UPM) calculated on these equal-
length intervals. Given an interval and a probability distribution, the UPM of that interval 
is defined as the probability of the interval divided by the length of the interval. The 
mTPI-2 design calculates the UPMs for the each of equal-length dosing intervals. If the 
interval with the largest UPM is from LI, EI or HI, then the corresponding dose decision 
would be E, S, or D, respectively. 
 
A dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95% or more probability of exceeding the target DLT rate    
pT (ie, P [DLT > 𝑝𝑇 | data] > 95%) with at least 3 evaluable subjects treated and 
evaluated at that dose level. 
 
After the escalation phase is completed, final DLT rates at each dose level will be 
estimated by isotonic regression (Ji et al, 2010). The MTD will be determined as the 
dose level with the DLT estimate closest to the target toxicity level of 25%. In the case of 
dose levels with estimated toxicity of equal distance (tied dose levels) from the target 
toxicity of 25%, the following approach will be used (Ji et al, 2010): among all tied dose 
levels the highest dose level with target toxicity ≤ 25% will be selected, unless all tied 


Product:  AMG 330 
Protocol Number:  20120252 
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Page 15 of 71 
CONFIDENTIAL  
 
 
dose levels have estimated toxicity >25%, in which case the lowest dose level will be 
selected. 
mTPI-2 Trial Monitoring Table 
Number of DLTs 
n=3 
n=4 
n=5 
n=6 
n=7 
n=8 
n=9 
0 
E 
E 
E 
E 
E 
E 
E 
1 
Sa 
S 
S 
E 
E 
E 
E 
2 
D 
D 
D 
D 
S 
S 
E 
3 
DU 
DU 
DU 
D 
D 
D 
D 
4 
. 
DU 
DU 
DU 
DU 
DU 
D 
5 
. 
. 
DU 
DU 
DU 
DU 
DU 
6 
. 
. 
. 
DU 
DU 
DU 
DU 
7 
. 
. 
. 
. 
DU 
DU 
DU 
8 
. 
. 
. 
. 
. 
DU 
DU 
9 
. 
. 
. 
. 
. 
. 
DU 
DLT = dose-limiting toxicity; E = escalate to the next higher dose level; S = stay at the current dose level; 
D = de-escalate to the next lower dose level; DU = current dose is unacceptably toxic; mTPI = modified 
toxicity probability interval.  
a  The original mTPI algorithm was “D” for this case and is modified to “S” to collect more information on this 
dose. The modified decision rule is similar to a 3+3 design. 
 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
4.2 
Subgroups 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses.  The analyses of biomarkers may be performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints. 
A safety analysis of CRS outcomes will be performed for subjects who were administered 
siltuximab in order to assess safety amongst subjects who receive siltuximab due to 
unavailability of tocilizumab for the treatment of CRS. 
5. 
Definitions 
5.1 
General Definitions 
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the clinical 
database. 


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Investigational Product  
The term ‘investigational product’ is used in reference to AMG 330. 
Cumulative Dose of AMG 330 
AMG 330: The cumulative dose in microgram (μg) is defined as the following with 
summation over infusions: 
(duration of infusion (days) for each dose received × dose received [µg/day]) 
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and RR 
interval (msec), as follows:  QTcB=QT/ (RR/1000)1/2. 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: QTcF=QT/ (RR/1000)1/3 
Derivations of QTcB and QTcF will be performed only when not available.  
5.2 
Study Points of Reference 
Baseline 
For any variable, unless otherwise specified, the baseline is the closest value taken prior 
to, or on the day of, the  first administration of AMG 330. For parameters/assessments not 
scheduled to be performed (or scheduled but not performed) on the same day as the first 
administration of AMG 330, the baseline value is the value from the screening period 
measured closest to the day of first administration of AMG 330. 
Baseline and Post-baseline ECG Values in Triplicate  
The baseline ECG is defined as the mean of all pre-dose assessments; the mean of values 
in a triplicate should be calculated before taking the mean of the triplicate averages.  
For all post-baseline ECG, the mean value for measurements taken at the same 
assessment will be calculated and used in the analysis.  
For pre- and post- dose ECG measurements, unscheduled ECG measurements of a 
triplicate will be included in the average for a timepoint. Where an ECG is missing within 
a triplicate, all available data will be averaged for that timepoint. 
Change from Baseline  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  


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Change (absolute) from Baseline = (Post-baseline Value – Baseline Value)  
Percent Change from Baseline 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline 
Value]x100  
5.3 
Study Dates 
Informed Consent Date 
The date on which the subject signs the informed consent form. 
Enrollment Date  
Enrollment date is defined as the date collected on the Subject Enrollment CRF page. 
Study Day 1 
Study Day 1 is defined as the first day that AMG 330 is administered to the subject. 
Study Day  
If date is on or after first administration of AMG 330: study day= (date - date of Study Day 
1) + 1  
If date is prior to date of first administration of AMG 330: study day= (date – date of Study 
Day 1)  
Last Investigational Product Dose Date  
The last IP dose date for each subject is defined as the end date of last infusion of 
AMG330.  
End of Investigational Product (IP) Administration Date 
End of IP Administration for each subject is defined as the date of decision was made to 
end IP reported on the End of IP Administration CRF page. 
End of study (EOS) 
End of study for an individual subject is defined as the date of the final study visit (EOS 
visit) when assessments and procedures are performed.  The EOS visit should occur 
approximately 4 weeks (+ 1 week) after the last dose of AMG 330 or prior to the initiation 
of other AML therapy, whichever occurs earlier.  Subjects who complete the EOS visit will 
be considered to have completed the study. 
Death Date  


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For subjects who die during the study, the death date will be recorded on the end of 
study CRF in the “date subject ended study” field. Incomplete death dates where only 
the day of death date is missing will be imputed using the following rules: 
Day 1 of the month will be used if year and month indicate that death happened in 
different month from last known alive date; 
One day after last known alive date will be used if death happened in the same month as 
last known alive date. 
The imputed death date will be used in calculation of duration of response, progression-
free survival and overall survival.  
Last Known Alive Date 
For subjects not known to have died, their last date known to be alive will be determined 
as the latest date associated with clinic visits before data cutoff date including, for 
example, but not limited to the following: 
 
Date of Enrollment on Subject Enrollment CRF 
 
Date First Taken, Date Last Taken on Concomitant Medications CRF 
 
Date Performed on ECOG Performance Status, Vital Signs, Electrocardiogram, 
Procedures CRFs 
 
Admission Date, Discharge Date on Hospitalizations CRF 
 
Date of Examination on Physical Measurement CRF 
 
Date Collected on Reproductive Status and Pregnancy Test (Local Lab), 
Chemistry (Local Lab), Hematology (Local Lab), Coagulation (Local Lab), 
Urinalysis (local Lab), Immunology (Local lab) CRFs and in central lab data 
 
Date of Assessment on revised IWG response criteria or modified IWG response 
criteria for Time Point in CRFs 
 
Start Date and End Date on Investigational Product Administration CRF 
 
Date Started and Date Ended or Resulted in Death on Events CRF 
 
Start date, stop date on Anti-Cancer Therapies, Other Protocol Required 
Therapy, Other Protocol Required Therapy (
, 
Dexamethasone), Hematopoietic Stem Cell Transplantation Autologous, 
Hematopoietic Stem Cell Transplantation Allogenic CRFs 
 
Subject Status Date if status is Alive on Survival Status CRF 
 
End of study date if the subject’s primary reason for ending study is not “Lost to 
follow-up”. 


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5.4 
Endpoints 
Treatment-Emergent Adverse Event (TEAE)  
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by "Did event start before first dose of 
investigational product (enter response based on earliest administration of 
 
, or AMG330, whichever occurred first)" equal to "No" or missing on the Events 
eCRF and up to 30 days after last administration of AMG330 or end of study date, 
whichever is earlier. Disease related events (DREs) will be included in the TEAE 
summary. 
The severity of each adverse event will be graded using the CTCAE version 4.0. Adverse 
events will be coded using MedDRA. For CRS events, revised grading system will be used 
as per protocol (Lee et al, 2014). 
Treatment-Related AE  
A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by the investigational product. 
Dose Limiting Toxicities (DLT)  
DLT will be determined by “Is this event a Dose Limiting Toxicity (DLT)?” equal to “Yes” 
on the Events eCRF. Investigators will determine whether an adverse event qualifies as a 
DLT per protocol Section 6.2.1.4.  
Overall Response: 
 
Overall response definitions are given below for different indications. 
 
Group 1 in dose-escalation cohort / Group 4 (R/R AML) 
Response is defined as any of the following:  
Complete remission (CR), CR with incomplete recovery (CRi) or morphologic 
leukemia-free state (MLFS) (all according to Revised International Working Group 
[IWG] response criteria for AML), or CR with partial hematologic recovery (CRh). 
 
Group 2 (MRD+ AML) (Primary) 
Response is defined as CR without minimal residual disease (CRMRD-) or CRi 
without minimal residual disease (CRiMRD-). MRD- is defined as MRD threshold 
below 0.1% as per ELN recommendations (Schuurhuis et al., 2018).  
Group 2 (MRD+ AML) (Exploratory) 


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Group 3 (MDS) 
Response is defined as any of the following:  
CR or marrow CR (all according to Revised IWG response criteria for MDS) 
 
Group 5 and Group 1 in dose-expansion cohort (R/R AML) 
Response is defined as any of the following: CRMRD-, CR, CRi, CRh, MLFS, PR. 
 
Minimum Residual Disease (MRD) Response (All groups): 
Minimum residual disease response is defined as MRD negative, indicating 
presence of leukemia cells to 0.1% or lower of white blood cells. 
 
Duration of Response (DOR): 
 
Duration of response is defined as the interval from the date of the first disease 
assessment indicating an overall response to the first documented relapse, disease 
progression, or death due to any cause, whichever occurs first. Subjects without relapse, 
disease progression or death until the analysis data cut-off date will be censored at the 
last adequate disease assessment date. Only subjects with a response will be evaluated 
for DOR. 
DOR time in days =  earlier of (date of first relapse or disease progression or death or date 
of censoring) – date of the first observation of overall response +1.  
DOR time in months= earlier of (date of first relapse or disease progression or death or 
date of censoring) – (date of the first observation of overall response +1)/30.4 
Overall Survival (OS)  
Overall survival is defined as the time from enrollment until death due to any cause. 
Subjects alive will be censored at the last known date. 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 date of last contact through the analysis trigger date. 
Event-free Survival: 
Event-free survival (EFS) is defined as the interval from first administration of AMG 
330 to the earliest of date of treatment failure, relapse for responders, or death due to any 
cause. Censoring is at the last evaluable post-baseline response assessment; otherwise, 


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at first administration of AMG330. For non-responders, the event date for treatment failure 
is assigned as the date of first administration of AMG 330. 
Event-free Survival in days = earlier of (date of treatment failure or relapse or death or 
date of censoring) – date of the first administration of AMG 330 +1.  
Event-free Survival in months = earlier of (date of treatment failure or relapse or death or 
date of censoring) – (date of the first administration of AMG 330 +1)/30.4. 
Time to Response (TTR) 
Time to response defined as the interval from the first administration of AMG 330 to the 
first documentation of response. Time to response is evaluated only for subjects who 
achieved a response.  
Time to response is calculated as the number of days:  
(date of first response – date of study day 1 +1). 
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
analysis set defined in Section 6.1. 
6.1 
Safety Analysis Set 
Safety analysis set is defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 330.  
6.2 
Dose Limiting Toxicity Evaluable Analysis Set 
The DLT-evaluable Analysis Set includes all DLT-evaluable subjects. The analysis of DLT 
will be restricted to the DLT-evaluable Analysis Set.  A subject is not DLT-evaluable if 
he/she drops out before completion of the DLT window for reasons other than an adverse 
event related to study drug or the subject has not received IP treatment for at least 14 
days at the target dose for a 3- or 4-week cycle or at least 7 days at a target dose for a 2-
week cycle. Furthermore, following drug interruptions, if a subject is unable to complete 2 
repeat cycles for reasons other than DLT, the subject will not be DLT evaluable. 
6.3 
Pharmacokinetic (PK) Analysis Set 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
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. 


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7. 
Planned Analyses 
The following data analyses are planned:  (1) dose decision analyses in the 
dose-escalation cohorts, (2) interim analyses for safety and preliminary efficacy updates, 
(3) data analysis prior to public disclosures (e.g. scientific meetings), (4) the primary 
analysis after all dose-escalation and dose-expansion subjects have completed 6 months 
of treatment, and (5) the final analysis after all subjects have ended the study. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Interim analyses are planned after all subjects in each indication and each phase have 
ended the study eg, for R/R AML: all subjects enrolled in Group 1 phase 1a, Groups 4 and 
5 have ended the study. Interim analyses may be combined if the analysis timing is close 
or if the number of subjects in each indication or phase is small. Formal interim analyses 
will be based on locked database. 
Ad-hoc interim analyses for safety and preliminary efficacy updates will be performed.  
Data analysis prior to public disclosures (e.g. scientific meetings) will also be performed.   
Safety data will be reviewed on an ongoing basis.  Amgen, in consultation with the site 
investigators, will review in DLRMs all available cumulative data prior to making dose 
escalation decisions. For R/R AML (Group 1), dose escalation decisions will be made in 
accordance with a standard 3+3 design using the rules noted below. 
 
If no DLT is observed within the DLT window in the initial 3 subjects of a cohort, then 
dose escalation to the next higher dose level cohort will occur. 
 
If 1 DLT is observed within the DLT window in the initial 3 subjects of a cohort, then 
the cohort will be expanded to 6 subjects. If no further DLT(s) are observed in the 
6 subjects, then dose escalation to the next higher dose level cohort will occur.  
If ≥ 2 subjects experience a DLT in a cohort, then enrollment into this cohort will be 
stopped. 
Ad-hoc interim analyses and DLRM will be based on as-is snapshot with routine data 
cleaning. Database will not be locked for these analyses. 
Dose escalation will occur at the planned dose levels until the MTD is determined or until 
the highest dose level is tested.  The MTD is defined as the highest dose level with an 
observed incidence of DLT in < 33% of subjects enrolled in a cohort dose level.  At least 
6 evaluable subjects will be treated at the MTD or highest tested dose.   
The mTPI-2 model will be used to make dosing recommendations for Group 2 and Group 
3 (see section 3.3 for details). Adverse events and DLTs observed in all subjects will be 


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evaluated continually and fully integrated into all DLRMs and considered in all enrollment 
and dosing decisions. 
Enrollment of a cohort can be suspended at any time based on safety findings at any dose 
level and in the expansion cohort, if at any time ≥ 33% of subjects treated at the MTD 
(including those treated at the MTD in the expansion phase) or RP2D experience a DLT 
within the DLT window, and a DLRM will be convened.  In addition, the study may be 
discontinued or modified at any time due to documented safety findings. 
Dose Level Review Team (DLRT)  
For each group, DLRMs will be held to review data, monitor safety, and make 
recommendations on dose escalation / change, or changes in pre-medication.  The DLRT 
will be composed of the investigators or designees, and the following Amgen 
representatives: early development leader, medical monitor, global safety officer or 
designee, clinical study manager, biostatistician, PK scientist (optional), and other 
functional area representatives as appropriate.  A quorum as defined below must be in 
attendance for the DLRM.  The quorum is defined as > 50% of the participating 
investigators 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 required voting members of the DLRT include: investigators, Amgen medical monitor, 
early development leader, and global safety officer or designee.   
The following recommendations can be made by the DLRT: 
- 
dose escalation / de-escalation decisions  
- 
expansion of a cohort 
- 
continuation, delay or termination of dosing 
- 
implementation of dose step(s) 
- 
extension of the run-in phase in case of dose step(s)  
- 
extension of the duration of treatment cycles 
- 
implementation of mandatory steroid pre-treatment in case of cytokine release 
syndrome-related adverse events 
- 
enrollment of additional subjects in the expansion cohort 
- 
duration of the DLT period based on emergent safety data 


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- 
level and duration of dose steps (schedule) adjustment based on safety, and 
available PK and PD data 
All available study data, including demographics, IP 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.  Data will not 
need to be source data verified and queries will not need to be resolved prior to the DLRM.   
Subject’s 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 the first 5 subjects have at least completed their first treatment 
cycle plus two weeks or dropped out of treatment / study, whichever occurs earlier. Once 
the first 10 subjects have at least completed their first treatment cycle plus two weeks or 
dropped out of study, all available study data will be reviewed by the DLRT. If there is at 
least 1 responding subject within these first 10 subjects, the DLRT will determine if an 
additional (up to 20) subjects may be enrolled.  If additional subjects are enrolled after the 
first 10 subjects, all available study data will be reviewed (with recruitment ongoing) by the 
DLRT after every 5 subjects have at least completed their first treatment cycle plus two 
weeks or dropped out of treatment / study.  Ad hoc meetings may be convened any time 
in case of important safety events 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject either 
completes 6 months on study or terminated the study early. Primary analysis will be based 
on locked database to prevent further changes. 
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 approximately 6 months after enrollment of the last study subject. Final 
analysis will be based on locked database to prevent further changes. 
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. 


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8.2 
Data Handling and Electronic Transfer of Data 
Amgen’s Clinical Data Management department will provide all data to be used in the 
planned analyses. Details of PK, Antibody, and external lab data transfer to the database 
will be outlined in the Clinical Data Management Plan (DMP). See details of this section 
in the DMP. 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 A. 
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.  
 
Biomarker data that are below the quantification limits will be considered equal to 
half of the lower limit of quantification for all analyses unless specified otherwise. 
 
PD concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PD 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. 
8.5 
Outliers 
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 CPMS practices. 
All excluded observations will be detailed by CPMS along with reasons for exclusion, in 
accordance with standard CPMS practices. 
Pharmacodynamic (PD) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard PD evaluation practice. Descriptive statistics will be used to identify potential 
outliers in key variables.  


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Suspected outliers will be included in all analyses unless there is sufficient scientific 
justification to exclude them. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. 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 demographic, safety, PK, PD and 
biomarker data by dose, dose schedule, time as appropriate, and each indication (Group1, 
Group2, Group3) separately. Unless otherwise stated, the data analysis will be conducted 
using subjects in the Safety Analysis Set. 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.  When data are summarized by time, the values recorded against 
the scheduled time points listed in the protocol will be used. When assessing 
minimum/maximum increases or decreases over the study, all assessments, including 
unscheduled assessments will be used. Data listings will include all available data from all 
enrolled subjects unless specified otherwise. Additional analysis for Group 4 and Group 5 
will be specified in SSAP. 
Data analysis will occur at the following time points:  
 
Interim analyses as described in Section 7.1. 
• 
The primary analysis will occur when target enrollment is complete and each 
subject either completes 6 months on study or terminated the study early.  


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• 
A final analysis is planned after all dose-escalation cohorts and dose-expansion 
subjects have ended the study. 
Confidence intervals 80% and 95% (CI) for proportions will be estimated using an exact 
method proposed by Clopper and Pearson, 1934. 
9.2 
Subject Accountability 
A summary of subject disposition with discontinuation reasons, and AMG 330 completion 
and discontinuation will be provided. Key study dates for the first subject enrolled, last 
subject enrolled, and last subject’s end of study will be presented.   
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 course of the study.  Eligibility deviations are defined in the protocol. A 
subject listing and summary table will be provided for Important Protocol Deviations. 
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristic will be summarized using 
descriptive statistics. If multiple races have been reported for a subject, the subject will be 
categorized as multiple race as well as by the combination of race.  
The baseline characteristics to be summarized include:  
Demographic  
 
Sex: Male, Female 
 
Age: 18-64, 65-74, 75-84, >=85 
 
Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other  
 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
Baseline characteristics for R/R AML 
 
Height  
 
Weight 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Type of AML (at initial diagnosis and at study entry) 
 
Prior lines of therapies 


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 
Responses to the prior lines of therapies 
 
Prior hematopoietic stem cell transplant 
 
Disease duration 
 
Bone marrow blast 
 
Baseline Tumor Burden 
 
ELN risk classification (at initial diagnosis and at study entry) 
 
White blood cells 
 
Absolute Neutrophil count 
 
Platelet count 
Baseline characteristics for MRD 
 
Height  
 
Weight 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Type of AML (at initial diagnosis and at study entry) 
 
MRD status 
 
Prior lines of therapies 
 
Responses to the prior lines of therapies 
 
Prior hematopoietic stem cell transplant 
 
Disease duration 
 
Bone marrow blast 
 
Baseline Tumor Burden 
 
White blood cells 
 
Absolute Neutrophil count  
 
Platelet count 
 
Baseline characteristics for MDS  
 
Height  
 
Weight 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Type of MDS (at initial diagnosis and at study entry) 
 
MDS Risk(IPSS-R) (at initial diagnosis and at study entry) 


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 
MDS status at study entry 
 
Prior lines of therapies 
 
Responses to the prior lines of therapies 
 
Prior hematopoietic stem cell transplant 
 
Disease duration 
 
Bone marrow blast 
 
Baseline Tumor Burden 
 
White blood cells 
 
Absolute Neutrophil count 
 
Platelet count 
9.5 
Efficacy Analyses   
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
  No efficacy parameter is considered in primary endpoints 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The proportion of subjects with an overall response (Section 5.4) with corresponding exact 
80% and 95% Confidence Intervals will be calculated using the Clopper-Pearson method 
(Clopper and Pearson, 1934) by cohort. The proportion of subjects who are event-free at 
6 months with corresponding exact 80% CI will be calculated using the Clopper-Pearson 
method. The proportion of subjects with MRD response at the 0.1% threshold and the 
0.01% threshold amongst subjects in the Safety Analysis Set will be summarized by 
cohort. 
Listings indicating time to response, duration of response (DOR), and event-free survival 
will be produced for responders for each indication separately. For subjects in dose 
expansion cohorts, Kaplan Meier curves may be presented for event-free survival and 
overall survival with estimates for rates and 80 CI at selected weeks. DOR and time to 
response will only be analyzed for subjects who achieved an overall response.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
The following statistical analyses will be considered exploratory and will be performed by 
clinical biomarker group in Department of Translational Medicine only when deemed 
appropriate. Relationships between changes in tumor dynamics and above biomarkers of 
interest listed as exploratory endpoints will be explored. Changes in expression levels of 
biomarkers and their relationship to dose may also be explored. Summary statistics over 
time will be provided and graphical presentations may be used. The relationship between 


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AMG 330 exposure and PD effects and related biomarkers in blood, or tumor specimens 
and/or AMG 330 exposure and clinical outcomes (eg, tumor response) will be also 
explored if deemed appropriate. Details of analysis will be provided in a Contributing 
Scientific Report for exploratory biomarker analysis. Pharmacodynamic (PD) biomarkers 
for AMG 330 mechanism of action (Depletion of LSCs, Lymphocyte counts, CD33+ 
monocytes ,T cells,  T cell activation (including T cell subsets), Other immune subsets, 
 
 
 
. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
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 330. Unless otherwise noted, treatment groups will be 
defined based on the planned doses for Cycle 1.  
9.6.2 
Analyses of Dose Limiting Toxicities 
The analysis of Dose limiting toxicities (DLT) will be based on the DLT Evaluable Analysis 
Set. A listing and summary of the subject incidence of dose limiting toxicities (DLT) will be 
provided.   
9.6.3 
Adverse Events and Disease-related Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later will be 
used to code all events categorized as adverse events and disease-related events to a 
system organ class and a preferred term. 
The subject incidence of adverse events (including disease related events) will be 
summarized for all treatment-emergent adverse events, 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 grade. In addition, SAEs and grade 3 and above adverse events will be 
summarized by preferred term in descending order of frequency.  
The severity of each adverse event will be graded using Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 criteria with the exception of cytokine release 


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syndrome (CRS), which will be graded using the criteria referenced in the publication by 
Lee et al (2014). 
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term and worst grade. CRS will be summarized by grade and symptom.  
TEAE summaries will be provided both by cohort and by overall groups. 
9.6.4 
Laboratory Test Results  
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each 
subject for DLRM. Values outside the normal laboratory reference ranges will be flagged 
as high or low on the listings. 
In interim, primary and final analyses, depending on the size and scope of changes in 
selected laboratory data, summaries of selected 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. Unscheduled assessments will be 
included in these summaries. 
9.6.5 
Vital Signs  
Vital signs data will be listed and reviewed for each subject for DLRM.  
In interim, primary and final analyses, depending on the size and scope of changes, 
summaries of vital signs (resting systolic/diastolic blood pressure, heart rate, respirations 
and temperature) data over time and/or changes from baseline over time may be provided. 
Unscheduled assessments will be included in these summaries. 
9.6.6 
Physical Measurements  
The change in weight from baseline to each scheduled assessment time point will be 
summarized.  
9.6.7 
Electrocardiogram  
All on-study electrocardiogram (ECG) data (QRS, QT, QTc, RR, and PR intervals) will be 
listed. 
Where multiple 12-lead ECG measurements are taken at the same assessment (they are 
planned to be recorded in triplicate <30 seconds apart) the mean value will be calculated 
and used in the analysis. Their primary approach will include all measurements taken at 
the assessment for the derivation of the mean value. The baseline ECG is defined as the 


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mean of all pre-dose assessments; the mean of values in a triplicate should be calculated 
before taking the mean of the triplicate averages. 
In the event of extreme outlier readings, an additional sensitivity analysis will be conducted 
where the outlier measurement is excluded from the derivation of the mean for that 
assessment. The criteria used to define an outlier measurement will be determined based 
upon inspection of the data.  
For pre- and post- dose ECG measurements, unscheduled ECG measurements taken up 
to 5 minutes after the last assessment of a triplicate will be included in the average for a 
time point. Where an ECG is missing within a triplicate, all available data will be averaged 
for that time point. 
Summaries over time and/or changes from baseline over time will be provided for all 12-
lead ECG parameters. The analysis of Fridericia’s (QTcF) QT correction and Bazett’s 
(QTcB) QT correction will be performed. 
Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcF and QTcB. Unscheduled assessments will be included in the 
determination of the maximum change. 
 
<= 30 msec 
 
30 – 60 msec  
 
>60 msec  
The number and percentage of subjects in each group will be summarized. A listing of the 
subjects with > 60 msec change from baseline in QTcF and QTcB will be provided. 
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF and QTcB. Unscheduled assessments will be included in the determination 
of the maximum post baseline value. 
 
<= 450 msec  
 
> 450 – 480 msec  
 
> 480 – 500 msec  
 
> 500 msec  
The number of subjects in each group will be summarized for each dosing group. A listing 
of the subjects with > 500 msec post baseline in QTcF and QTcB will be provided. 


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9.6.8 
Antibody Formation  
The incidence and percentage of subjects who develop anti-AMG 330 antibodies (binding) 
at any time by cohorts and indication (Group1, Group2, Group3) will be tabulated. Positive 
anti-AMG 330 antibody data will be listed and reviewed for each subject.  The impact of 
immunogenicity on safety may be explored by assessing adverse events and serious 
adverse events. 
9.6.9 
Exposure to Investigational Product  
Details of AMG 330 administration will be listed for every subject for DLRM. In primary 
and final analyses, a listing of the unique manufacturing lot numbers, and a listing of the 
subjects administered each manufacturing lot number will be provided. Descriptive 
statistics will be produced to describe the number of cycles initiated, completed and 
discontinued, the duration of therapy and the cumulative dose will be produced to describe 
the exposure to investigational product by groups and dose cohorts separately. 
9.6.10 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary.  A subject listing of all 
concomitant medications will be presented for DLRM. In the interim, primary and final 
analyses, the number and proportion of subjects receiving concomitant medications will 
be summarized by preferred term for each treatment group and indication as coded by 
the World Health Organization Drug (WHO DRUG) dictionary. 
9.7 
Other Analyses  
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
For AMG 330, pharmacokinetic parameters half-life, steady-state concentration, volume 
of distribution, and clearance) 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 330 exposure and either pharmacodynamic effect and/or clinical outcome 
may also be performed. 
Serum concentrations of AMG 330 will be determined using a validated assay. Parameters 
to characterize cellular kinetics related to cell expansion (eg, Cmax, Tmax and partial AUC) 
and cell persistence (eg, T1/2, Tlast and Clast) in PBMCs, parameters will be estimated using 
standard non-compartmental approaches and summarized by dose level using means, 
standard deviations, medians, minimums, and maximums.  


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Serum concentrations below the lower limit of quantifications will be set to zero for the 
estimation of the cellular kinetic 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 Cellular kinetic analyses, including but not limited to analysis of the relationship 
between AMG 330 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 330 exposure and either 
Pharmacodynamic effect and/or clinical outcome may also be performed. 
A preliminary assessment of dose proportionality will be made using the Power Model 
Statistical analysis of AUC(0-t) and Cmax of AMG 330 will be performed after log 
transformation of the data. The Power Model:  
Y = α doseβ 
where Y is the pharmacokinetic parameter and α is an intercept term. This becomes a 
linear relationship following a logarithmic transformation, to which a linear regression 
approach can be applied as,  
 log(Y) = β ×  log (dose) + log(α) 
The coefficient of the slope with 90% confidence intervals, on the log scale, will be 
calculated. 
Descriptive statistics will be provided for biomarker data by dose, dose schedule, and time 
as appropriate. 
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 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses. The analyses of biomarkers will be considered exploratory and may be 
performed after collection of all samples during the conduct of the study and therefore may 


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be reported after the primary analysis. Changes in expression or expansion level of 
biomarkers and their relationship to dose may be evaluated. Summary statistics over time 
may be provided and graphical presentations may be used. Details of analysis will be 
provided in Contributing Scientific Report for exploratory biomarker analysis. 
10. 
Changes From Protocol-specified Analyses 
 
The following inclusions in the SAP are in anticipation of incorporation in Protocol 
Amendment 10: 
o event-free survival endpoints replacing time to progression in R/R AML and 
MDS groups to address relapse/refractory AML subjects who are already 
in a progressive state and never respond. 
o removal of duration of response endpoint for MRD+ AML group 
o overall survival for all groups in the expansion cohort  
o Treatment-emergent definition accounts for long-term follow-up by defining 
events as treatment-emergent by looking up to the earlier of 30 days after 
last dose of AMG 330 or end of study date.  
o Summary of adverse events amongst subjects who take siltuximab.  


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11. 
Literature Citations / References 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka 1934; 26, 404-13.  
12. 
Prioritization of Analyses 
 NA 
13. 
Data Not Covered by This Plan 
NA 


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14. 
Appendices 
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates 
Imputation Rules for Partial or Missing Dates for Adverse Events and Concomitant 
Medications 
 
 
 
 
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: 
 
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. 
 


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 
If yyyymm for the date last known to be alive is greater than yyyymm for death date, 
assume death date is in error, do not impute and censor the subject survival time. 
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 
death date is in error, do not impute and censor the subject survival time. 
If a death date is totally missing: 
Do not impute and censor the subject survival time. 
 


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Appendix C. Summary of Changes  
Protocol Title: 
Replace: 
A Phase 1 First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 330 Administered as Continuous Intravenous 
Infusion in Subjects With Relapsed/Refractory Acute Myeloid Leukemia. 
With: 
A Phase 1 First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 330 Administered as Continuous Intravenous 
Infusion in Subjects with Myeloid Malignancies. 
 
Section: Objectives, Endpoints and Hypotheses, Hypotheses and/or Estimation 
Primary Objectives:   
Replace: 
 
Evaluate the safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory Acute Myeloid Leukemia (AML) 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
[eg, recommended phase 2 dose (RP2D)]  
With: 
 
Evaluate the safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory AML, MRD AML and MDS 
 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
[eg, recommended phase 2 dose (RP2D)] of AMG 330 in adult with relapsed/refractory 
AML, MRD+AML and MDS 
Secondary Objectives:   
Replace: 
 
the duration of response and time to response and time to progression 
With: 
 
the duration of response, event-free survival, time to response, and overall survival 
Added: 
 
the number and proportion of subjects with MDS who respond to treatment with AMG 
330. Response is defined as any of the following: CR or marrow CR (all according to 
Revised IWG response criteria).  
 
the number and proportion of subjects with MRD-positive AML (Group 2) who respond 
to treatment with AMG 330. Response is defined as conversion from MRD+ status 
with 0.1% threshold to MRD- status. 
Exploratory Objectives:   
Added: 


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 
Evaluate the effect of 
 premedication and alternative dosing 
schedules on the safety and tolerability of AMG 330 in adult subjects with 
relapsed/refractory AML  
 
Explore the additional thresholds of conversions to MRD- status in MRD+ AML 
subjects as an efficacy measure for AMG 330 treatment 
Deleted: 
 
Evaluate potential effect of AMG 330-mediated cytokine elevation on hepatic CYP3A 
activity. 
Primary Endpoint:   
Replace: 
 
Safety: subject incidence and grade of adverse events and DLTs. 
With: 
 
Safety:  subject incidence and grade of adverse events (AEs) and dose limiting 
toxicities (DLTs). 
Secondary Endpoints:   
Replace: 
 
Incidence of anti-AMG 330 antibody formation. 
 
Efficacy parameters: response (response defined as CR, CRi, morphologic leukemia-
free state [per modified IWG criteria] or CRh*), time to progression, duration of 
response, time to response. 
With: 
 
Anti-AMG 330 antibody formation 
 
Efficacy 
parameters 
for 
R/R 
AML: 
response 
(response 
defined 
as 
CR/CRi/morphologic leukemia-free state [per modified IWG criteria] or CRh), duration 
of response, time to response, event-free survival and overall survival (duration of 
response, event-free survival, and overall survival will only be measured in the 
expansion cohort). 
Added: 
 
Efficacy parameters for MRD-positive AML: response rate (response defined as 
conversion from MRD+ status with 0.1% threshold to MRD-), time to response, 
relapse-free survival, and overall survival (relapse-free survival and overall survival 
will only be measured in the expansion cohort) 
 
Efficacy parameters for MDS: response (response defined as CR or marrow complete 
remission [per International Working Group (IWG) standardized response criteria]), 
duration of response, event-free survival, time to response, event-free survival and 
overall survival (duration of response, event-free survival, and overall survival will only 
be measured in the expansion cohort) 
Exploratory Endpoints:   
Replace: 


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 
Lymphocyte counts, CD33+ monocytes and T cells, as well as T cell activation 
(including T cell subsets). 
With: 
 
Lymphocyte counts, cluster of differentiation (CD) 33+ monocytes and T cells, as well 
as T cell activation (including T cell subsets).  Other immune subsets may also be 
examined. 
Added: 
 
 
 
 
 
 
 
Frequency and severity of cytokine release syndrome (CRS) and other AEs following 
 premedication, and alternative dose step schedules of 
AMG330
Deleted: 
 
Quantification of CYP3A enzyme activity with markers (eg, plasma levels of 4β-
hydroxycholesterol, urinary 6β-hydroxycortisol/cortisol ratio level, CYP3A5*3 
genotype etc.)  
Hypotheses and/or Estimations: 
Replace: 
AMG 330 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML. 
With: 
AMG 330 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML and MDS. 
 
Section: Study Overview, Study Design, Sample Size, Adaptive Design 
Replace: 
Study Design: 
This is a first in human, open-label, phase 1 sequential dose escalation study. AMG 330 
will be evaluated as a continuous intravenous (cIV) infusion in adult subjects with 
relapsed/refractory AML.  
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) of AMG 330. Planned dose levels for the dose-escalation 
cohorts are as follows: 0.5, 
, and 960 μg/day.  
It is anticipated that two MTDs may be estimated, one for the initial dosing and one for the 
subsequent dosing. Each MTD will be estimated following 3+3 decision rules. Intermediate 
dose level(s) may be evaluated as necessary. In the event that one subject experiences 


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a DLT, then the dose administered for successive cohorts will escalate by no more than 
50% (ie, a dose increment of no more than 1.5 times the previous dose) after discussion 
at the Dose Level Review Meeting (DLRM).  
At completion of the dose escalation cohorts, additional subjects (up to 10) will be enrolled 
in a dose expansion cohort to gain further clinical experience, safety and efficacy data in 
subjects with AMG 330. 
With: 
Study Design: 
This is a first-in-human, open-label, phase 1 sequential dose escalation study.  AMG 330 
will be evaluated as a continuous intravenous (cIV) infusion in adult subjects with 
relapsed/refractory (R/R) AML (Group 1), MRD+ AML (Group 2) and MDS (Group 3).  The 
study will be conducted at approximately 17 sites in Germany, the Netherlands, Japan, 
the United States and Canada.  
The dose-escalation cohorts will estimate the MTD/biologically active dose, safety, 
tolerability, PK, and pharmacodynamics (PD) of AMG 330.   
For R/R AML (Group 1), planned dose levels for the dose-escalation cohorts are as 
follows: 0.5, 
 and 960 µg/day. 
Intermediate and/or higher dose level(s) up to 1.6 mg of AMG 330 may be evaluated as 
necessary to reach MTD. The same dose level may be tested in multiple cohorts, but with 
different dose steps and/or different cycle lengths.   
For MRD+ AML (Group 2), planned dose levels for the dose-escalation cohorts are as 
follows: 
and 960 µg/day.  Each target dose level will be preceded by dose 
steps and additional dose level(s) up to 1.6 mg of AMG 330 may be evaluated as 
necessary. Escalation can continue until MTD for MDS is established. Selected target 
dose levels, with the exception of the maximal tested dose, that have been deemed safe 
in subjects with R/R AML (Group 1) could be skipped in Group 3 phase 1a dose escalation 
cohorts based on available safety, PK, and PD data if recommended by the DLRT. 
It is anticipated that more than one MTD may be estimated, one for each dose step and 
one for the target dose.  Should the initial dose be limited by adverse events related to 
first dose effects (eg, cytokine release syndrome [CRS]), the second MTD for the target 
dose will be estimated after giving the initial dose at MTD (dose step). Starting with cohort 
6 (R/R AML, Group 1), a dose step in each cycle is mandatory for all newly enrolled 
subjects. Administration of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 


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hour prior to the dose step for prevention of cytokine release is mandatory. The additional 
assessments described in the schedule of assessments for dose steps (in Protocol Table 
14) apply.  


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For MDS (Group 3), planned dose levels for dose-escalation cohorts are as follows: 
 
 and 960 µg/day. Each target dose will be preceded by dose steps. Intermediate 
dose steps and additional dose level(s) up to 1.6 mg of AMG 330 may be evaluated as 
necessary. Escalation can continue until MTD for MDS is established. 
It is anticipated that more than one MTD may be estimated, one for each dose step and 
one for the target dose.  Should the initial dose be limited by adverse events related to 
first dose effects (eg, cytokine release syndrome [CRS]), the second MTD for the target 
dose will be estimated after giving the initial dose at MTD (dose step). Starting with cohort 
6 (R/R AML, Group 1), a dose step in each cycle is mandatory for all newly enrolled 
subjects. Administration of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 
hour prior to the dose step for prevention of cytokine release is mandatory. The additional 
assessments described in the schedule of assessments for dose steps (in Protocol Table 
14) apply.  


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Replace: 
Dose Escalation: 
For both MTDs (initial and target dose), dose escalation will estimate the MTD. The 
estimated MTD is defined as the maximum dose at which fewer than one-third of subjects 
experience as dose limiting toxicity (DLT) (minimum of 6 evaluable subjects). Dose 
Escalation will be conducted in two stages. In the single subject cohorts, single subjects 
will be enrolled at dose levels anticipated to be lower than those at which adverse events 


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will be observed. Once higher dose levels are open for enrollment or when drug related 
safety or efficacy signals are observed, the 3+3 design will be triggered.  
The starting dose and dose level schema is shown below in Table. 
Single Subject Cohorts: 
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. AMG 330 will initially be 
administered at escalating doses in a 2 weeks on / 1-4 weeks off schedule. This schedule 
may be modified by DLRT decision (see section 6.2.1.1 of protocol for details).  
The 3+3 design will be triggered if at least 1 subject experiences any of the  
following drug related safety or efficacy signals (whichever is earlier):  
 
Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 adverse 
events other than thrombocytopenia, anemia, or neutropenia  
 
DLT  
 
Objective response  
Multiple Subject Cohorts (3+3 Dose Level Decision Rules): 
It is anticipated that up to 8 additional cohorts will be enrolled using a standard 3+3 design. 
Each cohort will enroll up to 6 evaluable subjects. There will be at least a 96-hour interval 
between the start of treatment of the first and second subject in each cohort. 
Communication of safety data (clinical, basic laboratory and vital signs) to the sponsor 


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and other sites will occur during this period as needed before dosing other subjects. 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. Following this, no more than 
3 subjects should be enrolled in two weeks. Enrollment number decision rules for any 
given dose level cohort are shown in the table below.  
 
For each DLRM (refer to Appendix D), the DLRT will determine the values for dose 
escalation/de-escalation as well as determine the appropriateness of the upcoming 3+3 
decision rules.  
DLRT may select the proposed recommended phase 2 dose(s) (RP2D) even when the 
MTD is not yet reached. Once the proposed RP2D is identified, AMG 330 will be evaluated 
in expansion cohorts for each of the selected tumor subtypes.  
With: 
Dose Escalation: 
For Group 1 (R/R AML), dose escalation will be conducted in two stages.  In the single 
subject cohorts, single subjects will be enrolled at dose levels anticipated to be lower than 
those at which adverse events related to AMG 330 will be observed.  Once higher dose 
levels are open for enrollment or drug related safety or efficacy signals are observed, 
multiple subject cohorts of up to 6 subjects per dose level will open for enrollment (3+3 
design).  Subjects who complete the DLT period may proceed to a higher dose level for 
the following treatment cycle if no DLT has been reported for either this subject or any 
other subject in this dose cohort after completion of the DLT period, and once the next 
dose cohort is open for enrollment. (see Section 7.2.2 in protocol for details on 
assessments applicable in case of intra-subject dose escalation). 


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In Group 1 (R/R AML), should the initial dose be limited by adverse events related to first 
dose effects (eg, CRS), dose steps will be implemented. An optimal dose step schedule 
and MTD for the target dose will be estimated following decision rules. 
For Groups 2 and 3 (MRD+ AML and MDS), each dose escalation cohort will enroll a 
minimum of 3 to a maximum of 9 evaluable subjects. Dose escalation will be guided by a 
modified toxicity probability interval approach (mTPI-2; Guo et al, 2017). The DLRT will 
review all available safety, laboratory, PK and PD data and provide dose-finding 
recommendations.  
For Groups 1, 2 and 3, enrollment will occur simultaneously, and each Group will progress 
from the dose escalation to the dose expansion independently. The total number of 
subjects to be enrolled for the dose escalation will depend on the toxicities observed as 
the study progresses. Additional subjects may be required if other dose levels or alternate 
treatment schedules are explored. 
Enrollment in Group 4 is independent from enrollment in Groups 1, 2 and 3. For Group 4, 
enrollment in Arm 1 will occur first. Once all subjects in Arm 1 have initiated treatment, 
enrollment into Arm 2 will begin. Once all Group 4 subjects have completed the DLT 
period, enrollment into Group 5 can commence. If there are 2 arms in Group 5, all subjects 
in Arm 1 must have initiated treatment before enrollment into Arm 2 can begin. 
Replace:  
Expansion Cohort: 
The objective of dose expansion is to get further safety and efficacy data in subjects. At 
completion of the dose escalation cohorts, additional subjects (up to 10) will be enrolled 
in a dose expansion cohort to gain further clinical experience, safety and efficacy data in 
subjects with AMG 330. 
The dose or doses to be evaluated in the expansion phase will be based on results from 
the dose escalation phase. Subjects may be enrolled continuously (ie, without waiting for 
Cycle 1 completion of patients who have received the first dose) unless there is a more 
than 33% incidence of DLTs at any given time. After 10 subjects enroll in the expansion 
cohorts, TPI Bayesian model will be used to re-challenge the MTD concluded in dose 
escalation phase. The subsequent subjects to be enrolled in dose expansion may be 
dosed with the updated dose level, determined by the DLRT. Once all subjects are 
enrolled in expansion cohort and complete the DLT window, a final estimation of the RP2D 


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CONFIDENTIAL  
 
 
will be made based on the TPI Bayesian model utilizing all DLT-evaluable subjects from 
the dose escalation and dose expansion. 
 
With: 
Expansion Cohort: 
At completion of the dose escalation cohorts, additional subjects will be enrolled in dose 
expansion cohorts to gain further clinical experience, safety and efficacy data in subjects 
with AMG 330.  The dose to be evaluated will be at or below the MTD estimated in the 
dose escalation cohorts.  If there is at least 1 responding subject in the first 10 subjects 
enrolled in expansion cohort, additional (up to 20) subjects will be enrolled after evaluating 
safety, tolerability and anti-leukemia activity of AMG 330 using all available cumulative 
data.  Additional expansion cohorts testing alternative dose levels or biologic subsets may 
be considered by amendment. 
For each Group, a final estimate of the MTD and/or RP2D will be evaluated and confirmed 
utilizing all DLT-evaluable subjects from the dose escalation and the dose expansion 
cohorts. 
Study Schema: 
The overall study design is described by a study schema at the end of the protocol 
synopsis and below (Figure 1). 
Figure 1. Study Design and Treatment Scheme 


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Replace: 
Sample Size: 
It is anticipated that approximately 50 subjects will be enrolled in this study. Approximately 
40 subjects will be enrolled in the dose escalation cohorts and up to 10 additional subjects 
will be enrolled in the dose expansion cohort.  
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 
3 subjects per cohort, there is a 27-70% probability of observing at least one DLT if the 
true DLT rate is 10-33% and with 6 subjects per cohort, there is a 47-91% probability.  
In the dose expansion cohort, a subject number of 10 will provide a 65% probability of 
observing at least one adverse event with 10% incidence rate and 89% probability of 
observing at least one adverse event with 20% incidence rate. An exact 80% binomial 
confidence interval (CI) will be provided for overall response rate. With the 10 subjects 
and 20% response rate, the expected 80% CI would be 5.5% to 45.0% with the half-width 
19.8%. 
With: 
Sample Size: 


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Added: 
Adaptive Design: 
For MRD+ AML (Group 2) and MDS (Group 3), dose exploration will be guided by pre-
specified monitoring rules, which is based on a modified toxicity probability interval 


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algorithm (mTPI-2; Guo et al, 2017) with a target DLT rate of 25% and an acceptable 
toxicity probability interval of 20%-30%. Consistent with conventional oncology phase 1 
study designs (eg, 3 + 3 design) and given the imprecision with making decisions using 
as few as 3 subjects, in the instance of 1 DLT in the initial 3 subjects at a dose level then, 
as appropriate, the design allows expansion at the dose level beyond 3 subjects. 
The mTPI-2 algorithm employs a simple beta-binomial Bayesian model. Let 𝑝𝑇 be the 
target toxicity level and (𝑝𝑇 − ϵ1, 𝑝𝑇 + ϵ2) be the equivalence toxicity interval denoted as 
EI. The unit toxicity interval (0, 1) is divided into subintervals with equal length given by 
(ϵ1 + ϵ2). Let the under-dosing intervals (LI) denote for a set of intervals below EI, and the 
overdosing intervals (HI) for a set of intervals above EI. The 3 types of dosing intervals 
(EI, LI, HI) are associated with 3 different dose escalation decisions. The LI correspond to 
a dose escalation (E), the HI correspond to a dose de-escalation (D), and proper dosing 
intervals (EI) correspond to staying at the current dose (S). This study design uses a target 
toxicity level, 𝑝𝑇 of 25%, and EI of (20%, 30%).  
Decision rules are based on the unit probability mass (UPM) calculated on these equal-
length intervals. Given an interval and a probability distribution, the UPM of that interval is 
defined as the probability of the interval divided by the length of the interval. The mTPI-2 
design calculates the UPMs for the each of equal-length dosing intervals. If the interval 
with the largest UPM is from LI, EI or HI, then the corresponding dose decision would be 
E, S, or D, respectively. 
A dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95% or more probability of exceeding the target DLT rate    pT 
(ie, P [DLT > 𝑝𝑇 | data] > 95%) with at least 3 evaluable subjects treated and evaluated at 
that dose level. 
After the escalation phase is completed, final DLT rates at each dose level will be 
estimated by isotonic regression (Ji et al, 2010). The MTD will be determined as the dose 
level with the DLT estimate closest to the target toxicity level of 25%. In the case of dose 
levels with estimated toxicity of equal distance (tied dose levels) from the target toxicity of 
25%, the following approach will be used (Ji et al, 2010): among all tied dose levels the 
highest dose level with target toxicity ≤ 25% will be selected, unless all tied dose levels 
have estimated toxicity >25%, in which case the lowest dose level will be selected. 


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Section:  Covariates and Subgroups, Definitions 
Added: 
Planned Covariates: 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
Subgroups: 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses.  The analyses of biomarkers may be performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints. 
 
 
. 
Definitions: 
General Definitions 
Added: 
Investigational Product  
The term ‘investigational product’ is used in reference to AMG 330. 
Cumulative Dose of AMG 330 
AMG 330: The cumulative dose in microgram (μg) is defined as the following with 
summation over infusions: 
(duration of infusion (days) for each dose received × dose received [µg/day]) 
Study Points of Reference 
Replace: 


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Change from Baseline  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  
Change From Baseline Change (absolute) from Baseline=(Post-baseline Value – 
Baseline Value)  
Change (percent) from Baseline=[(Post-baseline Value – Baseline Value)/Baseline 
Value]x100 
With: 
Change from Baseline  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value)  
Percent Change from Baseline 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline 
Value]x100  
Study Dates 
Replace: 
Enrollment Date 
Enrollment date is defined as the enrolled on day 1 (cycle 1 day 1) when the cIV infusion 
with investigational product (AMG 330) is started. 
Study Day  
Post study day= (date - date of Study Day 1) + 1  
Pre study day: study day= (date – date of Study Day 1)  
Study Day 1 
It is defined as the first day that protocol-specified investigational product(s)/protocol 
required therapies is/are administered to the subject. 
With: 
Enrollment Date  
Enrollment date is defined as the date collected on the Subject Enrollment CRF page. 
Study Day  
If date is on or after first administration of AMG 330: study day= (date - date of Study Day 
1) + 1  
If date is prior to date of first administration of AMG 330: study day= (date – date of Study 
Day 1)  


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Study Day 1 
Study Day 1 is defined as the first day that AMG 330 is administered to the subject. 
Added: 
Informed Consent Date 
The date on which the subject signs the informed consent form. 
End of Investigational Product (IP) Administration Date 
End of IP Administration for each subject is defined as the date of decision was made to 
end IP reported on the End of IP Administration CRF page. 
End of study (EOS) 
End of study for an individual subject is defined as the date of the final study visit (EOS 
visit) when assessments and procedures are performed.  The EOS visit should occur 
approximately 4 weeks (+ 1 week) after the last dose of AMG 330 or prior to the initiation 
of other AML therapy, whichever occurs earlier.  Subjects who complete the EOS visit will 
be considered to have completed the study. 
Death Date  
For subjects who die during the study, the death date will be recorded on the end of 
study CRF in the “date subject ended study” field. Incomplete death dates where only 
the day of death date is missing will be imputed using the following rules: 
Day 1 of the month will be used if year and month indicate that death happened in 
different month from last known alive date; 
One day after last known alive date will be used if death happened in the same month as 
last known alive date. 
The imputed death date will be used in calculation of duration of response, progression-
free survival and overall survival.  
Last Known Alive Date 
For subjects not known to have died, their last date known to be alive will be determined 
as the latest date associated with clinic visits before data cutoff date including, for 
example, but not limited to the following: 
 
Date of Enrollment on Subject Enrollment CRF 
 
Date First Taken, Date Last Taken on Concomitant Medications CRF 


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 
Date Performed on ECOG Performance Status, Vital Signs, Electrocardiogram, 
Procedures CRFs 
 
Admission Date, Discharge Date on Hospitalizations CRF 
 
Date of Examination on Physical Measurement CRF 
 
Date Collected on Reproductive Status and Pregnancy Test (Local Lab), 
Chemistry (Local Lab), Hematology (Local Lab), Coagulation (Local Lab), 
Urinalysis (local Lab), Immunology (Local lab) CRFs and in central lab data 
 
Date of Assessment on revised IWG response criteria or modified IWG response 
criteria for Time Point in CRFs 
 
Start Date and End Date on Investigational Product Administration CRF 
 
Date Started and Date Ended or Resulted in Death on Events CRF 
 
Start date, stop date on Anti-Cancer Therapies, Other Protocol Required 
Therapy, Other Protocol Required Therapy (
, 
Dexamethasone), Hematopoietic Stem Cell Transplantation Autologous, 
Hematopoietic Stem Cell Transplantation Allogenic CRFs 
 
Subject Status Date if status is Alive on Survival Status CRF 
 
End of study date if the subject’s primary reason for ending study is not “Lost to 
follow-up”. 
Endpoints 
Replace: 
Treatment-Emergent Adverse Event (TEAE) 
An adverse event that occurs or worsens on or after the first administration of protocol 
specified treatment or within 30 days after the last dose of protocol-specified therapy. The 
severity of each adverse event will be graded using the CTCAE version 4.0. Adverse 
events will be coded using MedDRA. 
Duration of Response (DOR) 
Duration of response is defined as the number of days between the date of the first tumor 
assessment indicating an overall response through to the subsequent date of progression 
as classified by modified irRC or death due to any cause, or where applicable date of 
censoring [date of first progressive disease assessment or death or date of censoring – 
date of the first objective response result +1]. Subjects who respond and have not 
progressed while on study will be censored at the date of assessment of the last evaluable 
radiological assessment. Subjects who do not achieve an objective response will be 
excluded from the analysis of duration of response. Objective response is defined as any 


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of the following: complete remission (CR), CR with incomplete recovery (Cri) or 
morphologic leukemia-free state (all according to Revised International Working Group 
[IWG] response criteria) or CR with partial hematologic recovery (CRh*). 
Dose Limiting Toxicities (DLT): 
A DLT will be defined as any grade ≥ 3 adverse event occurring during a DLT window, 
and regarded by the investigator and/or sponsor to be related to AMG 330. 
With: 
Treatment-Emergent Adverse Event (TEAE)  
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by "Did event start before first dose of 
investigational product (AMG 330)" equal to "No" or missing on the Events eCRF and up 
to the End of Study date. Disease related events (DREs) will be included in the TEAE 
summary. 
The severity of each adverse event will be graded using the CTCAE version 4.0. Adverse 
events will be coded using MedDRA. For CRS events, revised grading system will be used 
as per protocol (Lee et al, 2014). 
Duration of Response (DOR) 
Duration of response is defined as the interval from the date of the first disease 
assessment indicating an objective response to the first documented relapse, disease 
progression, or death due to any cause, whichever occurs first. Subjects without relapse, 
disease progression or death until the analysis data cut-off date will be censored at the 
last adequate disease assessment date. Only subjects with a response will be evaluated 
for DOR. 
DOR time in days: (date of first relapse or disease progression or death or date of 
censoring – date of the first observation of overall response +1).  
DOR time in months: (date of first relapse or disease progression or death or date of 
censoring – date of the first observation of overall response +1)/30.4 
Dose Limiting Toxicities (DLT)  
DLT will be determined by “Is this event a Dose Limiting Toxicity (DLT)?” equal to “Yes” 
on the Events eCRF. Investigators will determine whether an adverse event qualifies as a 
DLT per protocol Section 6.2.1.4.  
Added: 
Treatment-Related AE  


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A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by the investigational product. 
Overall Response: 
Overall response definitions are given below for different indications. 
Group 1 in dose-escalation cohort / Group 4 (R/R AML)  
Response is defined as any of the following:  
Complete remission (CR), CR with incomplete recovery (CRi) or morphologic leukemia-
free state (all according to Revised International Working Group [IWG] response criteria) 
or CR with partial hematologic recovery (CRh*). 
Group 2 (MRD+ AML) 
Response is defined as conversion from MRD+ status with 0.1% threshold to MRD-. 
Group 3 (MDS) 
Response is defined as any of the following:  
CR or marrow CR (all according to Revised IWG response criteria) 
Group 5 and Group 1 in dose-expansion cohort (R/R AML) 
Response is defined as any of the following: CRMRD-, CR, CRi, MLFS, PR. 
Minimum Residual Disease (MRD) Response (All groups): 
Minimum residual disease response is defined as MRD negative, indicating presence of 
leukemia cells to 0.1% or lower of white blood cells. 
Overall Survival (OS)  
Overall survival is defined as the time from enrollment until death due to any cause. 
Subjects alive will be censored at the last known date. 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 date of last contact through the analysis trigger date. 
Event-free Survival: 
Event-free survival (EFS) is defined as the interval from first administration of AMG 
330 to the earliest of date of treatment failure, relapse for responders, or death due to any 
cause. Censoring is at the last evaluable post-baseline response assessment; otherwise, 
at first administration of AMG330. For non-responders, the event date for treatment failure 
is assigned as the date of first administration of AMG 330. 
Event-free Survival in days = earlier of (date of treatment failure or relapse or death or 
date of censoring) – date of the first administration of AMG 330 +1.  
Event-free Survival in months = earlier of (date of treatment failure or relapse or death or 
date of censoring) – (date of the first administration of AMG 330 +1)/30.4. 


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Time to Response (TTR): 
Time to response defined as the interval from the first administration of AMG 330 to the 
first documentation of confirmed response. Time to remission is evaluated only for 
subjects who achieved a response.  
Time to response is calculated as the number of days:  
(date of first response – date of study day 1 +1). 
 
Section: Analysis Sets, Planned Analyses  
Replace: 
Dose Limiting Toxicity Analysis Set:  
The Dose Limiting Toxicity Analysis Set will contain DLT-evaluable subjects (see protocol 
section 3.4 for definition of DLT-evaluable). Responder Analysis Set. The response 
analysis set will contain all subjects with objective responses [complete remission (CR), 
CR with incomplete recovery (CRi) or CR with partial hematologic recovery (CRh*)]. 
Interim Analysis and Early Stopping Guidelines: 
No formal interim analysis will be conducted. Safety data will be reviewed on an ongoing 
basis. Amgen, in consultation with the site investigator, will review in Dose Level Review 
Meetings (DLRMs) all available cumulative data by cohort prior to 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. 
With: 
Dose Limiting Toxicity Evaluable Analysis Set:  
The DLT-evaluable Analysis Set includes all DLT-evaluable subjects. The analysis of DLT 
will be restricted to the DLT-evaluable Analysis Set.  A subject is not DLT-evaluable if 
he/she drops out before completion of the DLT window for reasons other than an adverse 
event related to study drug or the subject has not received IP treatment for at least 14 
days at the target dose for a 3- or 4-week cycle or at least 7 days at a target dose for a 2-
week cycle. Furthermore, following drug interruptions, if a subject is unable to complete 2 
repeat cycles for reasons other than DLT, the subject will not be DLT evaluable. 
Interim Analysis and Early Stopping Guidelines: 
Interim analyses are planned after all subjects in each indication and each phase have 
ended the study eg, for R/R AML: all subjects enrolled in Group 1 phase 1a, Groups 4 and 


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5 have ended the study. Interim analyses may be combined if the analysis timing is close 
or if the number of subjects in each indication or phase is small. Formal interim analyses 
will be based on locked database. 
Ad-hoc interim analyses for safety and preliminary efficacy updates will be performed. 
Data analysis prior to public disclosures (e.g. scientific meetings) will also be performed.   
Safety data will be reviewed on an ongoing basis.  Amgen, in consultation with the site 
investigators, will review in DLRMs all available cumulative data prior to making dose 
escalation decisions. For R/R AML (Group 1), dose escalation decisions will be made in 
accordance with a standard 3+3 design using the rules noted below. 
 
If no DLT is observed within the DLT window in the initial 3 subjects of a cohort, 
then dose escalation to the next higher dose level cohort will occur. 
 
If 1 DLT is observed within the DLT window in the initial 3 subjects of a cohort, 
then the cohort will be expanded to 6 subjects. If no further DLT(s) are observed 
in the 6 subjects, then dose escalation to the next higher dose level cohort will 
occur.  If ≥ 2 subjects experience a DLT in a cohort, then enrollment into this cohort 
will be stopped. 
Dose escalation will occur at the planned dose levels until the MTD is determined or until 
the highest dose level is tested.  The MTD is defined as the highest dose level with an 
observed incidence of DLT in < 33% of subjects enrolled in a cohort dose level.  At least 
6 evaluable subjects will be treated at the MTD or highest tested dose.   
 The mTPI-2 model will be used to make dosing recommendations for Group 2 and Group 
3 (see section 3.3 for details). 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. 
Enrollment of a cohort can be suspended at any time based on safety findings at any dose 
level and in the expansion cohort, if at any time ≥ 33% of subjects treated at the MTD 
(including those treated at the MTD in the expansion phase) or RP2D experience a DLT 
within the DLT window, and a DLRM will be convened.  In addition, the study may be 
discontinued or modified at any time due to documented safety findings. 
Added: 
Analysis Sets: 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
analysis set defined in Section 6.1. 
Planned Analyses: 


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The following data analyses are planned: (1) dose decision analyses in the 
dose-escalation cohorts, (2) interim analyses for safety and preliminary efficacy updates, 
(3) data analysis prior to public disclosures (e.g. scientific meetings), (4) the primary 
analysis after all dose-escalation and dose-expansion subjects have completed 6 months 
of treatment, and (5) the final analysis after all subjects have ended the study. 
Dose Level Review Team (DLRT):  
For each group, DLRMs will be held to review data, monitor safety, and make 
recommendations on dose escalation / change, or changes in pre-medication.  The DLRT 
will be composed of the investigators or designees, and the following Amgen 
representatives: early development leader, medical monitor, global safety officer or 
designee, clinical study manager, biostatistician, PK scientist (optional), and other 
functional area representatives as appropriate.  A quorum as defined below must be in 
attendance for the DLRM. The quorum is defined as > 50% of the participating 
investigators 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 required voting members of the DLRT include: investigators, Amgen medical monitor, 
early development leader, and global safety officer or designee.   
The following recommendations can be made by the DLRT: 
- 
dose escalation / de-escalation decisions  
- 
expansion of a cohort 
- 
continuation, delay or termination of dosing 
- 
implementation of dose step(s) 
- 
extension of the run-in phase in case of dose step(s)  
- 
extension of the duration of treatment cycles 
- 
implementation of mandatory steroid pre-treatment in case of cytokine release 
syndrome-related adverse events 
- 
enrollment of additional subjects in the expansion cohort 
- 
duration of the DLT period based on emergent safety data 
- 
level and duration of dose steps (schedule) adjustment based on safety, and 
available PK and PD data 


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All available study data, including demographics, IP 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.  Data will not 
need to be source data verified and queries will not need to be resolved prior to the DLRM.   
Subject’s 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 the first 5 subjects have at least completed their first treatment 
cycle plus two weeks or dropped out of treatment / study, whichever occurs earlier. Once 
the first 10 subjects have at least completed their first treatment cycle plus two weeks or 
dropped out of study, all available study data will be reviewed by the DLRT. If there is at 
least 1 responding subject within these first 10 subjects, the DLRT will determine if an 
additional (up to 20) subjects may be enrolled.  If additional subjects are enrolled after the 
first 10 subjects, all available study data will be reviewed (with recruitment ongoing) by the 
DLRT after every 5 subjects have at least completed their first treatment cycle plus two 
weeks or dropped out of treatment / study. Ad hoc meetings may be convened any time 
in case of important safety events. 
Primary Analysis: 
The primary analysis will occur when target enrollment is complete and each subject either 
completes 6 months on study or terminated the study early. Primary analysis will be based 
on locked database to prevent further changes 
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 approximately 6 months after enrollment of the last study subject. Final 
analysis will be based on locked database to prevent further changes 
Section:   Data Screening and Acceptance 
Replace: 
Validation of Statistical Analyses: 
for example the SAS System and S-plus. 
With: 
Validation of Statistical Analyses: 
for example the SAS System version 9.4 or later. 
Deleted: 


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Outliers: 
Outlier data will not be excluded unless scientifically justified. 
 
Added: 
Data Handling and Electronic Transfer of Data: 
This study will use the RAVE database. 
Handling of Missing and Incomplete Data: 
 
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. 
 
Biomarker data that are below the quantification limits will be considered equal to 
half of the lower limit of quantification for all analyses unless specified otherwise. 
 
PD concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PD parameters. 
Outliers: 
Pharmacodynamic (PD) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard PD evaluation practice. Descriptive statistics will be used to identify potential 
outliers in key variables.  
Suspected outliers will be included in all analyses unless there is sufficient scientific 
justification to exclude them. 
Section:    Statistical Methods of Analysis 
Replace: 
Adverse Events and Disease-related Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 17.1 or later will be 
used to code all adverse events to a system organ class and a preferred term. The subject 
incidence of adverse events will be summarized for all treatment-emergent, serious 
treatment emergent, treatment-related, serious treatment-related, those leading to 
withdrawal of investigational product, fatal, and of special interest (if applicable). The 
identification of adverse events of special interest is a continuous process. Events may be 
identified and documented as the safety profile of the drug is characterized. The severity 
of each adverse event will be graded using CTCAE version 4.0 criteria. 


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Subject incidence of all treatment-emergent, serious, treatment-related, serious 
treatment-related, suspected immune-related, those leading to withdrawal of 
investigational product, and fatal adverse events will be tabulated by system organ class 
and preferred term in descending order of frequency. Where appropriate the tables will 
also be presented by worst grade. Listings and/or narratives of any on-study deaths, 
serious and significant treatment-emergent adverse events, including early withdrawals 
due to adverse events, also will be provided should they occur. 
Laboratory Test Results: 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject. 
Depending on the size and scope of changes in laboratory data, summaries of laboratory 
data over time and/or changes from baseline over time will be provided and tables of 
maximum shifts from baseline for selected laboratory values will be provided. 
Vital Signs: 
Vital signs will be listed 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 will be provided. Vital signs (resting systolic/diastolic blood pressure, heart rate, 
respirations, and temperature in a supine position for at least 5 minutes) will be 
summarized using descriptive statistics. 
Summary statistics for each vital sign parameter will be provided for baseline and each 
scheduled post-baseline assessment, as well as the change from baseline at each of the 
post-baseline scheduled time points. 
 
With: 
Adverse Events and Disease-related Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later will be 
used to code all events categorized as adverse events and disease-related events to a 
system organ class and a preferred term. 
The subject incidence of adverse events (including disease related events) will be 
summarized for all treatment-emergent adverse events, 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 grade. In addition, SAEs and grade 3 and above adverse events will be 
summarized by preferred term in descending order of frequency.  


Product:  AMG 330 
Protocol Number:  20120252 
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The severity of each adverse event will be graded using Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 criteria with the exception of cytokine release 
syndrome (CRS), which will be graded using the criteria referenced in the publication by 
Lee et al (2014). 
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term and worst grade. CRS will be summarized by grade and symptom.  
TEAE summaries will be provided both by cohort and by overall groups. 
Laboratory Test Result: 
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each 
subject for DLRM. Values outside the normal laboratory reference ranges will be flagged 
as high or low on the listings. 
In interim, primary and final analyses, depending on the size and scope of changes in 
selected laboratory data, summaries of selected 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. Unscheduled assessments will be 
included in these summaries. 
Vital signs: 
Vital signs data will be listed and reviewed for each subject for DLRM.  
In interim, primary and final analyses, depending on the size and scope of changes, 
summaries of vital signs (resting systolic/diastolic blood pressure, heart rate, respirations 
and temperature) data over time and/or changes from baseline over time may be provided. 
Unscheduled assessments will be included in these summaries 
Deleted: 
Subject Accountability: 
A subject listing and summary noting inclusion in each analysis subset will be provided for 
all subjects enrolled. A subject listing noting duration of AMG 330 administration, reason 
for discontinuation of treatment, and reason for discontinuing the study will be provided. A 
list of subjects screened but not enrolled (screen failures) will be provided. 
Important Protocol Deviations: 
If a snapshot is being taken during the study rather than a database lock at the end of the 
study, categories should be updated during the IPD reviews throughout the study prior to 
database lock. 


Product:  AMG 330 
Protocol Number:  20120252 
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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. 
Added: 
General Consideration:  
Additional analysis for Group 4 and Group 5 will be specified in SSAP. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper and Pearson (1934). 
Important Protocol Deviations: 
Eligibility deviations are defined in the protocol. 
Demographic and Baseline Characteristics R/R AML: 
ECOG performance status, Type of AML (at initial diagnosis and at study entry), Prior lines 
of therapies Responses to the prior lines of therapies, Prior hematopoietic stem cell 
transplant, Disease duration, Bone marrow blast, Baseline Tumor Burden, ELN risk 
classification, White blood cells, Absolute Neutrophil count, Platelet count. 
Baseline characteristics for MRD: 
Height, Weight, ECOG performance status, Type of AML (at initial diagnosis and at study 
entry), MRD Status, Prior lines of therapies Responses to the prior lines of therapies, Prior 
hematopoietic stem cell transplant, Disease duration, Bone marrow blast, Baseline Tumor 
Burden, ELN risk classification, White blood cells, Absolute Neutrophil count, Platelet 
count. 
Baseline characteristics for MDS: 
Height, Weight, ECOG performance status, Type of AML (at initial diagnosis and at study 
entry), Type of MDS (at initial diagnosis and at study entry), MDS Risk(IPSS-R) (at initial 
diagnosis and at study entry), MDS status at study entry, Prior lines of therapies, 
Responses to the prior lines of therapies, Prior hematopoietic stem cell transplant, 
Disease duration, Bone marrow blast, Baseline Tumor Burden, ELN risk classification, 
White blood cells, Absolute Neutrophil count, Platelet count. 
Analyses of Primary Efficacy Endpoint(s): 
No efficacy parameter is considered in primary endpoints. 
Analyses of Secondary Efficacy Endpoint(s): 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  29 October 2021 
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The proportion of subjects with an overall response (Section 5.4) with corresponding exact 
80% and 95% Confidence Intervals will be calculated using the Clopper-Pearson method 
(Clopper and Pearson, 1934) by cohort. The proportion of subjects who are event-free at 
6 months with corresponding exact 80% CI will be calculated using the Clopper-Pearson 
method. 
Listings indicating time to response, duration of response (DOR), and event-free survival 
will be produced for responders for each indication separately. For subjects in dose 
expansion cohorts, Kaplan Meier curves may be presented for event-free survival and 
overall survival with estimates for rates and 80  CI at selected weeks.  DOR and time to 
response will only be analyzed for subjects who achieved an overall response. 
 
Analyses of Exploratory Efficacy Endpoint(s): 
The following statistical analyses will be considered exploratory and will be performed by 
clinical biomarker group in Department of Translational Medicine only when deemed 
appropriate.  Relationships between changes in tumor dynamics and above biomarkers 
of interest listed as exploratory endpoints will be explored.  Changes in expression levels 
of biomarkers and their relationship to dose may also be explored.  Summary statistics 
over time will be provided and graphical presentations may be used.  The relationship 
between AMG 330 exposure and PD effects and related biomarkers in blood, or tumor 
specimens and/or AMG 330 exposure and clinical outcomes (eg, tumor response) will be 
also explored if deemed appropriate.  Details of analysis will be provided in a Contributing 
Scientific Report for exploratory biomarker analysis. Pharmacodynamic (PD) biomarkers 
for AMG 330 mechanism of action (Depletion of LSCs, Lymphocyte counts, CD33+ 
monocytes ,T cells,  T cell activation (including T cell subsets), Other immune subsets, 
 
 
 
. 
Analyses of Primary Safety Endpoint: 
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 330. Treatment groups will be defined based on the 
planned doses for Cycle 1. 
Analyses of Dose Limiting Toxicities: 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  29 October 2021 
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The analysis of Dose limiting toxicities (DLT) will be based on the DLT Evaluable Analysis 
Set. A listing and summary of the subject incidence of dose limiting toxicities (DLT) will be 
provided. 
Physical Measurements: 
The change in weight from baseline to each scheduled assessment time point will be 
summarized.  
Electrocardiogram (ECG): 
In the event of extreme outlier readings, an additional sensitivity analysis will be conducted 
where the outlier measurement is excluded from the derivation of the mean for that 
assessment. The criteria used to define an outlier measurement will be determined based 
upon inspection of the data.  
Antibody Formation: 
All medication will be coded using the WHO drug dictionary.  A subject listing of all 
concomitant medications will be presented for DLRM. In the interim, primary and final 
analyses, the number and proportion of subjects receiving concomitant medications will 
be summarized by preferred term for each treatment group and indication as coded by the 
World Health Organization Drug (WHO DRUG) dictionary. 
Exposure to Concomitant Medication: 
All medication will be coded using the WHO drug dictionary.  A subject listing of all 
concomitant medications will be presented for DLRM. In the interim, primary and final 
analyses, the number and proportion of subjects receiving concomitant medications will 
be summarized by preferred term for each treatment group and indication as coded by 
the World Health Organization Drug (WHO DRUG) dictionary. 
Section:    Other Analysis 
Added: 
Analysis of PK or PK/PD Endpoints: 
For AMG 330, pharmacokinetic parameters half-life, steady-state concentration, volume 
of distribution, and clearance) 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 330 exposure and either pharmacodynamic effect and/or clinical outcome 
may also be performed. 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  29 October 2021 
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Serum concentrations of AMG 330 will be determined using a validated assay. Parameters 
to characterize cellular kinetics related to cell expansion (eg, Cmax, Tmax and partial AUC) 
and cell persistence (eg, T1/2, Tlast and Clast) in PBMCs, 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 cellular kinetic 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 Cellular kinetic analyses, including but not limited to analysis of the relationship 
between AMG 330 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 330 exposure and either 
Pharmacodynamic effect and/or clinical outcome may also be performed. 
A preliminary assessment of dose proportionality will be made using the Power Model 
Statistical analysis of AUC(0-t) and Cmax of AMG 330 will be performed after log 
transformation of the data. The Power Model:  
Y = α doseβ 
where Y is the pharmacokinetic parameter and α is an intercept term. This becomes a 
linear relationship following a logarithmic transformation, to which a linear regression 
approach can be applied as,  
 log(Y) = β ×  log (dose) + log(α) 
The coefficient of the slope with 90% confidence intervals, on the log scale, will be 
calculated. 
Descriptive statistics will be provided for biomarker data by dose, dose schedule, and 
time as appropriate. 
 
Analysis of Biomarker Endpoints: 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses. The analyses of biomarkers will be considered exploratory and may be 


Product:  AMG 330 
Protocol Number:  20120252 
Date:  29 October 2021 
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performed after collection of all samples during the conduct of the study and therefore 
may be reported after the primary analysis. Changes in expression or expansion level of 
biomarkers and their relationship to dose may be evaluated. Summary statistics over 
time may be provided and graphical presentations may be used. Details of analysis will 
be provided in Contributing Scientific Report for exploratory biomarker analysis.