Clinical trial NCT03224819
Conditions: Acute Myeloid Leukemia
Sponsor: Amgen
Start date: 2017-09-07; Completion date: 2020-12-28
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of emerfetamab in adults with relapsed/refractory acute myeloid leukemia (AML) and to estimate the maximum tolerated dose (MTD) and/or a biologically active dose (eg, recommended phase 2 dose \[RP2D\]).

Detailed description:
This is a first-in-human, open-label, phase 1, sequential dose escalation study. Emerfetamab will be evaluated as a short term intravenous (IV) infusion in adults with relapsed/refractory AML The study will consist of a dose escalation phase and a dose expansion phase. The study was terminated prior to the start of the expansion phase.

Arms: arm 1: The dose-escalation cohorts to estimate the MTD will use 2 schedules of emerfetamab administration: Schedule A (Day 1/Day 5 dosing in 14-day cycles) and Schedule B (once daily dosing for cycle 1 followed by twice weekly dosing in following cycles).

For Schedule A the starting dose for the first cohort will be 0.05 μg emerfetamab administered as short term IV infusions on day 1 and day 5. The doses administered for the following cohorts will be recommended by the Dose Level Review Team (DLRT).

For Schedule B the starting dose will be 72 μg emerfetamab administered as short-term IV infusions daily (QD) during the 14-day cycle 1 after the 72 μg target dose is found to be relatively safe and tolerable by the DLRT for Schedule A. arm 2: For each schedule, upon completion of the dose escalation cohorts, additional participants may be enrolled to receive emerfetamab at a dose at or below the MTD estimated in the dose escalation cohorts.
Interventions: intervention 1: Emerfetamab
Intervention descriptions: intervention 1: Administered by intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 1 of 136 
CONFIDENTIAL 
Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
AMG 673 
Amgen Protocol Number 20160377 
IND number BB-IND 133933 
EudraCT number 2017-002980-16 
Clinical Study Sponsor: 
Amgen Inc.
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805 447 1000 
Key Sponsor 
Contact(s): 
, MD, PhD 
Early Development Leader 
Phone: 
 
E-Mail:
 
Global Early Clinical Development Manager 
Phone
E-mail: 
Date: 
18 April 2017 
Amendment 1: 
07 June 2017 
Amendment 2: 
01 June 2018 
Amendment 3: 
Amendment 4: 
17 January 2019 
24 June 2019 
Amendment 5: 
11 December 2019 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: 1-800-77-AMGEN; Amgen’s general number in the 
US (1-805-447-1000). 
Approved
NCT Number: NCT03224819
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 2 of 136 
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 673 
Administered as Short Term Intravenous Infusions in Subjects With Relapsed/Refractory 
Acute Myeloid Leukemia”, dated 11 December 2019, and agree to abide by all 
provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 3 of 136 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 673 Administered as Short Term Intravenous Infusions 
in Subjects With Relapsed/Refractory Acute Myeloid Leukemia 
Study Phase:  1   
Indication:  Relapsed/Refractory Acute Myeloid Leukemia (AML) 
Primary Objectives:   
• 
Evaluate the safety and tolerability of AMG 673 in adult subjects with relapsed/refractory AML  
• 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
[eg, recommended phase 2 dose (RP2D)] 
Secondary Objective(s):   
• 
Evaluate the pharmacokinetics (PK) of AMG 673 
• 
Evaluate the anti-leukemia activity of AMG 673 by evaluating: 
− 
the number and proportion of subjects who respond to treatment with AMG 673. 
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 duration of response, time to progression, and time to response 
Exploratory Objectives:  
Hypothesis:  AMG 673 will demonstrate evidence of anti-leukemic activity at a well-tolerated 
dose in subjects with AML. 
Primary Endpoint:   
• 
Safety: subject incidence and grade of adverse events and dose limiting toxicities (DLTs) 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
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CONFIDENTIAL 
 
 
Secondary Endpoints:   
• 
Pharmacokinetic parameters including, but not limited to: half-life, maximum observed 
concentration (Cmax), minimum observed concentration (Cmin), area under the 
concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUC0-last) and clearance (CL) of AMG 673 
• 
Efficacy parameters: 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  
Exploratory Endpoints:   
Study Design:   
This is a first-in-human, open-label, phase 1, sequential dose escalation study.  AMG 673 will be 
evaluated as a short term intravenous (IV) infusion in adult subjects with relapsed/refractory AML.  
The study will be conducted at approximately 10 sites in Australia, Germany and the United 
States. Additional sites may be added later. 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) using 2 schedules of AMG 673 administration:  Schedule A  
(D1/D5 dosing) and Schedule B (QD dosing for cycle 1 followed by twice weekly dosing in 
following cycles).   
For Schedule A, planned dose levels (dose per infusion) for the dose-escalation cohorts are as 
follows: 0.05 µg, 0.15 µg, 0.45 µg, 1.5 µg, 4.5 µg, 9 µg, 18 µg, 36 µg, 72 µg, 110 µg, 160 µg, 
240 µg, 360 µg and higher if MTD is not reached. The starting dose for the first cohort will be 
0.05 µg administered as short term IV infusions on D1 and D5.  The doses administered for the 
cohorts following cohort 1 will be recommended by the Dose Level Review Team (DLRT). The 
DLRT may recommend on the administration of up to 2 additional infusions on D12 and D19 of a 
cycle for a future cohort.  All subjects will be pre-treated with an 8-mg dose of IV dexamethasone 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
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CONFIDENTIAL 
 
 
1 hour prior to day 1 and day 5 AMG 673 doses and prior to each step-up dose of AMG 673. 
Each cycle will last for 14 days in the cohorts receiving only 2 doses (Day 1, 5) and 28 days in the 
cohorts receiving 4 doses (Day 1, 5, 12, 19). Each cycle will be followed by a treatment-free 
interval for 0 to 14 days depending on treatment response and recovery of blood counts, but may 
be extended as described in Section 6.2.1.1.1 after consultation with Sponsor.  The D5 infusion, 
and the D12/D19 infusions (if applicable) may be at the same dose as the preceding infusion or 
may be at a higher dose level (dose step). This will be based on tolerability of the lower dose 
level and other clinical signs, pharmacological and PD results and will be recommended by the 
DLRT. For a schematic description of the different dose step options see Figure 2.   There is a 
 ± 1 day window for dosing visits which may be implemented after consultation with Sponsor.  
For Schedule B, planned dose levels (dose per infusion) for the dose-escalation cohorts are as 
follows: 72 µg, 110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is not reached. The starting 
dose for cohort 1 on Schedule B will be 72 µg administered as short-term IV infusions daily (QD) 
during the 14-day cycle 1 after the 72 µg target dose is found to be relatively safe and tolerable 
by the DLRT for Schedule A.  Cohort 2 and higher will include step-up doses added in each 
cohort administered in two day increments after the previous step dose up to the target dose in 
cycle 1 (eg, cohort 2 will start with 72 µg for 2 days followed by 110 µg administered on D3 to 
D14; cohort 3 will start with 72 µg for 2 days followed by 110 µg on D3 for 2 days followed by 
160 µg on D5 to D14, etc).  Cycle 2+ doses will be given on days 1, 4, 8 and 11 at the target 
dose.  See Table 3 and Section 6.2.1.1.2 for Schedule B dosing schema by cohort.  All subjects 
will be pre-treated with an 8-mg dose of IV dexamethasone 1 hour prior to the first dose on day 1 
and prior to each step-up dose in cycle 1 and prior to all doses in cycle 2 and beyond. There is no 
treatment free interval between cycle 1 and cycle 2.  Beyond cycle 2, a treatment-free interval is 
allowed for 0 to 14 days depending on treatment response and recovery of blood counts and may 
be extended as described in Section 6.2.1.1.1 after consultation with Sponsor. Adjustments to 
dose level, dose frequency and a duration of step dosing may be considered after 
recommendation of DLRT based on review of available safety, PK, and PD data. 
Dose Escalation Cohorts 
Dose Escalation will be conducted in 2 stages: a single subject stage (Schedule A only) and a 
multiple subjects stage.  In the single subject cohorts, cohorts 1 and 2, single subjects will be 
enrolled at dose levels anticipated to be lower than those at which adverse events related to 
AMG 673 will be observed. Multiple subject cohorts, starting with cohort 3, will enroll and the 
cohort size will be extended to 3-4 subjects per cohort.  The Bayesian logistic regression model 
(BLRM) design will be used to guide dose escalation.   The actual dose selected at each dose 
decision may be at or below the model’s recommended dose as determined by the dose level 
review team (DLRT) after considering all information.  Subjects will be assessed for dose limiting 
toxicities (DLTs) for the duration of their first treatment cycle (ie, 2 weeks from D1 for subjects 
who receive 2 doses and 4 weeks for subjects who receive 4 doses in Schedule A and 4 weeks 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 6 of 136 
CONFIDENTIAL 
 
 
from D1 for subjects in Schedule B). Subjects who complete the DLT period may proceed to a 
higher dose level for the following treatment cycle after the next dose level has been deemed 
safe by the DLRT, after consultation with Sponsor, if no DLT was reported for that subject and no 
≥ grade 3 adverse event(s), deemed treatment related by the investigator, are reported for that 
subject. 
Estimation of initial and target MTDs 
For Schedule A, it is anticipated that at least 2 MTDs may be estimated, one for the initial dosing 
and one for the subsequent step dosing.  Should the initial dose be limited by adverse events 
related to first dose effects, the second MTD for the target dose will be estimated after giving the 
initial dose at MTD (step dose).  Each MTD will be estimated following the dose escalation guided 
by BLRM described above.  A second dose step may also be implemented in a cycle if this was 
considered appropriate and necessary to allow further dose escalation.  This second dose step 
would be performed the same way as described above.  In this case, a third MTD would be 
estimated for the dose to be administered after the second dose step. 
Schedule B will be initiated after preliminary safety data of AMG 673 in Schedule A (eg, MTD1 is 
estimated to be ≥72 µg) become available and may be conducted in parallel with Schedule A per 
Sponsor’s decision.  The MTD for Schedule B will be estimated following the dose escalation 
described in Section 6.2.1.1.2and guided by BLRM described above.   
Expansion Cohort 
For each schedule, upon completion of the dose escalation cohorts, additional subjects (up to 10) 
may be enrolled in a dose expansion cohort to gain further clinical experience, safety and efficacy 
data in subjects with AMG 673.  The dose to be evaluated will be at or below the MTD estimated 
in the dose escalation cohorts.  Additional expansion cohorts may be covered by a protocol 
amendment to test alternative dose levels or biologic subsets. 
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 each schedule. 
Sample Size:   
It is anticipated that approximately 95 subjects will be enrolled in this study.  Approximately 
40 subjects will be enrolled in the dose escalation cohorts for each schedule and up to 10 
additional subjects will be enrolled in the dose expansion cohorts for one or both schedules.   
The sample size in the dose escalation is based on practical considerations and is consistent with 
conventional oncology studies with the objective to estimate the MTD.  With 3 subjects per 
cohort, there is a 27-70% probability of observing at least 1 DLT if the true DLT rate is 10-33% 
and with 4 subjects per cohort, there is a 34-80% probability. 
In the dose expansion cohort, a subject number of 10 will provide a 65% probability of observing 
at least 1 adverse event with 10% incidence rate and 89% probability of observing at least 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 7 of 136 
CONFIDENTIAL 
 
 
1 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% overall response rate, the 
expected 80% CI would be 5.5% to 45.0% with the half-width 19.8%. 
Summary of Subject Eligibility Criteria:   
Male or female subjects ≥ 18 years of age at the time of informed consent who have AML as 
defined by World Health Organization (WHO) Classification (Appendix D) persisting or recurring 
following 1 or more treatment courses except promyelocytic leukemia (APML).  Subjects must 
have more than 5% myeloblasts in bone marrow. 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 673 will be manufactured and packaged by Amgen and distributed using Amgen clinical 
study drug distribution procedures.  The Investigational Product Instruction Manual (IPIM), a 
document external to this protocol, contains detailed information regarding the storage, 
preparation, destruction, and administration of AMG 673. Please refer to Section 6.2.1 and the 
IPIM for additional information.  
NOTE: A nurse trained in emergency medicine or a physician must be available when the 
infusion of AMG 673 is started for immediate intervention in case of complications. 
AMG 673 is supplied as a sterile, preservative-free lyophilized powder for IV administration after 
reconstitution with sterile water for injection (WFI). After reconstitution with 1.2 mL of sterile WFI, 
the 1 mg/mL AMG 673 drug product is formulated with 
 mM glutamic acid, % (w/v) sucrose, 
and 
% polysorbate 80, pH 
.  The final container is a single-use, 6R glass vial and contains 
a target extractable amount of 1 mg AMG 673.   
The intravenous solution stabilizer (IVSS) is supplied as a sterile solution in a 10-cc glass vial 
containing 10 mL deliverable product.  The IVSS does not contain an active pharmaceutical 
ingredient and is a buffered, preservative-free solution (
 mM citric acid, 
M lysine 
hydrochloride, 
% (w/v) polysorbate 80, pH 
).  The IVSS is intended for pre-treatment of 
IV bags prior to dilution of AMG 673 drug product.   
AMG 673 solution for infusion will be prepared in bags for IV infusion and delivered through 
infusion lines.   
For Schedule A, the drug will be administered as short term IV infusions on D1 and D5 of each 
treatment cycle. Up to 2 additional infusions per cycle (D12/D19) may be administered. The 
treatment-free interval prior to start of the following treatment cycle will have a duration of 0 to 
14 days (depending on treatment response), but may be extended to up to 7 weeks in case of 
prolonged marrow aplasia and aleukemic cytopenia after consultation with Sponsor.  It may also 
be extended for up to 3 days from the planned duration if necessary for logistical reasons.  The 
Approved 
 
 


Product:  AMG 673 
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CONFIDENTIAL 
 
 
DLRT may make recommendations on changes of the duration of the infusion-free interval for 
future cohorts after evaluation of PK data.  
Subjects will be hospitalized for a minimum of 8 days from start of the day 1 dose (ie, at least 
72 hours after the day 5 dose) and for a minimum of 72 hours following day 12 and day 19 doses 
in cycle 1. If the subject receives a second cycle of AMG 673 at the same dose, hospitalization 
will be for a minimum of 8 days from start of the day 1 dose (ie, at least 72 hours after the day 5 
doses). Hospitalization following day 12 and day 19 doses in cycle 2 and onwards will be at the 
discretion of the treating physician. For subjects receiving >2 cycles, hospitalization for cycle 3 
onwards for all doses will be at the treating physician’s discretion. However, in case of 
intra-subject dose escalation, subjects will be hospitalized as per the guidance for the first cycle.  
After re-start of treatment, after an interruption due to an adverse event(s), the subject will be 
hospitalized for a minimum of 48 hours. Subjects can be hospitalized for a longer time period at 
the discretion of the investigator.   
For Schedule B, the drug will be administered as daily short term IV infusions for 14 days (cycle 
1) and on D1, D4, D8 and D11 of each subsequent treatment cycle. There will be no infusion-free 
interval between cycle 1 and cycle 2, and the infusion-free interval after cycle 2 may range from 
0-14 days based on safety data and anti-leukemia response to AMG 673 treatment and may be 
extended as described in Section 6.2.1.1.  The DLRT may make recommendation to alter dosing 
frequency starting from cycle 1 and beyond after evaluation of available PK, PD and safety data. 
Subjects will be hospitalized for a minimum of 15 days (ie, from day -1 through day 14 or the last 
dose of cycle 1).  For cycle 2, subjects will be hospitalized for a minimum of 48 hours after each 
dose.  For subjects receiving additional cycles (beyond cycle 2), hospitalization will be at the 
discretion of the treating physician. In case of intra-subject dose escalation, subjects will be 
hospitalized at least 48 hours after each dose increase.  After an interruption due to an adverse 
event(s), the subject will be hospitalized for a minimum of 48 hours upon restart of treatment.  
Subjects can be hospitalized for a longer period at the discretion of the investigator.  
Up to 12 total treatment cycles can be administered as long as in the judgment of the investigator 
the subject is deriving benefit. 
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 
 
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  the Schedule 
of Assessments (Section 7.1. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
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CONFIDENTIAL 
 
 
Statistical Considerations:   
All subjects who are enrolled and receive at least 1 administration of the investigational product 
(AMG 673) will be included in the analysis, unless otherwise specified.  The primary analysis will 
occur when target enrollment is complete and each subject either had the opportunity to receive 
up to 2 cycles of treatment or terminated the study early.   
Descriptive statistics will be provided for selected demographics, safety, PK, PD and biomarker 
data by dose, dose schedule, and time as appropriate.  Descriptive statistics on continuous data 
will include means, medians, standard deviations and ranges, while categorical data will be 
summarized using frequency counts and percentages.  Graphical summaries of the data may 
also be presented. 
The number and percentage of subjects reporting any treatment-emergent adverse events will be 
tabulated.  Clinical laboratory test, ECG, physical examination findings and vital sign data will be 
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. 
The proportion of responding subjects (defined as any of the following: CR, CRi, morphologic 
leukemia-free state per modified IWG criteria, or CRh*) with corresponding exact 80% CI will be 
calculated using the Clopper-Person 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. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
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Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Phase  
AMG 673 short term infusions, up to 12 treatment cycles  
DOSE ESCALATION 
 
Schedule A*: D1/D5 on a 14 day cycle 
*First 2 cohorts are single subject cohorts 
 
Schedule B: QD on a 14 day cycle for 
cycle 1 and D1, D4, D8 and D11 for cycle 2 
and beyond  
 
Number of cohorts, subjects per cohort and 
actual doses dependent on observation of 
DLTs and Dose Level Review Team 
recommendations 
Enrollment (Day 1) 
End of Treatment 
Safety Follow-Up 
 (4 weeks after last dose of AMG 673) 
DOSE EXPANSION 
Will begin at or below the MTD or 
highest tested dose from Schedule A 
(± dose step) and/or Schedule B 
n=10 each 
Screening  
(14 days) 
End of Study  
Approved 
 
 


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Study Glossary 
Abbreviation or Term Definition/Explanation 
ADA 
Anti-drug antibodies 
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 
AUC 
Area under the concentration-time curve 
AUC0-last 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUCinf 
Area under the concentration-time curve from time zero to infinity 
BiTE® 
Bispecific T-cell engager 
BM 
Bone marrow 
CAR-T 
Chimeric antigen receptor T cell 
CD33 
Cluster of differentiation 33 
CI 
Confidence interval 
cIV 
Continuous intravenous 
CL 
Systemic clearance 
Cmax 
Maximum observed serum concentration 
Cmin 
Minimum observed serum concentration 
CNS 
Central nervous system 
Css 
Steady-state drug concentration in plasma during constant-rate infusion 
CR 
Complete response/remission (see Appendix E for details) 
CRh* 
Complete response/remission with partial recovery of peripheral blood 
counts (ANC > 500/µL, platelets > 50,000/µL) (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 
Approved 
 
 


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Abbreviation or Term Definition/Explanation 
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 
EC20 
20% maximal effective concentration: concentration of a drug, antibody 
or toxicant which induces a response that is 20% of the maximum 
response 
EC50 
Half maximal effective concentration: concentration of a drug, antibody 
or toxicant which induces a response halfway between the baseline and 
maximum 
EC90 
Concentration of a drug, antibody or toxicant which induces a response 
that is 90% of the maximum response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
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 
EOL-1 
Human acute myeloid (eosinophilic) leukemia cell line 
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) 
Fc 
Fragment crystallization  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
Gemtuzumab ozogamicin 
Approved 
 
 


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Abbreviation or Term Definition/Explanation 
Heart rate 
Number of cardiac cycles per unit of time 
HED 
Human equivalent dose for safety 
HepBsAg 
Hepatitis B surface antigen 
HepCAb 
Hepatitis C virus antibody 
HiDAC 
High dose cytarabine 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HSCT 
Hematopoietic stem cell transplantation 
HuM195 
Humanized anti-CD33 antibody 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
IVSS 
Intravenous Solution Stabilizer 
IWG 
International Working Group 
KG-1 
Human acute myeloid leukemia cell line 
LAIP 
Leukemia-associated immunophenotype 
LDH 
Lactate dehydrogenase 
 
 
MABEL 
Minimum Anticipated Biological Effect Level 
MOLM-13 
Human acute myeloid leukemia cell line genetically-engineered to 
express luciferase 
Morphologic 
leukemia-free state 
Less than 5% blasts in bone marrow without recovery of peripheral blood 
counts (see Appendix E for details) 
Approved 
 
 


Product:  AMG 673 
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Abbreviation or Term Definition/Explanation 
 
 
MRI 
Contrast-enhanced magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
NHL 
Non-Hodgkin’s lymphoma 
NK 
Natural killer cell 
NOAEL 
No observed adverse effect level 
NOD/SCID 
Non-obese diabetic/severe combined immunodeficiency disease 
NYHA 
New York Heart Association 
 
 
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 
Single chain 
SC 
Subcutaneous(ly) 
 
 
SCR 
Screening 
SD 
Standard deviation 
SOC 
System Organ Class 
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Abbreviation or Term Definition/Explanation 
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 
TPI 
Toxicity probability interval 
ULN 
Upper limit of normal 
US 
United States 
Vss 
Apparent volume of distribution at steady state 
WBC 
White blood cell 
WFI 
Water for injection 
WHO 
World Health Organization 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema ............................................................................ 10 
1. 
OBJECTIVES ......................................................................................................... 21 
1.1 
Primary ....................................................................................................... 21 
1.2 
Secondary .................................................................................................. 21 
1.3 
Exploratory ................................................................................................. 21 
2. 
BACKGROUND AND RATIONALE ........................................................................ 21 
2.1 
Disease ....................................................................................................... 21 
2.2 
Amgen Investigational Product Background ............................................... 23 
2.2.1 
Nonclinical Pharmacology .......................................................... 23 
2.2.2 
Nonclinical Pharmacokinetics ..................................................... 24 
2.2.3 
Nonclinical Toxicology ................................................................ 25 
2.2.4 
Dosing Experience With Other BiTE® Antibody 
Constructs .................................................................................. 25 
2.3 
Risk Assessment ........................................................................................ 26 
2.4 
Rationale .................................................................................................... 28 
2.5 
Clinical Hypotheses .................................................................................... 29 
3. 
EXPERIMENTAL PLAN ......................................................................................... 29 
3.1 
Study Design .............................................................................................. 29 
3.2 
Number of Sites .......................................................................................... 35 
3.3 
Number of Subjects .................................................................................... 35 
3.4 
Replacement of Subjects ............................................................................ 36 
3.5 
Estimated Study Duration ........................................................................... 36 
3.5.1 
Study Duration for Subjects ........................................................ 36 
3.5.2 
End of Study ............................................................................... 37 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 37 
4.1 
Inclusion Criteria ......................................................................................... 38 
4.2 
Exclusion Criteria ........................................................................................ 38 
5. 
SUBJECT ENROLLMENT ..................................................................................... 40 
5.1 
Treatment Assignment ............................................................................... 41 
6. 
TREATMENT PROCEDURES ............................................................................... 42 
6.1 
Classification of Product ............................................................................. 42 
6.2 
Investigational Product ............................................................................... 42 
6.2.1 
Amgen Investigational Product AMG 673 ................................... 42 
6.2.1.1 
Dosage, Administration, and Schedule .................... 42 
6.2.1.2 
Overdose ................................................................. 47 
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6.2.1.3 
Dose-cohort Study Escalation and 
Stopping Rules, Dose Limiting Toxicities 
(DLTs) ...................................................................... 48 
6.2.1.4 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 50 
6.3 
Other Protocol-required Therapies ............................................................. 53 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 54 
6.4.1 
Criteria for Permanent Withholding of AMG 673 due to 
Potential Hepatotoxicity .............................................................. 54 
6.4.2 
Criteria for Conditional Withholding of AMG 673 due to 
Potential Hepatotoxicity .............................................................. 55 
6.4.3 
Criteria for Rechallenge of AMG 673 After Potential 
Hepatotoxicity ............................................................................. 55 
6.5 
Concomitant Therapy ................................................................................. 55 
6.6 
Specific Recommendations for Cytokine Release Syndrome, 
Tumor Lysis Syndrome and Infection Prophylaxis ..................................... 56 
6.7 
Medical Devices ......................................................................................... 60 
6.8 
Product Complaints .................................................................................... 60 
6.9 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period ................................................................................... 61 
7. 
STUDY PROCEDURES ......................................................................................... 61 
7.1 
Schedule of Assessments .......................................................................... 61 
7.2 
General Study Procedures ......................................................................... 75 
7.2.1 
Screening ................................................................................... 76 
7.2.2 
Treatment ................................................................................... 77 
7.2.3 
End of Treatment Visit ................................................................ 79 
7.2.4 
End of Study Visit ....................................................................... 79 
7.3 
Description of Study Procedures ................................................................ 80 
7.3.1 
Informed Consent ....................................................................... 80 
7.3.2 
Demographic Data ...................................................................... 80 
7.3.3 
Medical History and Prior Therapy ............................................. 80 
7.3.4 
Concomitant Medications ........................................................... 81 
7.3.5 
Clinical Evaluation ...................................................................... 81 
7.3.5.1 
Physical Examination ............................................... 81 
7.3.5.2 
ECOG Performance Status ...................................... 81 
7.3.5.3 
Height Measurements .............................................. 81 
7.3.5.4 
Weight Measurements ............................................. 81 
7.3.6 
Vital Signs ................................................................................... 82 
7.3.7 
Pulse Oximetry ........................................................................... 82 
7.3.8 
Electrocardiogram Performed in Triplicate ................................. 82 
7.3.9 
Clinical Laboratory Tests ............................................................ 83 
7.3.10 
Events ......................................................................................... 84 
7.3.11 
CT Scan or MRI Cranial ............................................................. 84 
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7.3.12 
Pharmacokinetic Blood Sampling ............................................... 84 
7.4 
Antibody Testing Procedures ..................................................................... 84 
7.6 
Disease Response ..................................................................................... 87 
7.7 
Blood and Bone Marrow Samples .............................................................. 88 
7.9 
Sample Storage and Destruction ................................................................ 89 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 90 
8.1 
Subjects’ Decision to Withdraw .................................................................. 90 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 91 
8.3 
Reasons for Removal From Treatment, or Study ....................................... 91 
8.3.1 
Reasons for Removal From Treatment ...................................... 91 
8.3.2 
Reasons for Removal From Study ............................................. 92 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 92 
9.1 
Definition of Safety Events ......................................................................... 92 
9.1.1 
Disease-Related Events ............................................................. 92 
9.1.2 
Adverse Events .......................................................................... 93 
9.1.3 
Serious Adverse Events ............................................................. 94 
9.2 
Safety Event Reporting Procedures ........................................................... 95 
9.2.1 
Reporting Procedures for Disease-Related Events .................... 95 
9.2.2 
Adverse Events .......................................................................... 95 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 95 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 96 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 97 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported by the Sponsor to Regulatory 
Agencies in an Expedited Manner ........................... 98 
9.3 
Pregnancy and Lactation Reporting ........................................................... 98 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 99 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 99 
10.1.1 
Study Endpoints ......................................................................... 99 
10.1.2 
Analysis Sets .............................................................................. 99 
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10.1.3 
Covariates and Subgroups ....................................................... 100 
10.2 
Sample Size Considerations .................................................................... 100 
10.3 
Planned Analyses ..................................................................................... 100 
10.3.1 
Interim Analyses and Early Stopping Guidelines ...................... 101 
10.3.2 
Dose Level Review Team (DLRT) ............................................ 101 
10.3.3 
Primary Analysis ....................................................................... 102 
10.3.4 
Final Analysis ........................................................................... 102 
10.4 
Planned Methods of Analysis ................................................................... 103 
10.4.1 
General Considerations ............................................................ 103 
10.4.2 
Primary Endpoint ...................................................................... 103 
10.4.3 
Secondary Endpoints ............................................................... 104 
10.4.3.1 
Pharmacokinetics Data Analysis ............................ 104 
10.4.3.2 
Efficacy Endpoint Analyses .................................... 104 
10.4.4 
Exploratory Endpoints .............................................................. 105 
11. 
REGULATORY OBLIGATIONS ........................................................................... 105 
11.1 
Informed Consent ..................................................................................... 105 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 106 
11.3 
Subject Confidentiality .............................................................................. 107 
11.4 
Investigator Signatory Obligations ............................................................ 107 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 107 
12.1 
Protocol Amendments and Study Termination ......................................... 107 
12.2 
Study Documentation and Archive ........................................................... 108 
12.3 
Study Monitoring and Data Collection ...................................................... 109 
12.4 
Investigator Responsibilities for Data Collection ...................................... 110 
12.5 
Language.................................................................................................. 110 
12.6 
Publication Policy ..................................................................................... 110 
12.7 
Compensation .......................................................................................... 111 
13. 
REFERENCES ..................................................................................................... 112 
14. 
APPENDICES ...................................................................................................... 114 
List of Tables  
Table 1.  Important Identified and Potential Risks of AMG 673 ....................................... 27 
Table 2.  Schedule A Planned Dose Escalation Schematica ........................................... 43 
Table 3.  Schedule B - Cycle 1 Dosing ........................................................................... 45 
Table 4.  Schedule B – Cycle 2 and Higher Dosing ........................................................ 46 
Table 5.  Grading and Management of Cytokine Release Syndrome ............................. 57 
Table 6.  Schedule of Assessments:  Doses D1-D5 (Cycle 1) ........................................ 62 
Table 7.  Schedule of Assessments:  Doses D1-D5  (Cycle 2) ....................................... 64 
Table 8.  Schedule of Assessments:  Doses D1-D5 (Cycle 3 and beyond) .................... 65 
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Table 9.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 1) ......................... 66 
Table 10.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 2) ....................... 67 
Table 11.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 3 and 
Beyond) .................................................................................................... 68 
Table 12.  Schedule of Assessments:  Schedule B (Cycle 1) ......................................... 70 
Table 13.  Schedule of Assessments:  Schedule B (Cycle 1 Step-Up Dose 
Visit) ......................................................................................................... 72 
Table 14.  Schedule of Assessments:  Schedule B (Cycle 2 and Higher) ....................... 73 
Table 15.  List of Analytes ............................................................................................... 83 
List of Figures  
Figure 1.  In Vitro MABEL for AMG 673 .......................................................................... 28 
Figure 2.  Example of Establishing Step Dosing Once MTD1 is Established in 
Schedule A ............................................................................................... 30 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 115 
Appendix B.  Sample Serious Adverse Event Form and eSerious Event 
Contingency Form .................................................................................. 117 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 122 
Appendix D.  World Health Organization Classification for Acute Myeloid 
Leukemias .............................................................................................. 124 
Appendix E.  Revised International Working Group Response Criteria 
Revised Response Criteria .................................................................... 126 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ............................................................. 129 
Appendix G.  Expected Disease-related Events by System Organ Class 
(SOC) ..................................................................................................... 130 
Appendix H.  Two-Parameter BLRM Design ................................................................. 131 
 
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1. 
OBJECTIVES 
1.1 
Primary 
The primary objectives of this study are to: 
• 
Evaluate the safety and tolerability of AMG 673 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)] 
1.2 
Secondary 
The secondary objectives of this study are to: 
• 
Evaluate the pharmacokinetics (PK) of AMG 673 
• 
Evaluate the anti-leukemia activity of AMG 673 by evaluating 
− 
the number and proportion of subjects who respond to treatment with 
AMG 673.  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 duration of response, time to progression, and time to response 
1.3 
Exploratory 
The exploratory objectives of this study are to: 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
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 2016, an estimated 19,950 new cases of 
AML were expected in the US with approximately 10,430 deaths occurring from this 
disease (American Cancer Society, 2016).   
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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 complete 
response (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 
1 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 1 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 1 year have been traditionally treated 
with HiDAC containing salvage regimens but only a minority achieve a second CR and 
many are not candidates for a potentially curative allogeneic hematopoietic stem cell 
transplant (HSCT) performed in second CR (Estey, 2000).  Apart from duration of first 
CR, other predictors of outcome of 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 unfavorable.   
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 
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 
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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). 
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 673, which targets CD33 and engages host T cells via CD3 binding, is a novel 
BiTE® molecule intended to treat patients with AML. AMG 673 is a half-life extended 
(HLE) BiTE® antibody construct combining the binding specificities for CD33 and CD3 
genetically fused to the N-terminus of a single chain IgG Fc (fragment crystallizable; 
scFc) region. The fusion to the Fc domain is a well-established strategy to prolong the 
half-life of protein therapeutics.  This key Half-Life Extension (HLE) modification, 
designed to maintain very efficient CD33-dependent target cell killing, should permit 
intermittent short IV infusions to be delivered over a course of several days up to 2 to 
3 weeks. The in vivo biological half-life of AMG 673 is anticipated to be 21 days. 
For additional information on AMG 673, please refer to the Investigator’s Brochure (IB). 
2.2.1 
Nonclinical Pharmacology 
In vitro Pharmacology: 
AMG 673 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 673 is time- and dose-dependent, with mean concentrations inducing 
half-maximal target cell lysis ranging from 0.39 pM to 6.75 pM with human effector cells.   
In the presence of target cells, AMG 673 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-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-10 and IL-6. 
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CD33 can be shed from the cell surface and was found in bone marrow plasma of AML 
patients at concentrations ranging from 0.4 to 29.6 ng/mL.  A recombinantly produced 
extracellular domain of CD33 at concentrations of up to 100 ng/mL barely affected 
AMG 673-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 
 
 
 
  Although the CD33+ T cells are potential targets for AMG 673 the 
removal of this small cell population will most likely not affect the anti-tumor activity of 
AMG 673 in cancer patients. 
In vivo Pharmacology: 
Anti-tumor activity of AMG 673 was evaluated in acute myeloid leukemia xenograft 
models. 
In an orthotopic AML model NOD/SCID mice were intravenously injected with  
EOL-1 AML and human T cells.  Administration of AMG 673 (1, 0.2 and 0.04 mg/kg) 
every 5 days for a total of 6 administrations resulted in a significant prolonged survival 
even at a dose of 0.04 mg/kg AMG 673.   
In a second orthotopic AML model NOD/SCID mice were intravenously injected with 
MOLM-13-luc and human T cells.  Animals were treated 6 times with 1, 0.2 or 
0.04 mg/kg AMG 673 by intravenous bolus administration every 5 days starting on 
day 6.  
AMG 673 significantly prolonged survival of animals in all dose groups compared with 
control animals with all animals in the high dose group surviving until end of the in-life 
phase on day 43. No human CD33+ cells were detected in the bone marrow of these 
animals at the end of the study.  
2.2.2 
Nonclinical Pharmacokinetics 
In cynomolgus monkeys, the PK of AMG 673 was investigated after administration via 
short (30-minute) IV infusions at doses of 5 and 15 µg/kg, respectively.  Serum 
concentrations of AMG 673 declined in a biphasic manner with concentration-time 
profiles that suggested linear elimination.  AMG 673 PK appeared to be linear within this 
dose range, with mean systemic clearance (CL) and steady-state volume of distribution 
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(VSS) values of 1.4 mL/hr/kg and 256-268 mL/kg, respectively.  The mean t1/2 values of 
AMG 673 ranged between 167-178 hours after IV administration.  In addition, for an 
increase in dose of 3-fold, maximum observed serum concentrations (Cmax) and area 
under the concentration-time curve until the last quantifiable time point (AUClast) were 
increased by 3.95-fold and 3.02-fold, respectively, suggesting approximately 
dose-proportional PK within these 2 dose levels. 
2.2.3 
Nonclinical Toxicology 
The nonclinical safety assessment of AMG 673 consisted of a 28-day 
intravenous (IV) toxicology study in monkeys.  The monkey was selected as the 
toxicology species based on target binding affinity and bioactivity data.  The intravenous 
route of administration was chosen based on the intended clinical route of 
administration.  The results of the 28-day monkey toxicology study with AMG 673 were 
consistent with its expected pharmacology, ie, cytotoxic T-cell redirected lysis of 
CD33-expressing bone marrow cells and leukocytes, and included increased cytokines, 
decreased circulating leukocytes, red cell mass and platelets, changes in clinical 
chemistry parameters suggestive of an acute phase response, and increased heart rate.  
All of these changes exhibited full or partial reversibility.  One animal from the high-dose 
group (30 µg/kg) had decreased activity approximately 4.5 hours after administration of 
the first dose and was euthanized soon thereafter due to poor clinical condition; the 
morbidity in this animal was attributed to complications from cytokine release.  All other 
animals survived to scheduled termination; there were no AMG 673-related light 
microscopic changes in these animals.  All surviving animals developed antidrug 
antibodies (ADA) that were associated with complete or nearly complete loss of 
exposure by day 14.  Despite the loss of exposure, the study is valid to support the 
proposed clinical trial because all of the AMG 673-related changes were as expected for 
a CD33-directed activator of T-cells.  Based on the unscheduled euthanasia at 30 µg/kg, 
the highest non-severely toxic dose (HNSTD) was determined to be 15 µg/kg.   
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 673.   
Most clinical experience exists with a BiTE® molecule called blinatumomab (specificity 
for CD3 and CD19) which has shown that administration of BiTE® by continuous 
intravenous (cIV) infusion can be performed with an acceptable safety profile and can 
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lead to clinical responses in subjects with late-stage hematological malignancies 
(Nagorsen et al, 2012).  Blinatumomab was granted breakthrough status by FDA and 
was subsequently 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%) are 
pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, 
rash, and constipation.  According to the US prescribing information (BLINCYTO® 
[blinatumomab] Prescribing Information, Amgen), 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.   
2.3 
Risk Assessment 
Based on the mode of action targeting CD33, expression on myeloid cells and clinical 
observations with other BiTE® molecules developed in hematological malignancies, 
cytokine release syndrome (CRS), neutropenia and infections are anticipated with 
AMG 673 administration.  For a listing of important identified and potential risks for 
AMG 673 refer to Table 1 below. See also section 6.6 for specific recommendations for 
CRS, tumor lysis syndrome, and infection prophylaxis.  
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Table 1.  Important Identified and Potential Risks of AMG 673 
Identified Risk 
Description 
Cytokine Release 
Syndrome (CRS) / 
Infusion Reactions 
Signs and Symptoms may include the following: 
• 
constitutional - fever, rigors, fatigue, malaise 
• 
neurologic - headache, mental status changes, dysphasia, 
tremors, dysmetria, gait abnormalities, seizure 
• 
respiratory - dyspnea, tachypnea, hypoxemia 
• 
cardiovascular - tachycardia, hypotension 
• 
gastrointestinal - nausea, vomiting, transaminitis, 
hyperbilirubinemia 
• 
hematology - bleeding, hypofibrinogenemia, elevated D-dimer 
• 
skin – rash 
Infusion reactions may be clinically indistinguishable from manifestations 
of CRS 
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. 
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 673 administration. 
See also section 2.2.3 for nonclinical safety observations.   
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2.4 
Rationale 
The starting dose for previous BiTE® molecules was chosen based on the minimum 
anticipated biological effect level (MABEL) and was also used to select the starting dose 
for AMG 673.  In this case, redirected lysis of KG-1 AML cells by T cells was considered 
the most sensitive parameter of AMG 673 activity.  BiTE®-mediated redirected lysis by 
T cells from 13 different donors was analyzed and based on individual dose-response 
curves an in vitro MABEL (mean EC50) of 0.016 ng/mL was determined (Figure 1).   
Figure 1.  In Vitro MABEL for AMG 673 
 
Human 
 (n=13) were co-cultured with KG-1 cells (E:T cell ratio = 5:1) and serial dilutions of AMG 673 
drug substance. Target cell lysis was monitored by flow cytometric determination of propidium iodide uptake 
after 48 h. Error bars indicate the SD of triplicates (A). EC50 values calculated with aid of the nonlinear 
regression function in the GraphPad Prism software and mean of the individual values were plotted in 
panel B. 
MABEL, Minimum Anticipated Biological Effect Level; 
  
Source: Study 123416 
Combining the predicted human PK and understanding of the MABEL of AMG 673, a 
starting dose of 0.05 µg represents the human dose predicted to approximate maximum 
serum concentrations equivalent to the MABEL (0.016 ng/mL).  The use of the in vitro 
EC50 as the MABEL and basis for the FIH starting dose is supported by the previous and 
safe implementation of this strategy to identify the maximum recommended starting 
doses of previous BiTE® molecules in clinical development.  This approach ensures that 
the selection of the starting dose is safe while minimizing the number of dose steps 
necessary to reach exposures that would be associated with BiTE® pharmacologic 
activity (as opposed to the traditional use of the EC20).  Furthermore, relative to the use 
of 1/6th of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys 
A
B
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(15 µg/kg; Study 118912) as the basis for defining the starting dose for anti-cancer drugs 
(ICH S9, 2009), a 0.05 µg dose still remains a more conservative approach 
(a 0.05 µg starting dose is 1/6000th of the HNSTD on a body surface area basis). This 
approach is also supported by the calculation of the expected human exposure margins, 
which exceed several hundred-fold at a starting dose of 0.05 µg. 
As of 26 September 2019, 30 subjects have been enrolled in this FIH study and have 
received AMG 673 at doses ranging from 0.05 to 72 µg.  Preliminary PK analysis from 
the ongoing FIH study suggests dose-related increases in AMG 673 maximum observed 
concentration (Cmax) and area under concentration-time curve (AUC) under Schedule A.  
Schedule B is designed to assess higher density exposure to AMG 673. Please refer to 
the Investigator’s Brochure (IB) Section 6 for additional information. 
2.5 
Clinical Hypotheses 
AMG 673 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a first-in-human, open-label, phase 1 sequential dose escalation study.  AMG 673 
will be evaluated as a short term IV infusion in adult subjects with relapsed/refractory 
AML.  The study will be conducted at approximately 10 sites divided across Australia, 
Germany, Japan and the United States. More sites may be added later. 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) using 2 dosing schedules of AMG 673 administration:  
Schedule A and Schedule B.   
Schedule A:   
Planned dose levels (dose per infusion) for the dose-escalation cohorts are as follows: 
0.05 µg, 0.15 µg, 0.45 µg 1.5 µg, 4.5 µg, 9 µg, 18 µg, 36 µg, 72 µg, 110 µg, 160 µg, 
240 µg, 360 µg and higher if MTD is not reached. (Table 2).   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 673.   
The starting dose for the first cohort will be 0.05 µg administered as short term IV 
infusions (approximately 30 minutes to 3 hours) on D1 and D5 of each cycle. The doses 
and frequencies administered for the cohorts following cohort 1 will be recommended by 
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the DLRT. The DLRT may recommend on the administration of up to 2 additional 
infusions on D12 and D19 of a cycle for a future cohort based on rules described in 
Section 10.3.2. The D5 infusion, and the D12/D19 infusions (if applicable) may be at the 
same dose as the preceding infusion or may be at a higher dose (= dose step). This will 
be based on tolerability of the lower dose level; occurrence of DLTs due to cytokine 
release syndrome, infusion related reactions or tumor lysis syndrome will trigger step 
dosing to evaluate MTD2.  The DLRT may determine MTD3 based on the same rules. 
Starting with an initial lower dose / lower doses may improve tolerability of subsequently 
administered higher doses due to initial reduction of the bulk of blast cells, thereby 
improving efficacy. For a schematic overview of the different dose step options see 
Figure 2. below. The term “dose level” administered to a cohort may therefore either 
refer to 2 – 4 infusions of the same dose (cohorts without a dose step) or to 2 – 4 
infusions with up to 3 different doses (cohorts with 1 or more dose steps). In case of a 
dose step, the extended assessments for D1 and following apply also for D5/12/19 
infusions (see Schedule of Assessments, 7, Table 10).  
Figure 2.  Example of Establishing Step Dosing Once MTD1 is Established in 
Schedule A 
 
 
 
 
 
 
 
 
 
 
Administration of a prophylactic steroid dose (8 mg IV dexamethasone) within 1 hour 
prior to start of AMG 673 infusion on day 1 and day 5 and prior to each step-up dose of 
AMG 673, to mitigate cytokine release syndrome, is mandatory. 
Approved 
 
 


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There is a ± 1 day window for dosing visits which may be implemented after discussion 
with the sponsor. 
Intermediate dose level(s) may be evaluated as necessary based on DLRT 
recommendation after considering all information. For example,  in the event that 
1 subject experiences a dose limiting toxicity (DLT, see section 6.2.1.3 for DLT 
definitions), the Dose Level Review Team (DLRT) will consider both the BLRM 
recommendation and all available data, including the nature and severity of the DLT.  
The DLRT will recommend the dose administered for the next cohort, which may be a 
dose lower than the next planned dose level.  
Schedule B:   
Schedule B will be initiated after preliminary safety data of AMG 673 in Schedule A (eg, 
MTD1 is estimated to be ≥72 µg) become available and may be conducted in parallel with 
Schedule A per Sponsor’s decision.  For Schedule B, planned dose levels (dose per 
infusion) for the dose escalation cohorts are as follows:  72 µg, 110 µg, 160 µg, 240 µg, 
360 µg, 480 µg and higher if MTD for Schedule B is not reached.  The starting dose for 
the first cohort on Schedule B will be 72 µg administered as short-term IV infusions daily 
(QD) during the 14-day cycle 1.  The doses administered for the subsequent cohorts will 
include step-up doses administered in increments of 2 days as described in Table 4.  
The DLRT may recommend shortening the duration of steps to 1 day or to extend the 
duration of steps up to 5 days based on the emergent safety, PK and PD data.  All 
subjects will be pre-treated with an 8-mg dose of IV dexamethasone 1 hour prior to the 
day 1 dose of AMG 673 and prior to each step-up dose of AMG 673 in cycle 1 and prior 
to all doses in subsequent cycles.  Cycle 2 will start immediately after cycle 1 has 
completed and will consist of 4 AMG 673 infusions: day 1, day 4, day 8, and day 11 of a 
14-day cycle at the target dose.  Each cycle on Schedule B is planned for 14 days and 
intervals between cycles up to 2 weeks may be permitted after completion of cycle 2 
upon discussion and agreement with Sponsor. Please refer to Section 6.2.1.1.2 for 
additional information on Schedule B dose schedule, requirements and treatment-free 
intervals. 
Estimation of MTDs 
The estimate of the MTD or the estimate of each MTD if step dosing is used will use 
Bayesian logistic regression model (BLRM) design once a DLT is observed. DLTs 
experienced by subjects both during and after completing the DLT period will be 
considered in the BLRM design to account for any late onset toxicity. Schedule A may 
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result in 2 or more estimates of MTD; MTD1 without step dose, MTD2 with step dose 
and MTD3 with 2 step doses.  Schedule B will utilize the step-up dose schedule 
described in Section 6.2.1.1.2 to estimate MTD.  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 each schedule. 
 
MTD1 (Schedule A) 
Dose escalation for the initial dosing MTD (MTD1) will proceed using 2 parts, single 
subject cohorts and multiple subject cohorts.  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 673 will be observed.  When an adverse event related to 
first dose effects is observed, the cohort size will be extended to N = 3 to 4 subjects.    
When the initial DLT is observed, the BLRM design will be used to guide dose level 
selection.  After each cohort, the model’s recommended MTD dose level for evaluation is 
the dose level with the highest probability of the target toxicity probability interval (TPI), 
but with a less than 0.25 probability of an excessive or unacceptable TPI.  The actual 
dose selected at each dose decision may be at or below the model’s recommended 
dose as determined by the dose level review team (DLRT) after considering all 
information.  
The dose escalation will be stopped when any of the following occurs: 
• 
A minimum of 6 subjects have been treated at the MTD1 level 
• 
When the sample size reaches 40 subjects 
• 
Or as determined by the DLRT after considering all information. 
 
MTD2 (Schedule A) 
Dose escalation for the MTD following the initial dosing (MTD2) will proceed after MTD1 
is determined and implements a dose step.  The cohort for which a dose step will be 
implemented will start treatment for the first dose at the MTD1 assessed in the dose 
escalation for the first MTD.  After this run-in dose, there may be a dose increase to the 
next higher dose as per the dosing schedule shown in Figure 2 of the protocol.  If this 
treatment schedule is tolerated, following dose cohorts will continue to receive the run in 
(initial) dose at MTD1 to assess the MTD2. The target (2nd) dose will be increased until 
a MTD2 is reached.  Dose escalation for the target (2nd) dose will be guided in the same 
way by the BLRM and the DLRT review after considering all information. An additional 
step may be added and the DLRT may determine MTD3 based on the same rules. 
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MTD Schedule B 
Dose escalation for the MTD using the Schedule B may be conducted in parallel with 
Schedule A after  the 72 µg dose level is found to be safe and well tolerated by the 
DLRT.  The first cohort is planned to receive daily short term infusions of AMG 673 at 
72 µg for 14 days (cycle 1) and on days 1, 4, 8 and 11 for cycle 2 and beyond (see 
Section 6.2.1.1.2 for additional information).  If this treatment schedule is tolerated, 
subsequent dose cohorts will continue to receive the run in (initial) dose at 72 µg 
followed by incremental step-up doses until MTD is reached (refer to Table 3 for cohort 
specific dose schemas).  Dose escalation to the target dose will be guided by the BLRM 
as previously described and recommendations following DLRT review after considering 
all information. 
Dose Escalation Cohorts 
Single Subject Cohorts (Schedule A only) 
In the first 2 dose escalation cohorts, only a single subject will be enrolled to a cohort 
because the dose level is not anticipated to be clinically active.   
Multiple Subject Cohorts  
Based on PK/PD modeling of ANCs in cynomolgus monkeys, a dose of 72 µg is 
predicted to generate trough concentrations that may be potentially efficacious. 
However, this was based on limited ANC data from 1 study in cynomolgus monkeys with 
2 dose levels (5 and 15 µg/kg). It is anticipated that up to 9 additional cohorts will be 
enrolled using the BLRM design.  Each cohort will enroll up to 4 evaluable subjects.  
There will be at least a 7-day (168-hour) interval between the start of treatment of the 
first and second subject in each cohort (ie. at the same dose and schedule).  On day 7 of 
this interval, the site investigator will evaluate all available safety and laboratory data for 
the treated subject and 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 
subject in the cohort after receipt of this confirmation.  If deemed necessary, the 7-day 
interval may be extended until sufficient data are available to allow an assessment of the 
feasibility of treatment start of the next subject.  In addition, there will be at least a 
96-hour interval between the start of treatment of the second subject and all subsequent 
subjects in each cohort.  The same process as described above will apply for 
determination if further subjects can be enrolled. In case dose step(s) will be 
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implemented, there will be a 72-hour interval between the dose step(s) and enrollment of 
the next subject for the first 10 subjects who will receive step dosing.  
The same guidance applies in case of intra-subject dose escalation, if applicable.  
Intra-subject dose escalation should only occur if:  
• 
the next dose cohort has been deemed safe by the DLRT 
• 
after consultation with the sponsor 
• 
no DLT is reported during or after completion of the DLT period for that subject 
• 
no ≥ grade 2 adverse events (deemed treatment related by the investigator) are 
reported during treatment for that subject.  
See Section 7.2.2 for details on assessments applicable in case of intra-subject dose 
escalation.  
Following this, no more than 3 subjects should be enrolled into a cohort in 2 weeks.   
Dose escalation decisions will be made based on the recommendation of the BLRM 
model and the DLRT review after considering all information. The estimate of MTD will 
use BLRM design. The model’s estimated MTD dose is the dose with the highest 
probability of the target toxicity probability interval (TPI), but with a less than 0.25 
probability of an excessive or unacceptable TPI. The target TPI is (0.20, 0.33), and TPIs 
of (0.33, 0.60) and (0.60, 1.00) are defined as excessive and unacceptable, respectively.  
See section 3.4 for replacement of subjects. 
Dose escalations will continue until either of the following occurs. 
• 
No DLTs are observed on study and 
o Minimum of 6 treated subjects at highest planned dose level 
• 
DLTs are observed on study and 
o BLRM repeats the recommendation of a dose level (minimum of 6 treated 
subjects) or 
o A maximum of 40 subjects are enrolled within a schedule. If fewer than 
6 subjects are treated at the MTD, additional subjects beyond 40 may be 
enrolled to confirm safety and tolerability. 
The MTD is defined as the highest dose level whose DLT rate has the highest probability 
of the target TPI, an excessive/unacceptable TPI of < 0.25, and a minimum of 6 subjects 
have been treated at the MTD.  
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Expansion Cohort 
At completion of the dose escalation cohorts within a schedule, 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 673. The dose to be evaluated will be at or below 
the MTD estimated in the dose escalation cohorts.   
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 2 weeks or dropped out of treatment / study, whichever occurs 
earlier. The MTD will be further evaluated by applying BLRM using all available data, 
including data from subjects in the expansion phase.  Ad hoc meetings may be 
convened any time in case of important safety events (see also section 10.3.2). 
A final estimate of the MTD and RP2D using BLRM will be evaluated and confirmed 
utilizing all DLT-evaluable subjects from the dose escalation and the dose expansion 
cohorts for each schedule .  For definition of DLT-evaluable, see section 6.2.1.3.  
Additional expansion cohorts testing alternative dose levels or biologic subsets may be 
considered by amendment. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section.   
The study endpoints are defined in Section 10.1.1 
3.2 
Number of Sites 
This study will be conducted at approximately 10 sites in Australia, Germany, Japan and 
US.  Additional countries or sites may be added if necessary.   
Sites that do not enroll subjects into an open cohort within 6 months of site initiation may 
be closed or replaced.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.” 
It is anticipated that approximately 95 subjects will be enrolled in this study.  For 
Schedule A, 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.  For 
Schedule B, up to 40 subjects will be enrolled in the dose escalation cohorts and up to 
10 additional subjects will be enrolled in the dose expansion cohort.  For ethical and 
operational reasons subjects who already are in the screening phase at the time of 
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enrollment stop (end of expansion phase) may 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, or a schedule may be 
discontinued. 
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 may be replaced (see Section 6.2.1.3 for definition of a 
DLT-evaluable subject).   
For Schedule A, a subject is not DLT-evaluable if he/she drops out earlier than 1 week 
after the last planned infusion (eg, day 5 or day 19, depending on the cohort) in cycle 1 
for reasons other than an AE.  All available safety data for subjects who are not DLT 
evaluable will still be evaluated and considered in DLRM recommendations. A cycle will 
be considered complete and the subject will be DLT-evaluable if the subject has 
received IP treatment as planned (ie, infusions on D1, D5, and D12/D19 if applicable) 
and has remained on study for at least 1 week after the last dose in cycle 1.  
For Schedule B, a subject must complete the 28 day DLT window and is not 
DLT-evaluable if they have not completed at least 70% of planned target doses in cycle 
1 for reasons other than a DLT.   
Exception: If a subject has completed treatment as planned but drops out of study 
earlier than described above due to progressive disease, they will still be considered 
DLT-evaluable and will not be replaced.   
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 12 months. 
This includes a screening period lasting 14 days, a treatment period lasting 
approximately 10 months, and a safety follow-up period lasting approximately 4 weeks 
after the last dose.  The actual duration for individual subjects will vary depending upon 
tolerability of AMG 673, evidence of clinical progression, and willingness to participate in 
the study. 
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After completion of a first cycle without a DLT, up to 12 total 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 673 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 primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the purposes of final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, whether 
the study concluded as planned in the protocol or was terminated early.  
The primary completion date is the date when the last subject either had the opportunity 
to receive up to 12 cycles of treatment or terminated the study early. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit); the final analysis will occur at this time.  
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).     
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
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4.1 
Inclusion Criteria 
101. 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102. 
Subjects ≥ 18 years of age at the time of signing consent. 
103. 
AML as defined by the WHO Classification (Appendix D) persisting or recurring 
following 1 or more treatment courses except promyelocytic leukemia (APML). 
1. More than 5% myeloblasts in bone marrow. 
104. 
Eastern Cooperative Oncology Group (ECOG, Appendix F) Performance Status 
of ≤ 2. 
105. 
Renal function as follows: serum creatinine < 2.0 mg/dL (176.84 µmol/L) and 
estimated glomerular filtration rate > 30 mL/min/1.73 m2. 
106. 
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) 
4.2 
Exclusion Criteria 
201. Active extramedullary AML in the central nervous system (CNS). 
202. Known hypersensitivity to immunoglobulins. 
203. White blood cells (WBC) > 15,000 cells/mcL (15 cells x 10^9/L) at screening.  In 
subjects with WBC > 15,000 cells/mcL at screening with lymphocyte 
predominance, subject may be deemed eligible for the trial by the Amgen 
physician, after discussion with the investigator.  
204. Prior malignancy (other than in situ cancer) unless treated with curative intent and 
without evidence of disease for > 2 years before screening. 
205. Autologous HSCT within 6 weeks prior to start of AMG 673 treatment. 
206. Allogeneic HSCT within 3 months prior to start of AMG 673 treatment. 
207. Non-mangeable graft versus host disease. 
208. 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. 
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• 
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). 
209. History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
3 months. 
210. Active infection requiring intravenous antibiotics within 1 week of study enrollment 
(day 1). 
211. 
Known positive test for human immunodeficiency virus (HIV). 
212. 
Positive for hepatitis B surface antigen. 
213. 
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. 
214. 
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. 
215. 
Antitumor therapy (chemotherapy, antibody therapy, investigational agents, 
molecular-targeted therapy or retinoid therapy) within 14 days of day 1.  
Exception:  hydroxyurea to control peripheral blood leukemic cell counts is 
allowed until start of IP treatment. 
216. 
Treatment with systemic immune modulators including, but not limited to, 
nontopical systemic corticosteroids (exception: physiological replacement and 
pre-medication for blood products are permitted), cyclosporine, and tacrolimus 
within 2 weeks before enrollment (day 1). 
217. 
Prior treatment with chimeric antigen receptor T cell (CAR-T) infusion for the 
treatment of AML (CD33 target) 
218. 
(Criterion removed in Protocol Amendment 4) 
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219. 
Major surgery within 28 days of study day 1 with the exception of biopsy and 
insertion of central venous catheter. 
220. 
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. 
221. 
Males and females of reproductive potential who are unwilling to practice a highly 
effective method(s) of birth control while on study through 15 weeks after 
receiving the last dose of study drug.  Acceptable methods of highly effective 
birth control include sexual abstinence (males, females); vasectomy; bilateral 
tubal ligation/occlusion; or a condom with spermicide (men) in combination with 
hormonal birth control or intrauterine device (IUD) (women). Males who are 
unwilling to abstain from sperm donation while on study through 5 half-lives after 
receiving the (last [multiple-dose studies]) dose of study drug. 
222. Females who are lactating/breastfeeding or who plan to breastfeed while on study 
through 15 weeks after receiving the last dose of study drug. 
223. Females with a positive pregnancy test. 
224. Females planning to become pregnant while on study through 15 weeks after 
receiving the last dose of study drug. 
225. Subject 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 (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the ICF before commencement of study-specific 
activities/procedures.  Adverse events and disease-related events are to be collected for 
an eligible subject once they are enrolled in the study.  The Investigator is to document 
the enrollment decision and date in the subject’s medical record. 
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, 377).  The next 5 digits will 
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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 37726001001, and the second subject at the same 
site will receive the number 37726001002.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
Subjects who do not meet the eligibility criteria within the 14-day screening period will 
not be eligible for enrollment.  Subjects may be re-screened up to 3 times at the 
discretion of the investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside the 14-day screening period.  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 673.   
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 
An Amgen representative will notify the site(s) in writing when a cohort is open to screen 
new subjects.  In the first 2 dose escalation cohorts in Schedule A, only a single subject 
will be enrolled to a cohort because the dose level is not anticipated to be clinically 
active. Enrollment will be performed according to the BLRM design (see section 3.1 for 
details) from Schedule A cohort 3 onwards, and for all of Schedule B cohorts.  Each 
cohort will enroll up to 4 evaluable 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 673.  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.  
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 42 of 136 
CONFIDENTIAL 
 
 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product 
The Amgen Investigational Product (IP) used in this study is AMG 673.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 673.  
6.2 
Investigational Product 
The IP will be administered 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 673 
AMG 673 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.   
AMG 673 is supplied as a sterile, preservative-free lyophilized powder for IV 
administration after reconstitution with sterile WFI. After reconstitution with 1.2 mL of 
sterile WFI, the 1 mg/mL AMG 673 drug product is formulated with 1mg/mL 
 mM 
glutamic acid, % (w/v) sucrose, and 
% polysorbate 80, pH 
.  The final container 
is a single-use, 6R glass vial and contains a target extractable amount of 1 mg 
AMG 673.   
The intravenous solution stabilizer (IVSS) is intended for pre-treatment of IV bags prior 
to dilution of AMG 673 drug product. The IVSS is supplied as a sterile solution in a  
10-cc glass vial containing 10 mL deliverable product.  The IVSS does not contain an 
active pharmaceutical ingredient and is a buffered, preservative-free solution  
(
 mM citric acid, 
M lysine hydrochloride, 
% (w/v) polysorbate 80, pH 
).   
6.2.1.1 
Dosage, Administration, and Schedule 
AMG 673 will be delivered using infusion pumps (for the higher doses) and syringe 
pumps (for the lower doses), respectively, which are both approved for use by the 
appropriate regulatory authority for the country in which the subject is undergoing 
treatment.   
AMG 673 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines.  
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 43 of 136 
CONFIDENTIAL 
 
 
Please refer to the IPIM for more information regarding the storage, preparation, 
destruction, and administration of AMG 673. 
6.2.1.1.1 
Schedule A 
The drug will be administered as short term IV infusions (approximately 30 minutes to 
3 hours) on D1 and D5 of each treatment cycle followed by an infusion-free interval prior 
to the start of the following treatment cycle. Up to 2 additional infusions on D12 and D19 
of a cycle may be implemented by DLRM recommendation.   
The planned dose levels for the dose escalation cohorts are: 0.05 µg, 0.15 µg, 0.45 µg, 
1.5 µg, 4.5 µg, 9 µg, 18 µg, 36 µg, 72 µg, 110 µg, 160 µg, 240 µg, 360 µg and higher if 
MTD is not reached (testing doses higher than 360 µg will be done via a substantial 
amendment for EU).  The MTD or highest tested dose (or doses, in case of dose step) 
will be administered in the dose-expansion cohort.  
Table 2.  Schedule A Planned Dose Escalation Schematica 
Number of Subjects 
Target Doseb 
1 c 
0.05 µg/infusion 
1 c,  
0.15 µg/infusion 
3-4 c 
0.45 µg/infusion 
3-4 
1.5 µg/infusion 
3-4 
4.5 µg/infusion 
3-4 
9 µg/infusion 
3-4 
18 µg/infusion 
3-4 
36 µg/infusion 
3-4 
72 µg/infusion 
3-4 
110 µg/infusion 
3-4 
160 µg/infusion 
3-4 
240 µg/infusion 
3-4 
360 µg/infusion 
a actual doses for a cohort will be up to DLRM recommendation 
b intermediate dose level(s) may be evaluated as necessary 
c in case of occurrence of a drug related safety or efficacy signal as listed below, the BLRM design would be 
triggered 
The infusion-free interval will have a duration of 0 to 14 days depending on treatment 
response and recovery of blood counts, but may be extended to up to 5 weeks in case of 
prolonged marrow aplasia and aleukemic cytopenia after consultation with the sponsor. 
It may also be extended for up to 3 days from the planned duration if necessary for 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 44 of 136 
CONFIDENTIAL 
 
 
logistical reasons.  The DLRT may recommend on changes of the duration of the 
infusion-free interval for future cohorts after evaluation of PK data. 
Depending on the treatment response, the following scenarios are possible in the first 
treatment cycle (shown for a 2-week cycle – infusions on D1 and D5 as an example): 
• 
Tumor assessment on day 14: Subjects who show no detectable leukemic blasts 
in bone marrow and in peripheral blood  will start the next cycle at day 21. 
Subjects who show detectable leukemic blasts in bone marrow or blood will start 
the next cycle at day 15.  
The infusion-free interval may be extended up to a maximum of 7 weeks in case of 
insufficient recovery of peripheral blood counts (neutrophils < 500/µl, platelets 
< 20,000/µl without transfusion) after consultation with the sponsor.  In case the 
infusion-free interval is extended to 42 days, a bone marrow assessment is 
recommended 4 weeks after the last infusion of a cycle. In the case this assessment 
shows leukemic infiltration of the bone marrow (≥ 5% blasts), treatment may be resumed 
immediately and start the next cycle on day 15. 
For longer treatment cycles, refer to Schedule of Assessments (Section 7.1) for bone 
marrow assessments. 
Subjects will be hospitalized for a minimum of 8 days from start of the first infusion in 
cycle 1 (ie, until at least 72 hours after start of the second infusion on  day 5) and for a 
minimum of 72 hours following day 12 and day 19 doses in cycle 1. If the subject 
receives a second subsequent cycle of AMG 673 at the same dose, hospitalization will 
be for a minimum of 8 days from start of the day 1 dose (ie, at least 72 hours after the 
day 5 doses). In the absence of DLTs and SAEs, shorter hospitalization may be 
considered upon PI recommendation and Medical Monitor agreement during cycle 2.  
Hospitalization following day 12 and day 19 doses in cycle 2 and onwards will be at the 
discretion of the treating physician. For subjects receiving >2 cycles, hospitalization for 
cycle 3 onwards for all doses will be at the treating physician’s discretion. 
6.2.1.1.2 
Schedule B 
Schedule B will be initiated after preliminary safety data of AMG 673 in Schedule A (eg, 
MTD1 is estimated to be ≥72 µg) become available and may be conducted in parallel 
with Schedule A per sponsor’s decision.  For Schedule B, planned dose levels (dose per 
infusion) for the dose escalation cohorts are as follows:  72 µg, 110 µg, 160 µg, 240 µg, 
360 µg, 480 µg and higher if MTD is not reached.  The drug will be administered as short 
term IV infusions (approximately 30 minutes to 3 hours).  The starting dose for the first 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 45 of 136 
CONFIDENTIAL 
 
 
cohort on Schedule B will be 72 µg administered as short-term IV infusions daily (QD) 
during the 14-day cycle 1. No significant AMG 673 accumulation following QD dosing is 
predicted based on the preliminary PK analysis of Schedule A dosing. The doses 
administered for the cohorts following cohort 1 will include step-up doses administered in 
2 day increments after the previous step-up dose (eg, cohort 2 will start with 72 µg for 
2 days followed by 110 µg administered from day 3 to day 14; cohort 3 will start with 
72 µg for 2 days followed by 110 µg from day 3 to day 4, followed by 160 µg from day 5 
to day 14, etc).  See Table 3below for more details. 
Table 3.  Schedule B - Cycle 1 Dosing  
 
D1c 
D2c 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
Cohort 1 
72ab 
72 
72 
72 
72 
72 
72 
72 
72 
72 
72 
72 
72 
72b 
Cohort 2 
72ab 
72 
110ab 
110 
110 
110 
110 
110 
110 
110 
110 
110 
110 
110b 
Cohort 3 
72ab 
72 
110a 
110 
160ab 
160 
160 
160 
160 
160 
160 
160 
160 
160b 
Cohort 4 
72ab 
72 
110a 
110 
160a 
160 
240ab 
240 
240 
240 
240 
240 
240 
240b 
Cohort 5 
72ab 
72 
110a 
110 
160a 
160 
240a 
240 
360ab 
360 
360 
360 
360 
360b 
Cohort 6 
72ab 
72 
110a 
110 
160a 
160 
240a 
240 
360a 
360 
480ab 
480 
480 
480b 
D = dose; Unit of dosage = µg 
a Dexamethasone 8 mg IV will be administered 1 hour prior to dose.  
b Additional PK samples will be taken at these time points as described in Table 12-Table 14.   
• 
Table 13 PK sampling will be used only at the first dose of the target dose (highest dose planned) 
to be tested in Cycle 1 for each subject   
• 
All subjects will undergo day 1 PK sampling as described in Table 12.   
• 
PK sampling will occur on day 14-19 of Cycle 1 per Table 12 if the subject will not receive cycle 2 
immediately following cycle 1.  If subject proceeds to Cycle 2, day 14 (post-dose) through day 19 
samples will not be collected and Cycle 2 day 1 (eg day 15 after 1st dose) should be collected per 
Table 14. 
c Upon recommendation of DLRT and Sponsor agreement, a lower starting dose may be used (eg, 36 µg) 
for up to the first 2 doses  
The DLRT may recommend shortening the duration of steps to 1 day or to extend the 
duration of steps up to 5 days based on the emergent safety, PK and PD data.  If the 
duration of step-up doses is extended, the duration of a cycle can be extended from 
14 days to 28 days.  All subjects will be pre-treated with an 8-mg dose of IV 
dexamethasone 1 hour prior to AMG 673 dose on day 1 and prior to each step-up dose 
of AMG 673.   
Cycle 2 will consist of 4 AMG 673 infusions:  day 1, day 4, day 8, and day 11 of a 
14-day cycle at the target dose (maximum planned dose received from cycle 1) (see 
Table 4 below).  Cycle 1 schedule may be repeated 1 time before cycle 2 schedule is 
initiated upon agreement between the Investigator and Sponsor if the patient will likely 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 46 of 136 
CONFIDENTIAL 
 
 
gain additional benefit per Investigator’s assessment.  If cycle 1 is not repeated, cycle 2 
should begin immediately after cycle 1 with no dose free interval.   
Table 4.  Schedule B – Cycle 2 and Higher Dosing 
 
Day of Dose (14-Day Cycle) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Cohort 1 
72a 
 
 
72 
 
 
 
72 
 
 
72 
 
 
 
Cohort 2 
110a 
 
 
110 
 
 
 
110 
 
 
110 
 
 
 
Cohort 3 
160a 
 
 
160 
 
 
 
160 
 
 
160 
 
 
 
Cohort 4 
240a 
 
 
240 
 
 
 
240 
 
 
240 
 
 
 
Cohort 5 
360a 
 
 
360 
 
 
 
360 
 
 
360 
 
 
 
Cohort 6 
480 a 
 
 
480 
 
 
 
480 
 
 
480 
 
 
 
Unit of dosage = µg 
a Dexamethasone 8 mg IV will be administered 1 hour prior to dose. 
Upon recommendation from DLRT, the number of AMG 673 infusions in cycle 2 and 
higher may be adjusted based on emergent PK, safety, and PD data (eg, weekly [day 1 
and day 8 of each cycle]).  Subjects will be hospitalized for the whole duration of cycle 1 
(ie, a minimum of 15 days), and for at least 48 hours after each AMG 673 administration 
in cycle 2 and higher.  In the absence of any DLTs or SAEs, shorter hospitalization may 
be considered upon PI recommendation and Medical Monitor agreement after Cycle 2.   
6.2.1.1.3 
Schedule A and B 
Up to 12 treatment cycles can be administered to each subject as long as the subject is 
deriving benefit in the judgment of the investigator.   
If the next higher dose is deemed reasonably safe by the DLRT, intra-subject dose 
escalation is allowed (see Section 3.1) and additional hospitalization and procedures are 
required (see Section 7.2.2).  
Additionally, subjects will be hospitalized for a minimum of 72 hours under the following 
circumstances:  
− 
after each dose step, if applicable 
− 
after dose increase in case of intra-subject dose escalation 
Subjects will be hospitalized for a minimum of 48 hours under the following 
circumstances:  
− 
after re-start of treatment after an interruption due to adverse event 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 47 of 136 
CONFIDENTIAL 
 
 
Subjects can be hospitalized for a longer time period at the discretion of the investigator.   
A nurse trained in emergency medicine or a physician must be available when the 
infusion of AMG 673 is started for immediate intervention in case of complications. The 
hospitalization period may be extended at the discretion of the investigator. During 
hospitalization periods, an immediately accessible emergency room with resuscitation 
equipment must be available.  
Prior to hospital discharge, vital signs will be measured in order to detect possible signs 
and symptoms of cytokine release syndrome.  If required for logistical reasons (eg, long 
travel times), subjects may be hospitalized the day before start of dosing (day -1) of any 
cycle for required PK samples.   
The start time of infusion should be chosen carefully so as to avoid any interference or 
inconvenience with time points of safety assessments or PK/PD measurements. The site 
should record any unscheduled interruption of an infusion on the eCRF, and provide the 
start and stop date/time of the infusion. 
AMG 673 should be administered through a central venous access at a constant flow 
rate.  The drug should not be administered as a bolus.  In the event that administration 
through a central venous access is not possible, AMG 673 may be administered through 
a peripheral venous line.  The IPIM will have further information regarding drug 
preparation and administration for AMG 673. 
The quantity administered, start date/time, stop date/time, and lot number of IP are to be 
recorded on each subject’s eCRF.     
6.2.1.2 
Overdose 
The effects of overdose of this product are not known. The administered AMG 673 dose 
may be up to 10% lower or higher than specified in the protocol. A dose of up to 
10% higher than the intended dose may not require specific intervention.    
In any case of overdose, consultation with the Amgen medical monitor is strongly 
recommended for prompt reporting of clinically apparent or laboratory adverse events 
possibly related to overdosage. Consultation with the Amgen medical monitor is also 
strongly recommended even if there are no adverse events, in order to discuss further 
management of the subject. If the overdose results in clinically apparent or symptomatic 
adverse events, the subject should be followed carefully until all signs of toxicity are 
resolved and the adverse event(s) should be recorded / reported per Section 9.2.2.2.   
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 48 of 136 
CONFIDENTIAL 
 
 
A dose of >10% higher than the intended AMG 673 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 
Dose-cohort Study Escalation and Stopping Rules, Dose Limiting 
Toxicities (DLTs) 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT window, unless clearly attributable to causes other than AMG 673.  The DLT 
window for Schedule A will start on D1 (start of the administration of the first infusion) 
and last for 14 days for cohorts receiving 2 doses (ie, day 1 and day 5 dose) and for 
28 days for subjects receiving 4 doses (ie, days 1,5,12,19).  The DLT window for 
Schedule B will start on D1 (start of the administration of the first infusion) and last for 
the duration of cycle 1 and 2 (ie, 28 days).  The CTCAE (version 4) will be used to 
assess will be used to assess toxicities/adverse events with the exception of CRS (see 
Table 5 for grading of CRS).   
DLT Evaluation 
A subject is not DLT-evaluable if he/she drops out before completion of the DLT window 
for reasons other than an AE.  All available safety data for subjects who are not DLT 
evaluable will still be evaluated and considered in DLRM recommendations. A subject 
will be DLT-evaluable if the subject has received the minimum cycle 1 doses planned for 
the respective cohort defined below:.   
• 
Schedule A : 2 doses with a 14-day DLT window, or 4 doses with 28-day 
DLT window 
• 
Schedule B:  completed ≥ 70% of the planned target doses (eg, 10 doses out of 
a 14-day cycle 1 for cohort 1, at least 9 doses of the 12 planned at target dose 
cohort 2, etc) with 28-day DLT window 
Exception:  If a subject has completed treatment as planned but drops out of study 
before completing the DLT window due to progressive disease, they will still be 
considered DLT-evaluable and will not be replaced.  The DLT window may also be 
extended 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 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 49 of 136 
CONFIDENTIAL 
 
 
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 to be considered as DLTs and exceptions are listed below: 
• 
Any treatment-related death 
• 
Grade 4 neutropenia persisting at 42 days after the last infusion in treatment 
cycle1 in absence of evidence of active AML 
• 
Grade 3−5 non-hematologic toxicity not clearly resulting from the underlying 
leukemia EXCEPT: 
o Alopecia 
o Grade 3 rash 
o Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
o Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization 
o Infection, bleeding, or other expected direct complication of cytopenias 
due to active underlying leukemia 
o Grade 3 infusion reaction , if successfully managed and resolves within 
72 hours 
o Grade 3 tumor lysis syndrome if it is successfully managed clinically and 
resolves within 7 days without end-organ damage. 
• 
Grade 3 or 4 isolated electrolyte lab abnormalities (ie, those occurring without 
clinical consequence) that resolve, with or without intervention, to  
< Grade 2 levels in < 72 hours will not be considered a DLT 
• 
Grade 3 or 4 asymptomatic enzyme elevations including AST, ALT (without 
bilirubin elevation), GGT, lipase and amylase that resolve, with or without 
intervention, to ≤ Grade 2 within 7 days will not be considered a DLT. 
• 
Grade 2 or 3 CRS meeting any of the criteria listed below: 
o Grade 2 CRS that does not resolve, with or without intervention to 
≤ Grade 1 within 7 days will be considered a DLT   
o 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  
o Grade 3 CRS reported at the initial dose (ie, at MTD1; applicable only 
after MTD1 has been defined) will be considered a DLT  
o Two separate grade 3 CRS events will be considered a DLT 
Grade 4 CRS occurring during AMG 673 treatment. 
See section 6.2.1.3 and 6.2.1.4 for description of dose escalation and stopping rules and 
section 3.4 for description of replacement of subjects.  
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 50 of 136 
CONFIDENTIAL 
 
 
6.2.1.4 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Treatment Interruption 
Significant events requiring a change in treatment will be managed by immediate 
treatment interruption.  
Note: The definition of treatment interruption may include interruption of infusion or 
delay of the subsequent infusion.  
Events leading to treatment interruption may include:  
• 
The subject experiences a clinically relevant grade 4 adverse event related or 
not-related to IP  
• 
The subject experiences a grade ≥ 3 CRS  
• 
Technical problem with the infusion pump / syringe pump 
• 
The investigational product is incorrectly prepared or administered (eg, overdose) 
Treatment Interruption and Re-Start in Case of Logistical Issues 
If the infusion interruption or the delay of the next infusion was up to 3 days, the next 
dose can be administered as planned. If the infusion interruption or the delay of the next 
infusion was > 3 days, the instructions for re-start after interruptions due to adverse 
events described below should be followed.  
Treatment Interruption and Re-Start in Case of Adverse Events 
Specific instructions apply in case of CRS: In case of grade 2 or 3 CRS, treatment must 
be interrupted and delayed until the event resolves to CRS grade ≤ 1. The Amgen 
medical monitor has to be consulted prior to a planned re-start. In case of grade 4 CRS, 
treatment must be permanently discontinued. See section 6.6 for further details. 
For all other adverse events, the following instructions apply:   
Any clinically relevant (as determined by the investigator) grade 4 adverse event related 
to IP should lead to an interruption of treatment.  Treatment should be interrupted until 
the event has resolved to grade ≤ 1.  Treatment may be resumed at the same dose or a 
lower dose after the event is resolved to grade ≤ 1 (see below for guidelines). Drug 
interruptions are also allowed in case of SAE not related to IP per investigator’s 
discretion. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 51 of 136 
CONFIDENTIAL 
 
 
Re-start at a lower dose level:  
In the following cases, the next infusion administered should be at the previous (lower) 
dose level: 
• 
If the event occurred during the infusion and caused an interruption of the 
infusion of >72 hours, or  
• 
if the event is defined as DLT and the subject has derived clinical benefit in the 
opinion of the PI after consultation with the Sponsor  
In both cases, re-escalation to the target dose can be considered for the next infusion if 
treatment at the lower dose has been well tolerated.  An intermediate dose level may be 
administered prior to stepping up to the target dose after consultation with the Amgen 
medical monitor. After the dose step, assessments of vital signs, pulse oximetry and 
clinical evaluation should be performed as per the schedule of assessments for D1, D2 
and D3 (Table 6 for Schedule A or Table 12 for Schedule B).  
Re-start at the same dose can be performed if the infusion was interrupted for 
< 72 hours or if the event occurred after the end of the infusion and did not cause a 
delay of the start of the next infusion ≥ 72 hours.   
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 reduction should be considered. 
In any case, restarting treatment after an interruption due to an adverse event should be 
performed under medical supervision.  The following assessments should be performed 
as described in the Schedule of Assessments (Table 6 for Schedule A or Table 12 for 
Schedule B) for D1, D2, and D3: vital signs, pulse oximetry, and clinical evaluation. The 
subject should be hospitalized for at least 72 hours after re-start of the infusion.   
If possible, the number of infusions at the target dose in a cycle should sum up to the 
planned number of infusions (ie, 2 or 4 for Schedule A or a minimum of 70% of the 
planned target doses for Schedule B).  In this case, the subject would still be 
DLT-evaluable. However, if the next infusion could only be administered with a delay of 
5 days, a new cycle should be started and the interrupted cycle would not be evaluable 
for DLT. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 52 of 136 
CONFIDENTIAL 
 
 
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 the same dose level, 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 2 or 3 CRS meeting any of the criteria listed below: 
o Grade 2 or 3 CRS that does not improve to ≤ grade 1 within 7 days.  
o Grade 3 CRS that does not improve to ≤ grade 2 within 5 days. 
o Grade 3 CRS at the initial run-in dose for a cycle (ie, at the MTD1) (for 
cohorts with dose step only). 
o If a subject experiences 2 separate grade 3 CRS events. 
• 
Disease progression as defined by revised IWG response criteria (Appendix E). 
• 
Withdrawal of subject’s consent to treatment. 
• 
Subject or investigator not compliant with the study protocol. 
• 
Occurrence or progression of a medical condition which in the opinion of the 
investigator should preclude further participation of the subject in the study. 
• 
Hematological or extramedullary relapse subsequent to CR/CRh*/CRi/morphologic 
leukemia-free state on protocol treatment.  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.   
• 
A treatment interruption of more than 21 days due to an adverse event not clearly 
related to the underlying disease. Exception: For patients with Grade 4 neutropenia, 
the infusion free period may be extended up to 42 days. 
• 
Occurrence of CNS-related adverse event considered related to AMG 673 by the 
investigator and meeting 1 or more of the following criteria: 
o More than 1 seizure. 
o A CNS-related adverse event CTCAE Grade 4. 
o A CNS-related adverse event leading to treatment interruption that needed 
more than 1 week to resolve to CTCAE Grade ≤ 1. 
• 
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. 
• 
Females who become pregnant while on study  
• 
Males with pregnant partners or whose partners become pregnant while the subject 
is on study.   
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 53 of 136 
CONFIDENTIAL 
 
 
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. 
6.3 
Other Protocol-required Therapies  
All other protocol-required and recommended therapies including corticosteroids, that 
are commercially available are not provided or reimbursed by Amgen (except if required 
by local regulation).  The investigator will be responsible for obtaining supplies of these 
therapies.   
Oxygen: Oxygen administration as a supportive measure is permitted during study 
treatment.   
Hydroxyurea: Hydroxyurea for 7 days at a dose of 1 – 10 g / day is permitted prior to 
the first cycle of IP treatment for subjects with high WBC (> 15,000 cells/mcL or 15 cells 
x 10^9/L).  Administration of hydroxyurea after the start of IP must be approved and 
discussed with the Amgen medical monitor.   
Dexamethasone: Premedication with dexamethasone is required prior to day 1 and day 
5 of AMG 673 dosing and prior to each step-up dose of AMG 673 to mitigate the risk of 
CRS in Schedule A. For Schedule B, premedication with dexamethasone is required 
prior to a dose administered on day 1 and each step-up dose in cycle 1, and prior to 
every dose in subsequent cycles. When dosed, dexamethasone should be administered 
as a single IV dose (8 mg) within 1 hour of start of infusion.   
Tocilizumab:  Tocilizumab may be added to CRS treatment regimen or required to be 
used in combination with dexamethasone to treat CRS as per protocol Section 6.6. 
For administration of tocilizumab or dexamethasone and tocilizumab after occurrence of 
CRS, follow guidance in Section 6.6. Additional details regarding these protocol-required 
therapies are provided in the IPIM. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 54 of 136 
CONFIDENTIAL 
 
 
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 Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
6.4.1 
Criteria for Permanent Withholding of AMG 673 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-1 antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis 
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic Fatty Liver Disease including steatohepatitis 
− 
non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 55 of 136 
CONFIDENTIAL 
 
 
6.4.2 
Criteria for Conditional Withholding of AMG 673 due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of AMG 673 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
normal transaminases and TBL at baseline or subjects with 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:  
− 
Any AST or ALT elevation:  > 8 × ULN at any time 
− 
Any AST or ALT elevation:  > 5 × ULN but < 8 × ULN for ≥ 2 weeks 
− 
Any AST or ALT elevation:  > 5 × ULN but < 8 × ULN and unable to adhere to 
enhanced monitoring schedule 
− 
Any AST or ALT elevation:  > 3 × 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 × ULN at any time 
• 
OR:  ALP > 8 × ULN at any time 
AMG 673 should be withheld pending investigation into alternative causes of the 
laboratory elevations.  If the investigational product is withheld, the subject is to be 
followed according to recommendations in Appendix A for possible DILI.  Rechallenge 
may be considered if an alternative cause for the elevated liver enzymes (ALT, AST, 
ALP) and/or elevated TBL (total bilirubin level) is discovered and the laboratory 
abnormalities resolve to normal or baseline (Section 2). 
Discontinuation of the product should be considered and the decision to re-challenge 
should be discussed with the Amgen medical monitor before re-initiating treatment with 
investigational product. 
6.4.3 
Criteria for Rechallenge of AMG 673 After Potential Hepatotoxicity 
If signs or symptoms recur with rechallenge, then the investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.4.1) should 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. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 56 of 136 
CONFIDENTIAL 
 
 
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. 
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 CRS may include:   
• 
Constitutional – fever, rigors, fatigue, malaise 
• 
Neurologic – headache, mental status changes, dysphasia, tremors, dysmetria, 
gait abnormalities, seizure 
• 
Respiratory – dyspnea, tachypnea, hypoxemia 
• 
Cardiovascular – tachycardia, hypotension 
• 
Gastrointestinal – nausea, vomiting, transaminitis, hyperbilirubinemia 
• 
Hematology – bleeding, hypofibrinogenemia, elevated D-dimer 
• 
Skin – rash 
Subjects may experience CRS, identified as a safety risk factor for AMG 673 treatment, 
during the first few days following the initial infusion of AMG 673 and after a dose step. 
CRS may be life-threatening or fatal.  Infusion reactions may be clinically 
indistinguishable from manifestations of CRS. Throughout the infusion with AMG 673 
and at least 4 hours after the end of infusion, monitor subjects intensively for clinical 
signs (eg, fever, hypotension, tachycardia, dyspnea, tremors) and laboratory changes 
(eg, transaminase increase) which may be related to CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in Table 5 [based on the adopted grading system referenced in 
Lee et al, 2014]. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 57 of 136 
CONFIDENTIAL 
 
 
Table 5.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of 
AMG 673 
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).  
• 
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, 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 1 
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 . Dose may be 
repeated every 8 hours for up to 
3 additional doses. 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 
worsens or 
persists 2 hours 
after adequate 
medical 
management, 
interrupt AMG 673 
until CRS is Grade 
≤ 1.  
Refer to re-start 
criteria below. If 
symptoms 
progress to 
grade 3 criteria, 
see row below.  
Permanently 
discontinue 
AMG 673 if there is 
no improvement to 
CRS ≤ grade 1 
within 7 days. 
Page 1 of 2 
Footnotes defined on next page of the table 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 58 of 136 
CONFIDENTIAL 
 
 
Table 5.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of 
AMG 673 
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 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. 
Administer tocilizumab as an 
additional therapy in this setting at a 
dose of 8 mg/kg. Dose may be 
repeated every 8 hours for up to 
3 additional doses. 
Immediately 
interrupt AMG 673 
until event resolves 
to CRS grade ≤ 1.  
Permanently 
discontinue 
AMG 673 if there is 
no improvement to 
CRS ≤ grade 2 
within 5 days or 
CRS ≤ grade 1 
within 7 days. 
Permanently 
discontinue 
AMG 673 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. 
Dose may be repeated every 
8 hours for up to 3 additional doses. 
Immediately stop 
the infusion and 
permanently 
discontinue 
AMG 673 therapy.  
Page 2 of 2 
CRS, Cytokine Release Syndrome; CTCAE, Common Terminology Criteria for Adverse Events; 
IV, Intravenous; MTD = maximum tolerated dose 
a Revised grading system for CRS (Lee et al, 2014) 
b High dose vasopressors (all doses are required for ≥3 hours): Norepinephrine monotherapy ≥20 µg/min; 
Dopamine monotherapy ≥10 µg/kg/min, Phenylephrine monotherapy ≥200 µg/min, Epinephrine 
monotherapy ≥10 µg/min; If on vasopressin, vasopressin + norepinephrine equivalent of ≥10 µg/min; If on 
combination vasopressors (not vasopressin), norepinephrine equivalent of ≥20 µg/min 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 59 of 136 
CONFIDENTIAL 
 
 
Re-start of treatment after CRS: 
After grade 2 or 3 CRS, the next infusion may be administered if all of the following 
criteria are met: 
• 
The Amgen medical monitor must be consulted prior to re-starting treatment 
• 
If CRS occurred during AMG 673 infusion, infusion has been interrupted for at 
least 72 hours 
• 
The event has resolved to grade ≤ 1 prior to re-starting treatment 
AMG 673 therapy should be restarted 1 dose level below the dose at which the event 
occurred. If this lower dose level is well tolerated (ie, absence of grade ≥ 3 CRS), then a 
dose step up to the subject’s target dose level can occur. An intermediate dose may be 
administered after consultation with the Amgen medical monitor prior to stepping up to 
the target dose.  
Please also refer to the general guidance for re-start of treatment after adverse events in 
Section 6.2.1.4 
For Grade 3 and 4 CRS, please see Section 2 for DLT considerations. 
Tumor Lysis Syndrome 
Subjects with AML and WBC <10,000/mcl or 10 cells x 10^9/L 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 or 
15 cells x 10^9/L.  
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 
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 6.2.1.3 for DLT 
considerations. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 60 of 136 
CONFIDENTIAL 
 
 
Infection Prophylaxis 
Subjects who may experience neutropenia for 7 days or longer are at a high risk for 
infectious complications. As appropriate, these subjects should be administered 
prophylactic antibacterial (eg, fluoroquinolones), antifungal and antiviral medications.  
These subjects should be monitored for early signs of breakthrough infections after the 
initiation of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. 
6.7 
Medical Devices 
Depending on the dose, the investigational product must be administered using either 
syringe pumps (for lower doses) or infusion pumps (for higher doses) approved for use 
by the appropriate regulatory authorities for the country in which the subject is 
undergoing treatment.  Investigational product infusion for solution will be prepared in 
syringes or bags for IV infusion and delivered through infusion lines.   
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), device(s), or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 61 of 136 
CONFIDENTIAL 
 
 
6.9 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period 
Any anti-tumor therapy other than the investigational product, including cytotoxic and/or 
cytostatic drugs, hormonal therapy, immunotherapy or any biological response modifiers, 
any other investigational agent, chronic systemic corticosteroid therapy, other 
immunosuppressive therapies, or stem-cell transplantation is not allowed.   
Exception: Hydroxyurea is allowed to control WBCs as described in section 6.3. 
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the Amgen medical monitor first.  Investigators should ensure that the need for 
radiation does not indicate progressive disease and that for subjects with measurable 
disease, radiation is not to the sole site of measurable disease.   
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 
insertion of central venous catheter) 
• 
Treatment with another investigational drug or device during the study 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 62 of 136 
CONFIDENTIAL  
 
 
Table 6.  Schedule of Assessments:  Doses D1-D5 (Cycle 1) 
 
Footnotes defined on next page of the table 
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 63 of 136 
CONFIDENTIAL  
 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening 
a The Dose Level Review Team may recommend to change timing of D5 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: At screening 2 triplicates (total of 6 ECGs) should be done, at predose C1D1: 1 triplicate (total of 3 ECGs), post 1hr -end 
of infusion, 24 hours post dose and at EOS. Schedule for ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle.   
f Serum pregnancy test will be performed for all females unless surgically sterile or > 2 years postmenopausal 
 
h Assessment should be taken at the end of infusion   
 
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 64 of 136 
CONFIDENTIAL  
 
 
Table 7.  Schedule of Assessments:  Doses D1-D5  (Cycle 2) 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening 
a The Dose Level Review Team may recommend to change timing of D5 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: at predose C2D1: 1 triplicate (total of 3 ECGs), post 1hr -end of infusion, 24 hours post dose and at EOS.  
f Assessment should be taken at the end of infusion   
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 65 of 136 
CONFIDENTIAL  
 
 
Table 8.  Schedule of Assessments:  Doses D1-D5 (Cycle 3 and beyond) 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening  
a The Dose Level Review Team may recommend to change timing of D5 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: at predose C3D1: 1 triplicate(total of 3 ECGs), post 1hr -end of infusion, 24 hours post dose and at EOS.  
f Assessment should be taken at the end of infusion   
Cycle Day
14b EoT EoS
0
1
2
3
4
0
1
2
3
4
Informed consent
Hospitalization
Concomitant Medications
Serious adverse events
Adverse events
Disease-related events
Clinical Evaluationc
X
X
X
X
X
Vital signs, pulse oximetryd
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measuremente
X
Xf
Xf
X
Coagulation
X
X
X
X
X
Hematology, Chemistry 
X
X
X
X
X
Urinalysis 
X
X
X
X
Hepatitis Serology
AMG 673 short term IV Infusion
X
X
AMG  673 PK Collection
X
X
X
X
X
Bone marrow assessments
X
X
Treatment Period
1
5a 
Hours
Pre-
dose
Relative to start of 
infusion
Pre-
dose
Relative to start of 
infusion
DISEASE and BIOMARKER ASSESSMENTS
GENERAL AND SAFETY ASSESSMENTS
LABORATORY ASSESSMENTS
INVESTIGATIONAL PRODUCT DOSING
PK ASSESSMENTS
at discretion of investigator
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 66 of 136 
CONFIDENTIAL  
 
 
Table 9.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 1) 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening 
X* = at end of infusion perform corresponding assessment (ie, ECG at timepoint 1hr C3D1 with X* should be taken at end of infusion). 
NOTE: Use Table 6 in combination with Table 9 for Cycle 1, intra subject, dose step escalation, 4 dose schedule. 
a The Dose Level Review Team may recommend to change timing of D 5/12/19 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: at predose, post 1hr -end of infusion, 24 hours post dose and at EOS.  
f Serum pregnancy test will be performed for all females unless surgically sterile or > 2 years postmenopausal 
SCR
Cycle Day
-14 to -1
2
3
4
6
7
8
13a 14a 15a
20 21 22 28b EoT EoS
0
1
2
3
4
6
8 12 16 20 24 48 72
0
1
2
3
4
6
8 12 16 20 24 48
0
1
4
6
8 12 16 20 24 48 72
0
1
4
6
8 12 16 20 24 48 72
Informed consent
X
Hospitalization
X
X
Concomitant Medications
X
X
Serious adverse events
X
X
X
Adverse events
X
X
X
Disease-related events
Clinical Evaluationc
X
X
X
X
X
X
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
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
X
X
ECG triplicate measuremente
X
X
X*
X
X*
X
X
X*
X
X
X*
X
X
Serum pregnancy testf
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
Hematology, Chemistry 
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
Hepatitis Serology
X
AMG 673 short term IV Infusion
X
X
X
X
AMG  673 PK Collection
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
X
X
Bone marrow assessments
X
X
X
Treatment Period
1
5a 
Hours
Pre-
dose
Relative to start of infusion
Pre-
dose
Relative to start of infusion
GENERAL AND SAFETY ASSESSMENTS
12a 
19a
Pre-
dose
Relative to start of infusion
LABORATORY ASSESSMENTS
INVESTIGATIONAL PRODUCT DOSING
PK ASSESSMENTS
DISEASE and BIOMARKER ASSESSMENTS
Pre-
dose
Relative to start of infusion
 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 67 of 136 
CONFIDENTIAL  
 
 
Table 10.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 2) 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening 
X* = at end of infusion perform corresponding assessment (ie, ECG at timepoint 1hr C3D1 with X* should be taken at end of infusion). 
NOTE: Use Table 7 in combination with Table 10 for Cycle 2, 4 dose schedule. 
a The Dose Level Review Team may recommend to change timing of D5/12/19 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: at predose, post 1hr -end of infusion, 24 hours post dose and at EOS.  
Cycle Day
2
3
4
6
7
8
28b EoTEoS
0
1
2
3
4
6
8
12
16
20
24
48
72
0
1
2
3
4
6
8
12
16
20
24
48
0
1
4
0
1
4
Hospitalization
X
Concomitant Medications
X
Serious adverse events
X
X
Adverse events
X
X
Disease-related events
X
Clinical Evaluationc
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
X
X
X
X
X
X
X
X
X
X
ECG triplicate measuremente
X
X*
X
X*
X
X
X*
X
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
AMG 673 short term IV Infusion
X
X
X
X
AMG  673 PK Collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X*
X
X*
X
X
X
Bone marrow assessments
X
X
12a 
19a
Pre-
dose
Relative 
to start of 
infusion
Pre-
dose
Relative 
to start of 
infusion
Treatment Period
1
5b 
Hours
Pre-
dose
Relative to start of infusion
Pre-
dose
Relative to start of infusion
GENERAL AND SAFETY ASSESSMENTS
DISEASE and BIOMARKER ASSESSMENTS
at discretion of investigator
LABORATORY ASSESSMENTS
INVESTIGATIONAL PRODUCT DOSING
PK ASSESSMENTS
 
Approved 
 
 


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Page 68 of 136 
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Table 11.  Schedule of Assessments:  Doses D1/D5/D12/D19 (Cycle 3 and Beyond) 
 
Footnotes defined on next page of the table 
Cycle Day
28b EoT EoS
0
1
2
3
4
0
1
2
3
4
0
1
4
0
1
4
Hospitalization
Concomitant Medications
X
Serious adverse events
X
X
Adverse events
X
X
Disease-related events
X
Clinical Evaluationc
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
ECG triplicate measuremente
X
X*
X*
X
X*
X
X*
X
Coagulation
X
X
X
X
X
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
AMG 673 short term IV Infusion
X
X
X
X
AMG  673 PK Collection
X
X
X
X
X
X
X*
X
X*
X
X
X
Bone marrow assessments
X
X
Treatment Period
1
5a 
Hours
Pre-
dose
Relative to start of 
infusion
Pre-
dose
Relative to start of 
infusion
PK ASSESSMENTS
GENERAL AND SAFETY ASSESSMENTS
at discretion of investigator
DISEASE and BIOMARKER ASSESSMENTS
12a 
19a
Pre-
dose
Relative 
to start of 
infusion
Pre-
dose
Relative 
to start of 
infusion
at discretion of investigator
LABORATORY ASSESSMENTS
INVESTIGATIONAL PRODUCT DOSING
 
Approved 
 
 


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Protocol Number:  20160377 
Date:  11 December 2019 
Page 69 of 136 
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EOS = End of Study; EOT = End of Treatment; SCR = Screening 
X* = at end of infusion perform corresponding assessment (ie, ECG at timepoint 1hr C3D1 with X* should be taken at end of infusion). 
NOTE: Use Table 8 in combination with Table 11 for Cycle 3, 4 dose schedule. 
a The Dose Level Review Team may recommend to change timing of D 5/12/19 within a window of  ±1 day. In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of extended infusion-free interval, patients must be monitored per institutional practices. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: at predose, post 1hr -end of infusion, 24 hours post dose and at EOS.  
 
Approved 
 
 


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Table 12.  Schedule of Assessments:  Schedule B (Cycle 1) 
 
Footnotes defined on next page of the table 
 
Approved 
 
 


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EOS = End of Study; EOT = End of Treatment; SCR = Screening 
a Assessments should be taken at the time specified (in hours) from the start of infusion on that day.  If a time is not specified, all assessments and collections should 
be pre-dose.   
b The following assessments should be performed relative to the day 14 dose.  Cycle 2 should begin immediately after Cycle 1 with no treatment free interval (see 
Section 6.2.1.1.2).  The samples in dark gray are only collected if the subject will not initiate cycle 2 immediately after cycle 1.  If cycle 2 is initiated immediately after 
cycle 1, then collect per Table 14 (refer to footnote J).  
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry must be collected as described above but may be collected at site more frequently per institutional policy or by recommendation of PI.  
Additional assessments do not need to be reported to EDC unless related to an adverse event but must be kept in source.  Subjects will also be assessed prior to 
discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section 7.3.8. ECG's: At screening 2 triplicates (total of 6 ECGs) should be done, at predose C1D1: 1 triplicate (total of 3 ECGs), post 1hr -end 
of infusion, 24 hours post dose and at EOS. Schedule for ECGs during cycle 1 also applies in case of intra-subject dose escalation, regardless of actual study cycle.   
f Serum pregnancy test will be performed for all females unless surgically sterile or > 2 years postmenopausal 
g Refer to Table 3 for planned dosing regimen 
 
i This sample is optional.  See Laboratory Manual for details on collection requirements.  
j Cycle 1, PK samples must always be collected on day 1.  In addition, enhanced PK sampling, as described in Table 13, is required at the time of step-up to the 
maximum planned dose.  This is outlined Table 3. If subject is not planned to immediately initiate cycle 2 (eg, due to DLTs), day 14-19 PK samples should be collected.  
If subject proceeds to Cycle 2, day 14 (post dose)-19 PK samples are not collected and sampling should occur as described in Table 14.  
k During the same procedure, bone marrow samples will be collected for both response and biomarker assessments.  This sample is to be collected after the last dose 
in Cycle 1 (ie, day 14). 
 
Approved 
 
 


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Table 13.  Schedule of Assessments:  Schedule B (Cycle 1 Step-Up Dose Visit) 
 
EOS = End of Study; EOT = End of Treatment; SCR = Screening 
a Step-up doses are defined inTable 3. Day 1 in this schedule is each day where the planned dose is higher than the previous day.   
b Hours are calculated from the start of initial infusion of the higher dose (step-up) 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry must be collected as described above but may be collected at site more frequently per institutional policy or by recommendation of PI.  
Additional assessments do not need to be reported to EDC unless related to an adverse event, but must be kept in source.   
e ECGs are required per section 7.3.8. Triplicate ECGs are required at the times described above.  
f Enhanced PK sampling, as described above, is required at the time of step-up to the maximum planned dose (eg, day 3 cohort 2, day 5 cohort 3, day 7 cohort 4, etc). 
Additional information regarding Cycle 1 PK sampling can be found in Table 3.  
 
Approved 
 
 


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Protocol Number:  20160377 
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Table 14.  Schedule of Assessments:  Schedule B (Cycle 2 and Higher) 
 
Footnotes defined on next page of the table 
 
Approved 
 
 


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Date:  11 December 2019 
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EOS = End of Study; EOT = End of Treatment; SCR = Screening 
* Assessments should be taken at the time specified (in hours) from the start of infusion on that day.  If a time is not specified, all assessments and collections should 
be pre-dose.  
a  Subject must be hospitalized for a minimum of 48 hours following each dose  
b After Cycle 2, a treatment free interval may be added per the guidance in Section 6.2.1.1.2. 
c Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical history, and height will also be obtained. Pre-dose clinical 
evaluation may occur up to 3 days prior to dose. 
d Vital signs / pulse oximetry will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
e ECGs are required per section7.3.8. ECG should be taken at the end of the infusion of the first dose in each cycle.  
f Serum pregnancy test will be performed for all females unless surgically sterile or > 2 years postmenopausal 
h This sample is optional.  See Laboratory Manual for details on collection requirements.  
i PK samples are required as shown for cycles 2, 3, 5 and 8 only in addition to EOT/EOS visits. 
j PK samples only collected during cycle 2 and not subsequent cycles.  If Cycle 2 is not initiated immediately after Cycle 1, collect samples on day 14-19 relative to 
initiation of Cycle 1 per Table 12. 
kDuring the same procedure, bone marrow samples will be collected for both response and biomarker assessments. 
 
Approved 
 
 


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7.2 
General Study Procedures 
A signed and dated IRB/IEC approved ICF must be obtained prior to performing any 
study-specific procedures including discontinuing standard therapy for observing a study 
washout period.  
During the study, every effort should be made to perform the study procedures as 
indicated on the Schedules of Assessments (Section 7.1).  In case of a new dose step 
(ie, subject receives a dose in a later cycle that they have never received before), cycle 
1 assessments apply. 
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 673 infusion.  If a permanent 
central line with more than 1 lumen is used, blood draws can be done via the lumen that 
is not used for drug administration (see also section 7.3.12).  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).  For blood samples scheduled on the day 
of an infusion, the blood sample should be taken prior to infusion start unless indicated 
otherwise in the schedule of assessments.   
The study specific manuals provide additional details regarding the requirements for 
these procedures. 
Acceptable deviation windows are as follows (any greater deviations require the sponsor 
approval): 
• 
Dose time ± 10 minute window.  
• 
ECGs, biomarker blood draws (cycles 1 – 3), vital signs (incl. pulse oximetry):   
o ± 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). 
o ± 2 hour window if collected between 24 hours and 3 days after the start 
of an infusion.   
o Assessments after day 3 post infusion start should be performed on the 
indicated study day, but not at a certain hour of the day.   
o ± 1 day window if collected 1 week after infusion start or later, or at the 
EOI.   
• 
Bone marrow assessments post treatment start:  ± 3 days 
Approved 
 
 


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• 
PK blood draws in cycles 1 - 3:  
o within 2 hours prior to infusion start 
o ± 15 minute window for samples taken within the first 24 hours after start 
of each infusion and within 24 hours after EOI for each infusion.     
For dosing visits on D5, D12, and / or D19, a ± 1 day time window applies (if 
recommended by DLRT).  
Local laboratories should be used for the following assessments:  
Hematology, hematological bone marrow assessments, clinical chemistry, coagulation, 
urinalysis, hepatitis serology, and serum pregnancy tests.   
The following collections will be shipped to a central laboratory for analysis:  
Blood samples for determination of serum concentrations of AMG 673 and presence of 
Refer to the laboratory manual for detailed collection, processing, and shipping 
procedures. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion.  
7.2.1 
Screening  
After written informed consent has been obtained, subjects will be screened in order to 
assess eligibility for study participation.  All screening procedures must be performed 
within 14 days prior to start of IP administration, unless otherwise noted.  
Subjects who meet the inclusion and exclusion criteria will be eligible to be enrolled in 
the study.  
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 out of range assessments are 
repeated during the screening period, the value that is closest to the enrollment date will 
apply for the determination of eligibility.   
A subject may be rescreened up to 3 additional times during the study at the discretion 
of the investigator. The subject must be re-consented if a re-screening attempt occurs 
outside the 14-day screening period.  Hepatitis serology does not need to be repeated in 
Approved 
 
 


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case of re-screening, or for eligibility, if it was performed within 6 weeks prior to start of 
treatment with AMG 673.   
Subjects who do not meet the eligibility criteria within the 14-day screening period will 
not be eligible for enrollment.  Subjects who are deemed ineligible will be documented 
as screen failures. 
The following procedures are to be completed during the screening period at the time 
points designated in the Schedules of Assessments (Table 6).  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 673 can be used as screening assessments and do 
not need to be repeated to confirm 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 
• 
Bone marrow aspirate and biopsy 
• 
Serious adverse event reporting 
• 
Documentation of concomitant and rescue medications.   
7.2.2 
Treatment 
Treatment begins on day 1 (cycle 1 day 1) when the first IV infusion of investigational 
product is administered to a subject. 
In addition to the mandatory hospitalization period (see section 6.2.1.1), there will be at 
least twice weekly visits to the site during the treatment period.  Weekly visits will apply 
during the infusion-free interval between 2 treatment cycles. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedules of Assessments (Section 7.1).   
Approved 
 
 


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The results of the D1 laboratory tests taken prior to infusion start will not have to be 
available before starting treatment with AMG 673.  Laboratory assessments that were 
done within 24 hours prior to treatment start do not need to be repeated at D1 prior to 
infusion. 
• 
Hospitalization (see section 6.2.1.1 for minimum required hospitalization times) 
• 
investigational product infusions (See Section 6.2.1.1 for details) 
• 
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) 
• 
• 
AMG 673 PK sample collection 
• 
 sample collection 
• 
Bone marrow aspirate / biopsy  
• 
Serious adverse event reporting 
• 
Adverse event reporting 
• 
Disease-related event reporting 
• 
Documentation of concomitant and rescue medications 
• 
CT scan or 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: 
− 
ECG assessments should be performed as in cycle 1, regardless of actual study 
cycle 
− 
PK samples should be taken as in cycles 1 and 2, respectively, regardless of 
actual study cycle 
− 
All other assessments should be performed as per the schedule of assessments 
for the actual cycle.   
Approved 
 
 


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Date:  11 December 2019 
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7.2.3 
End of Treatment Visit 
The EOT visit will occur at the end of the last treatment cycle.  For subjects who 
prematurely discontinue IP treatment, the EOT visit should occur as soon as possible 
after the last dose of investigational product was administered.  The following 
procedures will be completed during the EOT visit as designated in the Schedules of 
Assessments (Section 7.1) 
• 
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 
• 
Laboratory assessments: hematology, chemistry, coagulation, urinalysis 
• 
• 
AMG 673 PK sample collection 
• 
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 673 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.  
Subjects who complete the EOS visit will be considered to have completed the study.  
The following procedures will be completed at the EOS visit as designated in the 
Schedules of Assessments (Section 7.1) 
Approved 
 
 


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Date:  11 December 2019 
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• 
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 
• 
• 
Bone marrow aspirate / biopsy 
• 
AMG 673 PK sample collection 
• 
 sample collection 
• 
Serious adverse event reporting 
• 
Adverse event reporting 
• 
Disease-related event reporting 
• 
Documentation of concomitant and rescue medications   
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 prior to first dose of AMG 673.  Medical history 
will include information on the subject’s concurrent medical conditions.  Record all 
findings on the medical history eCRF. 
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Relevant medical history, including antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, bleeding, and infection (resolved and ongoing) will 
be collected.  AML history must date back to the initial diagnosis and any response 
duration must be recorded.  The current toxicity grade will be collected for each condition 
that has not resolved.  
 
Exception: No toxicity grade should be recorded for ongoing AML history. 
All prior cancer treatment therapies will be collected.    
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 2 weeks prior to start of study treatment), concomitant medications for which 
washout periods have to be observed (refer to section 6.9) are to be collected starting 
2 weeks prior to start of study treatment. Collect therapy name, indication, dose, unit, 
frequency, route, start date, and stop date.   
7.3.5 
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 
time points specified in the Schedules of Assessments (Section 7.1).  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. 
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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. 
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 sets of 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. 
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Standard ECG machines should be used for all study-related ECG requirements. 
7.3.9 
Clinical Laboratory Tests 
The tests listed below in Table 15 will be conducted on samples collected and analyzed 
by standard laboratory procedures at the time points specified in the Schedule of 
Assessments (Section 7.1).  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. 
Table 15.  List of Analytes 
Local Laboratory 
Central Laboratory 
Chemistry 
Hematology 
Urinalysis 
Coagulation 
Other Labs 
Sodium 
Potassium 
Bicarbonate 
Or  Total CO2  
Chloride 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
AST 
ALT 
Amylase 
Lipase 
CRP 
LDH 
Uric Acid 
Ferritin 
eGFR (per 
institutional 
formula) 
Hemoglobin 
Hematocrit 
Platelets 
WBC total and 
Differential 
Total Neutrophils 
Seg. Neutrophils 
Lymphocytes 
Monocytes 
Bands/Stabs 
Eosinophils 
Basophils 
Blasts 
Absolute 
neutrophil count 
Myeloblasts 
 
Specific 
gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
Ketones 
Microscopic 
exam 
(performed 
at the 
discretion of 
the 
investigator) 
PT 
PTT 
INR 
Fibrinogen 
 
Pregnancy 
testa 
Serology 
(HepB, HepC) 
Bone marrow 
assessments: 
-morphology 
-molecular 
panel 
 
 
Standard bone 
marrow 
Pharmacokinetics 
Pharmacogenetics 
sample 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-HBc = Hepatitis B core antibody; 
AST = aspartate aminotransferase; CRP = C-reactive protein; 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. 
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Additional procedures (eg, collection of an unscheduled blood sample to measure 
cytokine levels) deemed necessary as part of standard of care or as required by local 
laws and regulations may be performed at the investigator’s discretion.   
A serum pregnancy test will be performed locally at each site on all females 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.   
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 Sections 9.2 and 9.1.1, respectively.  The 
severity of all events will be graded according to CTCAE, version 4.0 (Appendix A) 
unless specified otherwise. Exception: CRS will be graded according to the adopted 
grading system referenced in (Lee et al, 2014, see Table 5).  
7.3.11 
CT Scan or MRI Cranial 
A CT scan or 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 673 at 
the time points specified in the Schedules of Assessments (Section 7.1) Blood must not 
be drawn from the port catheter during IP infusion and 5 minutes after end of infusion.  If 
a permanent central line with more than 1 lumen is used, blood draws can be done via 
the lumen that is not used for drug administration.  However, the preference is for PK 
samples to be drawn peripherally during infusion. If the PK sample must be drawn 
through the central line, AMG 673 administration should be interrupted during sample 
withdrawal.  A 5-minute waiting time is recommended before PK sampling.  
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 (Section 7.1) or the measurement of 
 
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  Samples testing positive may be further characterized for quantity/titer, 
isotype, affinity, in vitro neutralizing activity, and presence of immune 
complexes.  Additional blood samples may be obtained to rule out anti-drug antibodies 
during the study.  Subjects who test positive for binding antibodies and have clinical 
sequelae that are considered potentially related to an 
 response 
may also be asked to return for additional follow-up testing. 
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7.6 
Disease Response 
Disease response assessments will be based upon review of cytogenetics, bone marrow 
aspirates/biopsies, and peripheral blood count.   
Response categories are defined as follows (Appendix E and Topp et al, 2015): 
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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/µl  
− 
platelet count ≥ 100,000/µl  
− 
independence of red cell transfusions 
CRi 
− 
all CR criteria except for incomplete recovery of peripheral blood counts 
(residual neutropenia [< 1,000/µl] or thrombocytopenia [<100,000/µl])  
Morphologic leukemia-free state 
− 
less than 5% myeloblasts in the bone marrow  
− 
absence of blasts with Auer rods 
− 
absence of extramedullary disease 
− 
no hematologic recovery required 
CRh* 
− 
less than 5% blasts in the bone marrow 
− 
no evidence of disease 
− 
partial recovery of peripheral blood counts: platelet count > 50,000/µl, and 
ANC > 500/µl 
− 
no extramedullary disease 
Response must be established from a bone marrow sample supplemented with 
neutrophil and platelet counts.   
7.7 
Blood and Bone Marrow Samples 
, and 
safety and response assessments at time points specified in the Schedule of 
Assessments (Section 7.1).   
Samples will be investigated by local and central laboratories as follows: 
Assessments of chemistry, hematology, and coagulation, urinalysis, pregnancy tests, 
serology, bone marrow aspirate 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: 
, PK, 
 
 
   
Refer to the laboratory manual for detailed collection and handling procedures for all 
blood samples. 
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 (Section 7.1) 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 673, characterize antibody 
response, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained, but are 
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not necessarily reported as part of this study.  Samples can be retained for up to 
20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker, biomarker development, or 
other exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, biomarker, PK, cytogenetic, and bone marrow aspirate and biopsy samples and 
any other components from the cells can be located and destroyed.  Samples will be 
destroyed once all protocol-defined procedures are completed.  However, information 
collected from samples prior to the request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
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(Section 7.1) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data, including endpoints, adverse 
events, disease related events, and device related events.  Subjects who have 
discontinued investigational product and/or protocol required therapies or procedures 
should not be automatically removed from the study.  Whenever safe and feasible it is 
imperative that subjects remain on-study to ensure safety surveillance and/or collection 
of outcome data.  The investigator must document the level of follow-up that is agreed to 
by the subject.    
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can recommend to withdraw a subject(s) from 
investigational product, medical device(s), and/or other protocol required therapies, 
protocol procedures, or the study as a whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  
8.3 
Reasons for Removal From Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
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• 
Confirmed disease progression as defined by revised IWG response criteria 
(Appendix E) or disease progression accompanied by worsening of symptoms or 
deterioration of the subject’s general condition 
• 
Protocol specified criteria: 
o Proceeding to HSCT 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
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).     
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 end of study are reported recorded using the Event CRF. 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious disease-
related event data to the sponsor within 24 hours of it being available. 
Disease-Related Events that do not qualify as Adverse Events or Serious Adverse 
Events: 
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease-Related Event. 
• 
Death due to the disease under study is to be recorded on the Event CRF. 
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Disease-Related Events that would qualify as an Adverse Event or Serious Adverse 
Event: 
• 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator for the subject’s condition, or if the investigator believes there is a 
causal relationship between the investigational product(s)/study 
treatment/protocol-required therapies and disease worsening, this must be reported 
as an Adverse Event or Serious Adverse Event. 
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, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study, or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
Every increase in severity of an adverse event needs to be recorded.  Decrease in 
severity only has to be recorded for DLTs and adverse events that lead to interruption of 
treatment / delay of a subsequent infusion.   
For situations when an adverse event or serious adverse event is due to AML, report all 
known signs and symptoms.  Death due to disease progression in the absence of signs 
and symptoms should be reported as the primary tumor type (eg, metastatic pancreatic 
cancer).  
Note:  The term “disease progression” should not be used to describe the 
disease-related event or adverse event.   
An adverse device effect is any adverse event related to the use of a 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. 
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The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease-Related Event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A Disease-Related event (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 
medicinal product(s)/protocol-required therapies and the event, 
• 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
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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 end of study are recorded on the Event CRF as a Disease-Related 
Event.   
Disease-Related Events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/ protocol-required 
therapies, and determined to be serious, must be recorded on the Event CRF as Serious 
Adverse Events.   
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 consent through the end of study 
are reported using the Event CRF. 
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 products, medical devices (syringe, 
infusion pump), or study procedure / activity 
• 
Action taken. 
The adverse event grading scale used will be the CTCAE, version 4.0.  The grading 
scale used in this study is described in Appendix A. Exception: CRS will be graded 
according to the guidelines provided in Table 5 [based on the adopted grading system 
referenced in Lee et al 2014]. 
The investigator must assess whether the adverse event is possibly related to the 
investigational products, medical devices and/or study procedure / activity.  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, medical device, and/or study procedure / activity?   
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The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the Investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur 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. 
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 Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form. 
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the Serious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational products, medical devices (syringe, infusion pumps) and/or study 
procedure / activity.  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 products, medical device, and/or study procedure / activity?  Relatedness 
means that there are facts or reasons to support a relationship between investigational 
product / medical device (syringe, infusion pumps) / study procedure / activity and the 
event.  
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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (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.  
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9.2.2.4 
Serious Adverse Events That are not to be Reported by the Sponsor 
to Regulatory Agencies in an Expedited Manner  
Expected disease related serious events (see Appendix G) will not be reported by 
Amgen to regulatory agencies in an expedited manner 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. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking AMG 673 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 15 weeks after the last dose of AMG 673.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the 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 female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur through 30 days after the last dose of protocol-required 
therapies.  
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. 
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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 dose limiting toxicities 
(DLTs) 
Secondary Endpoints:   
• 
Pharmacokinetic parameters including, but not limited to: half-life, maximum 
observed concentration (Cmax), minimum observed concentration (Cmin), area under 
the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUC0-last) and clearance (CL) of AMG 673 
• 
Efficacy parameters: 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  
Exploratory Endpoints:   
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 673. 
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The analysis of DLT will be restricted to DLT-evaluable subjects (see section 6.2.1.3 for 
definition).   
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected.  These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing.   
10.1.3 
Covariates and Subgroups 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
 
  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 95 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 for each Schedule.   
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 1 DLT if 
the true DLT rate is 10-33% and with 4 subjects per cohort, there is a 34-80% 
probability. 
In the dose expansion cohort, a subject number of 10 will provide a 65% probability of 
observing at least 1 adverse event with10% incidence rate and 89% probability of 
observing at least 1 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% overall response rate, the expected 80% CI would be 5.5% to 45.0% with the 
half-width 19.8%.  
10.3 
Planned Analyses 
The following data analyses are planned:  (1) the primary analysis after all 
dose-escalation and dose-expansion subjects had the opportunity to receive up to 
2 cycles of treatment, and (2) the final analysis after all subjects have ended the study. 
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10.3.1 
Interim Analyses and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations. In DLRMs, Amgen, in 
consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
decisions.  As a sensitivity analysis, a 1-parameter Continual Reassessment Method 
(CRM) model may be used to estimate the dose-toxicity relationship to help making dose 
escalation decisions.  Adverse events and DLTs observed in all subjects will be 
evaluated continually and fully integrated into all DLRMs and considered in all enrollment 
and dosing recommendations. 
An interim analysis for efficacy parameters will be conducted after dose escalation is 
completed. 
10.3.2 
Dose Level Review Team (DLRT) 
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 and global safety officer, or their approved designees, clinical study manager, and 
biostatistician and PK scientist (optional).  Other functional area representatives may 
participate as appropriate. The following members, or their qualified designees, are 
responsible for DLRT recommendations: investigators, Amgen medical monitor, and 
global safety officer.  All available study data, including data collected after the initial 
DLT window, and 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 decisions.  Modeling of 
available potential safety risk data (eg, for thrombocytopenia) to predict safety risk for 
dose escalation recommendations may also be considered. 
A quorum as defined below must be in attendance for the DLRM.  The quorum is defined 
as > 50% of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator), as well as the Amgen representatives responsible 
for DLRT recommendations listed above.  Investigators that are not able to participate in 
the meeting (eg, due to time difference) may also provide their vote in writing (eg, by 
email to Sponsor) after review of the data discussed at the meeting. The early 
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development leader or designee must attend for the quorum to be reached.  The DLRM 
will be rescheduled if a quorum is not reached.   
The following recommendations will be made by the DLRT: 
• 
dose escalation / de-escalation recommendations  
• 
based on the totality of the safety, efficacy and PK data, the DLRM may 
recommend to add 2 additional doses (days 12 and 19) if: 
o the 2 dose regimen (D1 and D5) is deemed safe and tolerable 
o it is determined from the observed AMG 673 exposures that AMG 673 is 
rapidly cleared and/or distributed (ie, its observed half-life is much shorter 
than 21 days) 
o efficacy (based on clinical data and pharmacodynamics markers eg, 
clearance of CD33+ blasts in the blood and/or bone marrow) is observed 
but is not sustained and addition of D12 and D19 doses may improve the 
duration or depth of response 
• 
number of subjects per cohort 
• 
continuation, delay or termination of dosing 
• 
implementation of dose step(s) 
• 
change of the D1/D5/D12/D19 dosing scheme within the pre-specified window of 
 ±1 day 
• 
extension of the treatment-free interval between treatment cycles 
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 2 weeks or dropped out of treatment / study, whichever occurs 
earlier. Ad hoc meetings may be convened any time in case of important safety events. 
10.3.3 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject had 
the opportunity to receive up to 2 cycles of treatment 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 close to the time point of the primary analysis.  
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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.  A 2-parameter BLRM will be used to 
estimate the dose-toxicity relationship. See Appendix H for the description of the 
2-parameter BLRM design.  
10.4.2 
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 673. 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels. 
Adverse Events 
Subject incidence of all treatment-emergent 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 dose level and will also be tabulated by 
relationship to study drug. 
Tables of disease-related events, fatal adverse events, serious adverse events, adverse 
events leading to withdrawal from investigational product or other protocol-required 
therapies, and significant treatment-emergent adverse events will also be provided. 
Subject incidence of all disease-related events, fatal disease-related events, serious 
disease-related events, disease-related events leading to withdrawal from investigational 
product or other protocol-required therapies, and significant disease-related events will 
also be provided.  Subject incidence of disease-related events and fatal disease-related 
events will be tabulated by system organ class and preferred term. 
Subject incidence of first dose effects will be used to fit the BLRM model to estimate the 
probability of having an adverse event related to first dose effects across dose levels.   
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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. 
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 673, pharmacokinetic parameters will be determined from the 
time-concentration profile using standard non-compartmental approaches and 
considering the profile over the complete sampling interval.  Based on the review of the 
data, analyses to describe the relationship between AMG 673 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.  The proportion of subjects with a CR/CRh*/CRi/morphologic 
leukemia-free state with corresponding exact 80% CI will be calculated using the 
Clopper-Pearson method (Clopper and Pearson, 1934) and tabulated for subjects 
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treated at the MTD.  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.   
10.4.4 
Exploratory Endpoints 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Study Manager to the investigator.  
The written informed consent form 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 
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of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician is 
to be documented in the subject’s medical records, and the informed consent form is to 
be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
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11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below. 
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
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the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Non-investigational product(s), and/or medical device(s) documentation. 
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In addition, all original source documents supporting entries in the CRFs 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, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs 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 CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
• 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the CRF, the data queries, and agrees with the content. 
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12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments Section 7.1), the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
CRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.  All written information and other 
material to be used by subjects and investigative staff must use vocabulary and 
language that are clearly understood.   
12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, and 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 
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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. 
REFERENCES 
AMG 673 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
Arber DA, Orazi A, Hasserjian R, Thiele J, et al. The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 
127(20): 2391-2405 
Babb J, Rogatko A, Zacks S.  Cancer Phase I Clinical Trias:  Efficient Dose Escalation 
with Overdose Control.  Statistics in Medicine 1998;17:1103-1120 
Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with 
acute myeloid leukemia in first relapse. J Clin Oncol 2005;23:1969-78. 
Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. 
J Clin Oncol 2011a;29:487-94. 
Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic 
leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC 
AML15 trial. J Clin Oncol 2011b;29:369-77. 
Caron PC, Schwartz MA, Co MS, et al. Murine and humanized constructs of monoclonal 
antibody M195 (anti-CD33) for the therapy of acute myelogenous leukemia. Cancer 
1994;73:1049-56. 
Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of 
adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, 
open-label, phase 3 study. Lancet 2012;379:1508-16. 
Cheson BD, Bennett JM, Kopecky KJ, et al.  Revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria, 
treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia.  J Clin Oncol.  2003;21(24):4642-9. 
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka 1934; 26, 404-13. 
Dohner H, Estey EH, Amadori S, et al.  Diagnosis and management of acute myeloid 
leukemia in adults:  recommendations from an international expert panel, on behalf of 
the European LeukemiaNet.  Blood  2010;115(3):453-474 
Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 
2000;14:476-9. 
Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M. A stratification system 
for evaluating and selecting therapies in patients with relapsed or primary refractory 
acute myelogenous leukemia. Blood 1996;88:756. 
FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
ICH Harmonised Tripartite Guideline: S9, October 2009. 
http://www.ich.org/products/guidelines/safety/safety-single/article/nonclinical-evaluation-
for-anticancer-pharmaceuticals.html 
Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-195 
Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: A historical perspective. 
Pharmacology and Therapeutics 2012; 136: 334-342 
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Neuenschwander B, Branson M, Gsponer T.  Critical aspects of the Bayesian approach 
to phase I cancer trials.  Statistics in Medicine 2008;27:2420-2439  
Oken MM, Creech RH, Tormey DC et al.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655 
Pearce DJ, Taussig DC, Bonnet D. Implications of the expression of myeloid markers on 
normal and leukemic stem cells. Cell Cycle 2006;5:271-3. 
Ravandi F. Relapsed acute myeloid leukemia: why is there no standard of care? Best 
practice & research 2013;26:253-9. 
Ravandi F, Estey EH, Appelbaum FR, et al. Gemtuzumab ozogamicin: time to resurrect? 
J Clin Oncol 2012;30:3921-3. 
Ravandi F. Gemtuzumab ozogamicin: one size does not fit all--the case for personalized 
therapy. J Clin Oncol 2011;29:349-51. 
Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of patients with acute 
myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction 
chemotherapy. Blood 2010;116:5818-23; quiz 6153 
Scheinberg DA, Tanimoto M, McKenzie S, Strife A, Old LJ, Clarkson BD. Monoclonal 
antibody M195: a diagnostic marker for acute myelogenous leukemia. Leukemia 
1989;3:440-5. 
Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid 
leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 
calicheamicin immunoconjugate. Blood 1999;93:3678-84. 
Society AC. Cancer Facts and Figures, 2016. Atlanta, George, USA: American Cancer 
Society; 2016. 
Tanimoto M, Scheinberg DA, Cordon-Cardo C, Huie D, Clarkson BD, Old LJ. Restricted 
expression of an early myeloid and monocytic cell surface antigen defined by 
monoclonal antibody M195. Leukemia 1989;3:339-48. 
Taussig DC, Pearce DJ, Simpson C, et al. Hematopoietic stem cells express multiple 
myeloid markers: implications for the origin and targeted therapy of acute myeloid 
leukemia. Blood 2005;106:4086-92. 
Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumumab for adult 
patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a 
multicentre, single-arm, phase 2 study. Lancet Oncology 2015; 16 (1): 57-66  
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14. 
APPENDICES 
 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE v4 will be used for grading all adverse events (other than cytokine release 
syndrome). The CTCAE can be found at  
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.4 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.4.1 and Section 6.4.2 or who experience AST or ALT elevations > 3 x ULN or 
2-fold increase above baseline values for subjects with evaluated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
• 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
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• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
Complete blood count (CBC) with differential to assess for eosinophilia 
− 
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, 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 CRFs. 
Approved 
 
 


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


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
Approved 
 
 


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Approved 
 
 


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


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Categories 
Myeloid sarcoma (syn.: extramedullary myeloid tumor; granulocytic sarcoma; chloroma) 
Myeloid proliferations related to Down syndrome 
Transient abnormal myelopoiesis (syn.: transient myeloproliferative disorder) 
Myeloid leukemia associated with Down syndrome 
Blastic plasmacytoid dendritic cell neoplasm 
Acute leukemias of ambiguous lineage 
Acute undifferentiated leukemia 
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1ǁ 
Mixed phenotype acute leukemia with t(v;11q23); KMT2A rearranged 
Mixed phenotype acute leukemia, B/myeloid, NOS 
Mixed phenotype acute leukemia, T/myeloid, NOS 
Page 2 of 2 
Adopted from Arber et al, 2016; for a diagnosis of AML, a marrow blast count of ≥ 20% is required, except 
for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv(16) or t(16;16) and some cases of 
erythroleukemia. 
* Other recurring translocations involving RARA should be reported accordingly: for example, AML with 
t(11;17)(q23;q12); ZBTB16-RARA; AML with t(11;17)(q13; q12); NUMA1-RARA;AML with t(5;17)(q35;q12); 
NPM1-RARA; or AML with STAT5BRARA (the latter having a normal chromosome 17 on conventional 
cytogenetic analysis). 
† Other translocations involving MLL should be reported accordingly: for example, AML with 
t(6;11)(q27;q23); MLLT4-MLL; AML with t(11;19)(q23;p13.3); MLLMLLT1; AML with t(11;19)(q23;p13.1); 
MLL-ELL;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. 
Approved 
 
 


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Appendix E.  Revised International Working Group Response Criteria Revised 
Response Criteria 
Category 
Definition 
Complete 
remission (CR)1 
Bone marrow blasts < 5%; absence of blasts with Auer rods; 
absence of extramedullary disease; absolute neutrophil count > 
1.0 x 109/L; platelet count > 100 x 109/L; independence of red cell 
transfusions 
CR with 
incomplete 
recovery (CRi)2 
All CR criteria except for residual neutropenia (< 1.0 x 109/L) or 
thrombocytopenia (< 100 x 109/L) 
Morphologic 
leukemia-free 
state3 
Bone marrow blasts < 5%; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery 
required 
Partial remission 
Relevant in the setting of phase 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 
Approved 
 
 


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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 
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. 
Approved 
 
 


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Progressive Disease* 
Progressive disease for patients with AML is defined as: 
• 
Greater than 50% increase in bone marrow blasts from the best assessment and at 
least 20% marrow blasts. 
• 
Greater than 50% increase in the peripheral blood absolute blast count and at least 
an absolute blast count of 1000/cmm. 
• 
Development of extramedullary disease.  If the patient has extramedullary disease at 
baseline, then the development of a new site of disease. 
• 
In patients who present with a bone marrow blast percentage sufficiently high to 
preclude the ability to determine disease progression by a > 50% increase in the 
marrow blast percentage, then disease progression will be determined by peripheral 
blood criteria or the development of new sites of extramedullary disease. 
* Patients may remain on study treatment if the investigator believes the patient is deriving some benefit. 
Relapse Criteria 
Relapse after complete remission 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).   
Approved 
 
 


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


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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  
Approved 
 
 


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Appendix H.  Two-Parameter BLRM Design 
A 2-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
exploration.  The maximum tolerated dose (MTD) target Toxicity Probability Interval 
(TPI) for dose-limiting toxicity (DLT) is (0.20, 0.33) and TPIs of (0.33, 0.60) and 
(0.60, 1.00) are defined as excessive and unacceptable, respectively.  The design seeks 
to identify a dose most likely to have a DLT rate in the target TPI, but with over-dose 
control that limits the possibility the dose has an excessive or unacceptable DLT rate 
(Babb et al, 1998).  The probability of a DLT at dose level di is assumed to follow a 
Bernoulli distribution with probability pi where the logit of pi increases linearly with the log 
of the standardized dose in the following 2-parameter logistic model: 
 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is one of the planned dose selected as the 
reference dose.   
Subjects will be grouped according to dosing schedule (eg, no dose step, one dose step, 
two dose steps, … in schedule A and schedule B) and evaluated independently of the 
other groups for the purpose of BLRM and DLRT recommendations. 
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference 
dose is 0.05.   The prior distribution of BLRM for step dosing may be adjusted based on 
the accumulative data. For example, the starting dose and the reference dose of BLRM 
prior to estimate MTD2 may be based on MTD1 and the expected MTD for MTD2.  
The operating characteristics of the 2-parameter BLRM design were evaluated via 
simulation for schedule A and B separately.  
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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


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Approved 
 
 


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Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  11 December 2019 
Page 1 of 53 
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Amendment 5 
Protocol Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
Amgen Protocol Number AMG 673 20160377 
IND number BB-IND 133933 
EudraCT number 2017-002980-16 
Amendment Date: 
11 December 2019 
Rationale: 
Changes in the protocol have been made to implement a new dosing schedule 
(Schedule B) to explore whether higher steady state concentrations of AMG 673 may be 
achieved and better tolerated by subjects utilizing a high density, multi-step, dosing 
regimen.  Multiple edits have been introduced to clarify existing guidelines and 
procedures. As a result, the following changes have been made:  
• 
Add Schedule B. 
• 
Update the number of subjects expected to enroll in this study. 
• 
Update the Schedule of Assessment tables for Schedule A and clarify formatting for 
hospitalization and assessments to be collected over multiple days. 
• 
Clarify the duration of infusion-free period, hospitalization and dose limiting toxicity 
(DLT) windows in Schedule A.  
• 
Clarified MTD definitions. 
• 
Clarified Exclusion criteria 218 was removed in a previous amendment. 
• 
Add language that 
 
 
• 
Clarify that all serious disease-related events will be submitted to the sponsor or 
designee within 24 hours and are to be reported in the same manner as a serious 
adverse events. 
• 
Reference Investigator’s Brochure and Investigational Product Instruction Manual in 
relevant sections. 
• 
Clarify DLRM attendees and voting members, include investigators unable to attend 
the Dose Level Review Meeting (DLRM) can provide their vote via email to sponsor 
after review of the data. 
• 
Delete language related to Self-Evident Corrections. 
• 
Add language to clarify adjustment of distribution of BLRM for step dosing. 
• 
Typographical and consistency edits have been made throughout the protocol where 
applicable.   
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  24 June 2019 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number 20160377 
 
Amendment Date: 
24 June 2019 
Rationale: 
Changes in the protocol have been made to implement new guidelines for Cytokine 
Release Syndrome (CRS) mitigation to allow for early management of symptoms, to 
avoid drug interruptions, and to improve drug exposure. The Dose Limiting Toxicity 
(DLT) definition has been updated to allow for effective and timely assessment of safety 
signals. Multiple edits have been introduced to clarify existing guidelines and 
procedures. Typographical edits have been made throughout the protocol where 
applicable. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  17 January 2019 
Page 1 of 5 
CONFIDENTIAL 
 
 
Amendment #3 
Protocol Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 673 20160377 
 
Amendment Date: 
17 January 2019 
 
Rationale: 
To incorporate an updated Risk and Discomfort Section identifying cytokine release 
syndrome as an important identified risk for AMG 673 20160377. Minor typographical 
errors were also corrected. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  01 June 2018 
Page 1 of 54 
CONFIDENTIAL 
 
 
Amendment #2 
Protocol Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 673 20160377 
 
Amendment 2 Date: 
01 June 2018 
 
Rationale: 
The purpose of this amendment is to add additional guidance and clarifications from the 
previous amendment and to incorporate changes agreed to with the German regulatory 
agency PEI. Tables, diagrams and schedule of assessments have been clarified to avoid 
safety concerns or human error.  The additional information and clarifications will provide 
further understanding of each cycle, schedule of assessments and other criteria 
including safety and pharmacokinetic parameter endpoints.  Assessments, procedures 
and tables for dose cohorts were added for clarity with reduction in some sample 
collection timepoints. Updates have been implemented along with typographical and 
formatting changes made throughout the protocol for clarity and consistency. 
AMG 673 targets CD33 on AML cells and CD3 on host T cells.  Based on the 
mechanism of action, cytokine release syndrome/infusion reactions were previously 
listed as an identified risk for AMG 673, prior to being administered to humans. In this 
amendment, we update Table 4 title from identified and potential risks to potential risks. 
The Investigational Brochure was also updated to make cytokine release 
syndrome/infusion reactions a potential risk. 
The 1.5 times escalation limit when 1 DLT is observed was removed. In the current 
version of the protocol, the 1.5 times upper limit restriction was incorporated to provide 
an additional dose limit for the dose escalation phase when 1 DLT occurred.  This dose 
limit restriction does not utilize information of the model, specifically, the estimated 
probability of having a dose-limiting toxicity (DLT) by the Bayesian logistic regression 
model (BLRM).  The following rationale supports the removal of the restriction:  In the 
dose escalation phase of this study, DLTs from current cohort and all previous cohorts 
are used in the BLRM to estimate the posterior distribution of the probability of having a 
Approved 
 
 


Product:  AMG 673 
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Date:  01 June 2018 
Page 2 of 54 
CONFIDENTIAL 
 
 
DLT for each dose level.  Based on this estimate, the model recommends the dose for 
the next cohort based on the estimated probability of the target toxicity probability 
interval (TPI) and the excessive/unacceptable TPI: the dose that has the largest 
probability of the target TPI, ie, (0.2, 0.33), and at the same time has the probability of 
the excessive/unacceptable TPI, ie, (0.33, 1), less than 0.25 is recommended for the 
next cohort.  After removing the 1.5 times upper limit, the recommended dose by the 
BLRM still has a small chance of having excessive/unacceptable toxicity given data from 
the current cohort and all previous cohorts even if it recommends escalating to the next 
planned dose level when 1 DLT is observed.   
In addition to the BLRM recommendation, the Dose Level Review Team (DLRT) will also 
consider all available data including the nature and severity of the DLT when 
recommending the next dose to be administered in the next cohort. Therefore, the next 
dose level may be a dose level that is lower than the model recommendation which can 
further lower the chance of excessive/unacceptable toxicity in the next cohort and retain 
the ability to test additional intermediate doses for observed toxicity.  
Other modifications made include:  
 
Removal of reference to other molecules (
), to avoid confusion.  
 
Infusion times were extended, in order to provide sites the ability to manage 
non-serious events such as infusion discomforts. Infusion durations previously 
30 minutes – 1 hour. have been extended to 30 minutes – 3 hours.  
 
Removal of 0.2 µm in-line filter in Section 6, treatment procedures. Compatibility 
testing for AMG 673 with commonly available IV administration containers, lines 
and filters showed that there were no visible particles or sub-visible particle 
counts exceeding USP limits in IV administration systems containing either 
100 ng/mL AMG 673 or 5000 ng/mL AMG 673.  The concentration and all other 
product quality attributes were as expected.  The use of an inline 0.2 µm filter is 
not required.   
 
Updates to inclusion and exclusion criteria with justifications are summarized 
below. 
Approved 
 
 


Product:  AMG 673 
Protocol Number:  20160377 
Date:  07 June 2017 
Page 1 of 17 
Amendment 1 
Protocol Title:  A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as 
Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 673 20160377 
 
Amendment Date: 
07 June 2017 
 
Rationale: 
Protocol is amended to incorporate FDA recommendations based on review of the IND. 
Also administrative, typographical and formatting changes were made throughout the 
protocol.   
CONFIDENTIAL 
 
 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 673   
Protocol Number:  20160377 
Date:  04 April 2022 
Page 1 of 47 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1 First-In-Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Efficacy of AMG 673 
Administered as Short Term Intravenous Infusions 
in Subjects With Relapsed/Refractory Acute Myeloid 
Leukemia 
Short Protocol Title: 
FIH study to evaluate safety, tolerability, PK, PD & 
Efficacy of AMG 673 
Protocol Number: 
20160377 
NCT Number: 
NCT03224819 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805 447 1000 
SAP Date: 
Document Version 
Date 
Original (v2.0) 
04 April 2022 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
25AUG2017 
Original 
Amendment 1 (v2.0) 
04APR2022 
 
Updated the SAP as per Protocol 
Amendment 5. Changed the 
amendment date from 24 June 2019 
to 11 December 2019 throughout the 
document. 
 
Clarification of some definitions, such 
as treatment-emergent adverse 
event (TEAE), overall response, 
duration of response (DOR), time to 
response (TTR), time to 
progression(event-free survival 
(EFS)).  
 
Detailed Summary of changes 
provided in the Appendix C 


Product:  AMG 673   
Protocol Number:  20160377 
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Table of Contents 
Table of Contents ............................................................................................................ 2 
1. 
Introduction ............................................................................................................. 5 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 5 
2.1 
Objectives and Endpoints ............................................................................ 5 
2.2 
Hypotheses and/or Estimations ................................................................... 6 
3. 
Study Overview ...................................................................................................... 6 
3.1 
Study Design ............................................................................................... 6 
3.2 
Sample Size .............................................................................................. 11 
4. 
Covariates and Subgroups ................................................................................... 11 
4.1 
Planned Covariates ................................................................................... 11 
 
 
5. 
Definitions ............................................................................................................. 12 
6. 
Analysis Sets ........................................................................................................ 16 
6.1 
Safety Analysis Set ................................................................................... 16 
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 16 
7. 
Planned Analyses ................................................................................................. 16 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 16 
7.2 
Primary Analysis ....................................................................................... 18 
7.3 
Final Analysis ............................................................................................ 18 
8. 
Data Screening and Acceptance ........................................................................... 18 
8.1 
General Principles ..................................................................................... 18 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 18 
8.3 
Handling of Missing and Incomplete Data ................................................. 18 
8.4 
Detection of Bias ....................................................................................... 19 
8.5 
Outliers ..................................................................................................... 19 
8.6 
Distributional Characteristics ..................................................................... 19 
8.7 
Validation of Statistical Analyses ............................................................... 19 
9. 
Statistical Methods of Analysis.............................................................................. 20 
9.1 
General Considerations ............................................................................. 20 
9.2 
Subject Accountability ............................................................................... 21 
9.3 
Important Protocol Deviations ................................................................... 21 
9.4 
Demographic and Baseline Characteristics ............................................... 21 
9.5 
Efficacy Analyses ...................................................................................... 22 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 22 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 22 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 22 
9.6 
Safety Analyses ........................................................................................ 22 


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9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 22 
9.6.2 
Adverse Events ......................................................................... 22 
9.6.3 
Laboratory Test Results ............................................................ 23 
9.6.4 
Vital Signs ................................................................................. 24 
9.6.5 
Physical Measurements ............................................................ 24 
9.6.6 
Electrocardiogram ..................................................................... 25 
 
 
9.6.8 
Exposure to Investigational Product .......................................... 26 
9.6.9 
Exposure to Non-investigational Product ................................... 26 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 26 
9.6.11 
Exposure to Concomitant Medication ........................................ 26 
9.7 
Other Analyses ......................................................................................... 26 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 26 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 27 
9.7.3 
Analyses of Health Economic Endpoints ................................... 27 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 27 
10. 
Changes From Protocol-specified Analyses.......................................................... 27 
11. 
Literature Citations / References ........................................................................... 28 
12. 
Prioritization of Analyses....................................................................................... 28 
13. 
Data Not Covered by This Plan............................................................................. 28 
14. 
Appendices ........................................................................................................... 29 
Appendix A.  Imputation Rules for Partial or Missing Start Dates .......................... 29 
 
Appendix C.  Summary of Changes ...................................................................... 32 
 
 
 


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List of Abbreviations 
 
Abbreviation 
Explanation 
AUC 
Area under concentration time curve 
Cmax 
maximum observed concentration 
CRF 
case report form 
CRS 
Cytokine Release Syndrome 
DLRM 
dose level review meeting 
DLT 
dose limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
end of study for individual 
subject  
defined as the last date that protocol-specified procedures are 
conducted for an individual subject 
end of treatment 
defined as the date of final assessment for the protocol specified 
treatment phase of the study for an individual subject 
end of study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the purposes of final collection of 
data for the primary endpoint(s).   
Ig 
Immunoglobulin 
ICF 
informed consent form 
IP 
Investigational Product 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PR 
the interval measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by electrocardiogram 
QRS 
 
the interval between the Q wave and the S wave in the heart’s 
electrical cycle as measured by electrocardiogram; represents 
the time it takes for depolarization of the ventricles 
QT 
measure of the time between the start of the Q wave and the 
end of the T wave in the heart’s electrical cycle as measured by 
electrocardiogram 
QTc 
QT interval corrected for heart rate using accepted methodology 
study day 1 
defined as the first day that protocol specified investigational 
product is administered to the subject 
 tmax 
time to maximum concentration 
 
 
 
 


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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 the protocol for study 20160377, AMG 673 
dated 11 December 2019. The scope of this plan includes the interim analysis, the 
primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 673 in adult subjects with 
relapsed/refractory AML 
 
Estimate the maximum tolerated dose 
(MTD) and/or a biologically active 
dose [eg, recommended phase 2 
dose (RP2D)] 
 
Safety: subject incidence and 
grade of adverse events and dose 
limiting toxicities (DLTs) 
 
Key Secondary 
 
Evaluate the pharmacokinetics 
(PK) of AMG 673 
 
Evaluate the anti-leukemia activity of 
AMG 673 by evaluating: 
- 
the number and proportion of 
subjects who respond to treatment 
with AMG 673. 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 duration of response, time to 
progression, and time to 
response. 
 
Pharmacokinetic parameters 
including, but not limited to: half-
life, maximum observed 
concentration (Cmax), minimum 
observed concentration (Cmin), 
area under the concentration-time 
curve from time 0 to the time of 
the last quantifiable concentration 
(AUC0-last) and clearance of AMG 
673. 
 
Efficacy parameters: 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. 
 
 
 


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Exploratory 
 
2.2 
Hypotheses and/or Estimations 
AMG 673 will demonstrate evidence of anti-leukemic activity at a well-tolerated dose in 
subjects with AML. 
3. 
Study Overview 
3.1 
Study Design 
This is a first-in-human, open-label, phase 1, sequential dose escalation study.  
AMG 673 will be evaluated as a short term intravenous (IV) infusion in adult subjects 
with relapsed/refractory AML.  The study will be conducted at approximately 10 sites in 
Australia, Germany and the United States. Additional sites may be added later. 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) using 2 schedules of AMG 673 administration:  Schedule A 


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(D1/D5 dosing) and Schedule B (QD dosing for cycle 1 followed by twice weekly 
dosing in following cycles).   
For Schedule A, planned dose levels (dose per infusion) for the dose escalation cohorts 
are as follows: 0.05 µg, 0.15 µg, 0.45 µg, 1.5 µg, 4.5 µg, 9 µg, 18 µg, 36 µg, 72 µg, 
110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is not reached. The starting dose for 
the first cohort will be 0.05 µg administered as short term IV infusions on D1 and D5.  
The doses administered for the cohorts following cohort 1 will be recommended by the 
Dose Level Review Team (DLRT). The DLRT may recommend on the administration of 
up to 2 additional infusions on D12 and D19 of a cycle for a future cohort.  All subjects 
will be pre treated with an 8-mg dose of IV dexamethasone 1 hour prior to day 1 and 
day 5 AMG 673 doses and prior to each step-up dose of AMG 673. Each cycle will last 
for 14 days in the cohorts receiving only 2 doses (Day 1, 5) and 28 days in the cohorts 
receiving 4 doses (Day 1, 5, 12, 19). Each cycle will be followed by a treatment-free 
interval for 0 to 14 days depending on treatment response and recovery of blood 
counts, but may be extended as described in Section 6.2.1.1.1 in the protocol fter 
consultation with Sponsor.  The D5 infusion, and the D12/D19 infusions (if applicable) 
may be at the same dose as the preceding infusion or may be at a higher dose level 
(dose step). This will be based on tolerability of the lower dose level and other clinical 
signs, pharmacological and PD results and will be recommended by the DLRT. For a 
schematic description of the different dose step options see Figure. There is a ± 1 day 
window for dosing visits which may be implemented after consultation with Sponsor.  
For Schedule B, planned dose levels (dose per infusion) for the dose escalation 
cohorts are as follows: 72 µg, 110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is 
not reached. The starting dose for the cohort 1 on Schedule B will be 72 µg 
administered as short-term IV infusions daily (QD) during the 14-day cycle 1 after 
the 72 µg target dose is found to be relatively safe and tolerable by the DLRT for Schedule 
A.  Cohort 2 and higher will include step-up doses added in each cohort 
administered in two day increments after the previous step dose up to the target 
dose in cycle 1 (eg, cohort 2 will start with 72 µg for 2 days followed by 110 µg 
administered on D3 to D14; cohort 3 will start with 72 µg for 2 days followed by 
110 µg on D3 for 2 days followed by 150 µg on D5 to D14, etc).  Cycle 2+ doses will 
be given on days 1, 4, 8 and 11 at the target dose.  See Table 3 and Section 
6.2.1.1.2  in the protocol for Schedule B dosing schema by cohort in the protocol.  
All subjects will be pre treated with an 8-mg dose of IV dexamethasone 1 hour 


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prior to the first dose on day 1 and prior to each step-up dose in cycle 1 and prior 
to all doses in cycle 2 and beyond. There is no treatment free interval between 
cycle 1 and cycle 2.  Beyond cycle 2, a treatment-free interval is allowed for 0 to 14 
days depending on treatment response and recovery of blood counts, and may be 
extended as described in Section 6.2.1.1.1 after consultation with the sponsor. 
Adjustments to dose level, dose frequency and a duration of step dosing may be 
considered after recommendation of DLRT based on review of available safety, 
PK, and PD data. 
 
 
Dose Escalation Cohorts 
Dose Escalation will be conducted in 2 stages: a single subject stage (Schedule A only) 
and a multiple subjects stage.  In the single subject cohorts, cohorts 1 and 2, single 
subjects will be enrolled at dose levels anticipated to be lower than those at which 
adverse events related to AMG 673 will be observed. Multiple subject cohorts, starting 
with cohort 3, will enroll and the cohort size will be extended to 3-4 subjects per cohort.  
The Bayesian logistic regression model (BLRM) design will be used to guide dose 
escalation.  The actual dose selected at each dose decision may be at or below the 
model’s recommended dose as determined by the dose level review team (DLRT) after 
considering all information.  Subjects will be assessed for dose limiting toxicities (DLTs) 
for the duration of their first treatment cycle (ie, 2 weeks from D1 for subjects who 
receive 2 doses and 4 weeks for subjects who receive 4 doses in Schedule A and 
4 weeks from D1 for subjects in Schedule B). Subjects who complete the DLT period 


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may proceed to a higher dose level for the following treatment cycle after the next dose 
level has been deemed safe by the DLRT, after consultation with Sponsor, if no DLT 
was reported for that subject and no ≥ grade 3 adverse event(s), deemed treatment 
related by the investigator, are reported for that subject. 
Estimation of initial and target MTDs 
For Schedule A, it is anticipated that at least 2 MTDs may be estimated, one for the 
initial dosing and one for the subsequent step dosing.  Should the initial dose be limited 
by adverse events related to first dose effects, the second MTD for the target dose will 
be estimated after giving the initial dose at MTD (step dose).  Each MTD will be 
estimated following the dose escalation guided by BLRM described above.  A second 
dose step may also be implemented in a cycle if this was considered appropriate and 
necessary to allow further dose escalation.  This second dose step would be performed 
the same way as described above.  In this case, a third MTD would be estimated for the 
dose to be administered after the second dose step. 
Schedule B will be initiated after preliminary safety data of AMG 673 in Schedule A 
(eg, MTD1 is estimated to be ≥72 µg) become available and may be conducted in 
parallel with Schedule A per Sponsor’s decision.  The MTD for Schedule B will be 
estimated following the dose escalation described in Section 6.2.1.1.2 in the 
protocol and guided by BLRM described above. 
Expansion Cohort 
For each Schedule, upon completion of the dose escalation cohorts, additional 
subjects (up to 10) may be enrolled in a dose expansion cohort to gain further clinical 
experience, safety and efficacy data in subjects with AMG 673.  The dose to be 
evaluated will be at or below the MTD estimated in the dose escalation cohorts.  
Additional expansion cohorts may be covered by a protocol amendment to test 
alternative dose levels or biologic subsets. 
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 
each schedule 
 
 
 
 


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Treatment Phase  
AMG 673 short term infusions, up to 12 treatment cycles  
DOSE ESCALATION 
 
Schedule A*: D1/D5 on a 14 day cycle 
*First 2 cohorts are single subject cohorts 
 
Schedule B: QD on a 14 day cycle for 
cycle 1 and D1, D4, D8 and D11 for cycle 2 
and beyond  
 
Number of cohorts, subjects per cohort and 
actual doses dependent on observation of 
DLTs and Dose Level Review Team 
recommendations 
Enrollment (Day 1)    
End of Treatment 
Safety Follow-Up 
 (4 weeks after last dose of AMG 673) 
DOSE EXPANSION 
Will begin at or below the MTD or 
highest tested dose from Schedule 
A (± dose step) and/or Schedule B 
n=10 each 
End of Study 
Screening  
(14 days) 


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3.2 
Sample Size 
It is anticipated that approximately 95 subjects will be enrolled in this study.  For 
Schedule A, 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.  For 
Schedule B, up to 40 subjects will be enrolled in the dose escalation cohorts and 
up to 10 additional subjects will be enrolled in the dose expansion cohort.  For 
ethical and operational reasons subjects who already are in the screening phase at the 
time of enrollment stop (end of expansion phase) may 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 or a schedule may be 
discontinued. 
The sample size in the dose escalation is based on practical considerations and is 
consistent with conventional oncology studies with the objective to estimate the MTD. 
With 3 subjects per cohort, there is a 27-70% probability of observing at least one DLT if 
the true DLT rate is 10-33% and with 4 subjects per cohort, there is a 34-80% 
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% overall response rate, the expected 80% CI would be 5.5% to 45.0% with the 
half-width 19.8%. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 


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5. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be collected using the age in years in the clinical 
database.  
AUC0-last  
Area under the concentration-time curve from time 0 (time of investigational product 
administration) to the time of the last quantifiable concentration. 
Baseline  
For any variable, unless otherwise defined, baseline is the last assessment taken prior to 
the first investigational product administration. 
ECG analysis value 
The mean value of triplicate will be calculated and used in the analysis.  If an ECG is 
missing within a triplicate, all available data will be averaged for that timepoint. Further, 
unscheduled ECG measurements taken up to 5 minutes after the last assessment of a 
triplicate at a timepoint will be included in the mean for that timepoint. 
Baseline ECG 
The baseline ECG is defined as the average of the mean of the triplicates at predose 
assessments from cycle 1 day 1; the mean of values in a triplicate should be calculated 
before taking the mean of the triplicate averages.  
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 
Change From Baseline 
Change from Baseline is the arithmetic difference between post-Baseline and Baseline. 
Cmax 
Maximum observed serum concentration. 


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Cmin 
Minimum observed serum concentration 
End-of-Study 
Primary Completion: The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the purposes of final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, whether 
the study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject either had the opportunity 
to receive up to 2 cycles of treatment or terminated the study early. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study: The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit); the final analysis will occur at this time. 
Enrollment Date 
Enrollment date is defined as the first dose of IP date. 
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 
Investigational Product 
The term ‘investigational product’ is used in reference to AMG 673. 
Percent Change From Baseline 


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Percent change from Baseline is the arithmetic difference between post-Baseline and 
Baseline divided by Baseline values times 100. 
Percent change from baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
Fold change from Baseline 
Fold change from Baseline equals the post-Baseline value divide by the Baseline value. 
Fold change from baseline = Post-baseline Value / Baseline Value 
Study Day 
Post study day 1: study day= (date - date of Study Day 1) + 1 
Pre study day 1: study day= (date – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product after 
enrollment. The day prior to Study Day 1 is considered Day -1.   
Treatment-Emergent Adverse Event (TEAE) 
Treatment-emergent adverse events are events categorized as Adverse Events (AEs) 
including disease related events starting on or after the first dose of investigational 
product, as determined by the flag indicating if the adverse event started prior to the first 
dose on the Events CRF and up to end of study (EOS). 
Treatment-Related AE  
A treatment-related AE is any treatment-emergent adverse event that per investigator 
review has a reasonable possibility of being caused by the investigational product. 
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 6.2.1.3 
 
 


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Maximum Tolerated Dose (MTD) 
The MTD is defined as the highest dose level whose DLT rate has the highest probability 
of the target TPI, an excessive/unacceptable TPI of < 0.25, and a minimum of 6 subjects 
have been treated at the MTD. 
Overall Response 
Overall response is defined as achieving any of the following response: CR, CRh*, 
CRi or MLFS. 
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 or death 
due to any cause, whichever occurs first. Subjects without relapse 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.  
Time to Response (TTR) 
Time to response defined as the interval from the first administration of AMG 673 
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). 
Time to Progression (Event-free Survival): 
Event-free survival (EFS) is defined as the interval from first administration of AMG 
673 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 AMG673. For non-responders, the 
event date for treatment failure is assigned as the date of first administration of 
AMG 673. 
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 673 + 1.  


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6. 
Analysis Sets 
6.1 
Safety Analysis Set 
All subjects that are enrolled and received at least 1 dose of AMG 673 
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected.  These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
7. 
Planned Analyses 
The following data analyses are planned:  
(1) Primary analysis after all dose escalation and dose-expansion subjects had the 
opportunity to receive up to 2 cycles of treatment. 
(2) Final analysis after all subjects have ended the study 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis. Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations. In DLRMs, Amgen, in 
consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
decisions. As a sensitivity analysis, a one-parameter Continual Reassessment Method 
(CRM) model may be used to estimate the dose-toxicity relationship to help making dose 
escalation decisions. Adverse events and DLTs observed in all subjects will be evaluated 
continually and fully integrated into all DLRMs and considered in all enrolment and dosing 
decisions. 
An interim analysis for efficacy parameters will be conducted after dose escalation is 
completed. 
 
 


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Dose Level Review Team (DLRT) 
DLRMs will be held to review data, monitor safety, and make decisions on dose 
escalation / change, or changes in pre-medication. The DLRT will be composed of the 
investigators or designees, and the following Amgen representatives: early development 
leader/Medical Monitor and global safety officer, or their approved designees, clinical 
study manager, and biostatistician and PK scientist (optional).  Other functional area 
representatives may participate as appropriate. The following members, or their 
qualified designees, are responsible for DLRT recommendations: investigators, Amgen 
medical monitor, and global safety officer. 
All available study data, including data collected after the initial DLT window, and 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 decisions. Modeling of available potential safety risk data (eg, for 
thrombocytopenia) to predict safety risk for dose escalation decisions may also be 
considered. 
A quorum as defined below must be in attendance for the DLRM.  The quorum is defined 
as > 50% of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator), as well as the Amgen representatives 
responsible for DLRT recommendations listed above.  Investigators that are not 
able to participate in the meeting (eg, due to time difference) may also provide 
their vote in writing (eg, by email to Sponsor) after review of the data discussed at 
the meeting. The early development leader or designee must attend for the quorum to 
be reached.   
The DLRM will be rescheduled if a quorum is not reached.   
The following decisions will be made by the DLRT: 
• dose escalation / de-escalation decisions 
• administration of additional infusions on D12/D19 of a cycle 
• number of subjects per cohort 
• continuation, delay or termination of dosing 
• implementation of dose step(s) 
• change of the D1/D5/D12/D19 dosing scheme within the pre-specified window of +/- 1 
day 


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• extension of the treatment-free interval between treatment cycles 
Subjects’ cytogenetic profiles (eg, potentially higher cytokine release in monocytic AML) 
should be taken into consideration for DLRT decisions. 
In the expansion phase, all available study data will be reviewed (with recruitment 
ongoing) by the DLRT once the first 5 subjects have at least completed their first 
treatment cycle plus two weeks or dropped out of treatment / study, whichever occurs 
earlier. Ad hoc meetings may be convened any time in case of important safety event 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete, and each subject 
had the opportunity to receive up to 2 cycles of treatment or terminated the study early 
7.3 
Final Analysis 
A final analysis is planned after all dose-escalation cohorts and dose-expansion subjects 
have ended the study. Primary and final analysis may be combined in case all subjects 
have ended study close to the time point of the primary analysis. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE a 
base. 
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. 
 
 


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The following imputation of missing values will be done:  
 
Incomplete adverse event and concomitant medication dates will be imputed as 
per Appendix A. If imputed dates are used, then they will be identified as such in 
the final study report.   
 
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. 
PK concentrations that are below the quantification limits will be set to zero when 
engaging non-compartmental model to compute PK parameters. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD and 
biomarker data by dose, dose schedule, and time as appropriate. Descriptive statistics on 
continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages. Graphical 
summaries of the data may also be presented. A two-parameter BLRM will be used to 
estimate the dose-toxicity relationship. 
A two-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
exploration. The maximum tolerated dose (MTD) target Toxicity Probability Interval 
(TPI) for dose-limiting toxicity (DLT) is (0.20, 0.33] and TPIs of (0.33, 0.60] and (0.60, 
1.00] are defined as excessive and unacceptable, respectively. The design seeks to 
identify a dose most likely to have a DLT rate in the target TPI, but with over-dose control 
that limits the possibility the dose has an excessive or unacceptable DLT rate 
(Babb et al 1998). The probability of a DLT at dose level di is assumed to follow a 
Bernoulli distribution with probability pi where the logit of pi increases linearly with the log 
of the standardized dose in the following 2-parameter logistic model: 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is one of the planned dose selected as the 
reference dose. 
A bi-variate normal prior distribution (Neuenschwander et al 2008) was selected for theta 
= (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference 
dose is 0.05.  The prior distribution of BLRM for step dosing may be adjusted 
based on the accumulative data. For example, the starting dose and the reference 
dose of BLRM prior to estimate MTD2 may be based on MTD1 and the expected 
MTD for MTD2. The operating characteristics of the 2-parameter BLRM design were 
evaluated via simulation for schedule A and B separately.  


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9.2 
Subject Accountability 
The number and percent of subjects who were screened, enrolled, received at least one 
dose of AMG 673, completed investigational product, discontinued from investigational 
product (including reasons for discontinuing), completed study, discontinued the study 
(including reasons for discontinuing) will be summarized overall and by dose cohort.  
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. A subject listing and summary noting inclusion in each 
analysis subset will be provided for all subjects enrolled. A subject listing noting, reason 
for discontinuation of treatment, and reason for discontinuing the study will be provided. 
A list of subjects screened but not enrolled (screen failures) will be provided. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
Demographic (ie, age, age groups [18-64, 65-74, 75-84 and >= 85], sex, race, ethnicity) 
and baseline characteristics will be summarized by dose cohort and overall using 
descriptive statistics. If multiple races have been reported for a subject, the subject will 
be categorized as multiple race as well as by the combination of race. 
 


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9.5 
Efficacy Analyses 
Not Applicable  
9.5.1 
 Analyses of Primary Efficacy Endpoint(s) 
Not Applicable  
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
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 Event free Survival . The proportion of subjects with a 
CR/CRh*/CRi/morphologic leukemia-free state 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/RP2D. 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. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Not Applicable 
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 673. 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The severity of each adverse event will be graded using CTCAE version 4.0 criteria. 
The severity of each CRS event will be graded according to the guidelines provided in 
Table 5 [based on the adopted grading system referenced in Lee et al (Blood 2014)] in 
the protocol. 


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Treatment-emergent adverse events are events with an onset after the administration of 
the first dose of investigational product.  
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 dose level and will also be tabulated by relationship 
to study drug. 
Tables of disease-related events, fatal adverse events, serious adverse events, adverse 
events leading to withdrawal from investigational product or other protocol-required 
therapies, and significant treatment-emergent adverse events will also be provided. 
Subject incidence of all disease-related events, fatal disease-related events, serious 
disease-related events, disease-related events leading to withdrawal from investigational 
product or other protocol-required therapies, and significant disease related events will 
also be provided. Subject incidence of disease-related events and fatal disease-related 
events will be tabulated by system organ class and preferred term. Subject incidence of 
first dose effects will be used to fit the BLRM model to estimate the probability of having 
an adverse event related to first dose effects across dose levels. 
9.6.3 
Laboratory Test Results 
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.  
 
Additionally, the number and percentage of subjects experiencing 0,1, 2, 3 and 4 
worsening CTCAE grade shifts from baseline will be presented. The direction of the 
laboratory worsening will again be denoted. 
 
Shifts tables indicating the change between the baseline and the maximum post dose 
CTCAE grades for an increased value, and the maximum post dose grade for a decreased 
value will be provided for selected laboratory parameters of interest. 
 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters of interest. 
 


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A summary of the change from baseline to the post dose maximum, time to post-dose 
maximum, change from baseline to the post dose minimum, and the time to the post dose 
minimum may also be provided for selected parameters of interest. 
Below is list of all lab tests performed:
 
9.6.4 
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. 
9.6.5 
Physical Measurements 
The change in weight from baseline to each scheduled assessment time point will be 
summarized. 


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9.6.6 
Electrocardiogram 
All on-study electrocardiogram (ECG) data will be listed and select parameters of 
interest may be plotted. 
 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. 
 
The analysis of Fridericia’s (QTcF) QT correction will use the results recorded on the CRF. 
Subjects’ maximum change from baseline in QT interval corrected by Fridericia’s formula 
will be categorized into the following groups per their maximum change from baseline in 
QTcF. 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. 
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF. 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. 


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9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by dosing schedule. The number of cycles, Total Number of Non-Zero Doses, number of 
doses of investigational product and the total dose in μg will be summarized. 
9.6.9 
Exposure to Non-investigational Product  
Not Applicable 
9.6.10 
Exposure to Other Protocol-required Therapy 
Not Applicable  
9.6.11 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary. A subject listing of all prior 
and concomitant medications will be presented.  
9.7 
Other Analyses 
All exploratory endpoints will be described in Supplemental Statistical analysis plan 
(SSAP) as applicable. 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Serum concentrations of AMG 673 will be determined using a validated assay.  
PK parameters will include, but are not limited to half-life (t1/2; if feasible), maximum 
observed concentration (Cmax), minimum observed concentration (Cmin), area under the 
concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUC0-last) and clearance. Pharmacokinetic parameters will be estimated using standard 
non-compartmental approaches and summarized by dose level using means, standard 
deviations, medians, minimums, and maximums. 
 
Serum concentrations below the lower limit of quantifications will be set to zero for the 
estimation of the pharmacokinetic parameters for each subject and for the calculation of 
the summary statistic for each time point. Actual dosing and sampling time will be used 
for all calculations. The reasons for excluding any sample from the analyses will be 
provided.  
 
Individual concentration-time data will be summarized by dose level. Individual 
concentration-time data will also be tabulated and presented graphically. Summary 
statistics will be computed for each sampling time and parameter as appropriate. 


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Additional PK analyses, including but not limited to analysis of the relationship between 
AMG 673 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 673 exposure and either pharmacodynamic 
effect and/or clinical outcome may also be performed. 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not Applicable 
9.7.3 
Analyses of Health Economic Endpoints 
Not Applicable  
9.7.4 
Analyses of Biomarker Endpoints 
Not Applicable 
10. 
Changes From Protocol-specified Analyses 
Time to Progression endpoint in protocol refers to Event Free Survival, to address 
the Relapse/refractory AML subjects who are already in progressive state and 
never respond. 
 
 


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11. 
Literature Citations / References 
 
Babb J, Rogatko A, Zacks S. Cancer Phase I Clinical Trias: Efficient Dose Escalation 
with Overdose Control. Statistics in Medicine 1998;17:1103-1120. 
 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria, 
treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642-9. 
 
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka 1934; 26, 404-13. 
 
Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-195 
 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Statistics in Medicine 2008;27:2420-2439 
 
Oken MM, Creech RH, Tormey DC et al.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655 
 
12. 
Prioritization of Analyses 
Not Applicable  
13. 
Data Not Covered by This Plan 
Not Applicable  


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14. 
Appendices 
Appendix A.  Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose [ of study drug]. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose; 2=Impute the first of the month; 3=Impute January 1 of the year; 4=Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
If yyyymm for the date last known to be alive equals yyyymm for death date, set 
death date to the day after the date last known to be alive. 
 
If yyyymm for the date last known to be alive is less than the yyyymm for death date, 
set death date to the first day of the death month. 
 
If yyyymm for the date last known to be alive is greater than yyyymm for death date, 
assume 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: 


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


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Appendix C.  Summary of Changes 
 
Section:  Study Design 
Replace: 
This is a first-in-human, open-label, phase 1, sequential dose escalation study.  
AMG 673 will be evaluated as a short term intravenous (IV) infusion in adult subjects 
with relapsed/refractory AML.  The study will be conducted at approximately 7 sites in 
Australia, Germany and the United States. Additional sites may be added later. 
The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) of AMG 673.  Planned dose levels (dose per infusion) for the 
dose escalation cohorts are as follows: 0.05 µg, 0.15 µg, 0.45 µg, 1.5 µg, 4.5 µg, 9 µg, 
18 µg, 36 µg, 72 µg, 110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is not reached. 
The starting dose for the first cohort will be 0.05 µg administered as short term IV 
infusions on D1 and D5.  The doses administered for the cohorts following cohort 1 will 
be recommended by the Dose Level Review Team (DLRT). The DLRT may recommend 
on the administration of up to 2 additional infusions on D12 and D19 of a cycle for a 
future cohort.  All subjects will be pre treated with an 8-mg dose of IV dexamethasone 
1 hour prior to day 1 and day 5 AMG 673 doses and prior to each step-up dose of 
AMG 673. Each cycle will last for 14 days in the cohorts receiving only 2 doses (Day 1, 
5) and 28 days in the cohorts receiving 4 doses (Day 1, 5, 12, 19). This cycle will be 
followed by a treatment-free interval for 2 weeks, which may be extended for up to 
5 weeks or longer for the cohorts at higher doses, based on a DLRM recommendation. 
The D5 infusion, and the D12/D19 infusions (if applicable) may be at the same dose as 
the preceding infusion or may be at a higher dose level (dose step). This will be based 
on tolerability of the lower dose level and other clinical signs, pharmacological and PD 
results and will be recommended by the DLRT. For a schematic description of the 
different dose step options see Figure 3 in Section 3.1. There is a ± 1 day window for 
dosing visits which may be implemented after consultation with the sponsor. 
With: 
This is a first-in-human, open-label, phase 1, sequential dose escalation study.  
AMG 673 will be evaluated as a short term intravenous (IV) infusion in adult subjects 
with relapsed/refractory AML.  The study will be conducted at approximately 10 sites in 
Australia, Germany and the United States. Additional sites may be added later. 


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The dose-escalation cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics (PD) using 2 schedules of AMG 673 administration:  Schedule A 
(D1/D5 dosing) and Schedule B (QD dosing for cycle 1 followed by twice weekly 
dosing in following cycles).   
For Schedule A, planned dose levels (dose per infusion) for the dose escalation cohorts 
are as follows: 0.05 µg, 0.15 µg, 0.45 µg, 1.5 µg, 4.5 µg, 9 µg, 18 µg, 36 µg, 72 µg, 
110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is not reached. The starting dose for 
the first cohort will be 0.05 µg administered as short term IV infusions on D1 and D5.  
The doses administered for the cohorts following cohort 1 will be recommended by the 
Dose Level Review Team (DLRT). The DLRT may recommend on the administration of 
up to 2 additional infusions on D12 and D19 of a cycle for a future cohort.  All subjects 
will be pre treated with an 8-mg dose of IV dexamethasone 1 hour prior to day 1 and 
day 5 AMG 673 doses and prior to each step-up dose of AMG 673. Each cycle will last 
for 14 days in the cohorts receiving only 2 doses (Day 1, 5) and 28 days in the cohorts 
receiving 4 doses (Day 1, 5, 12, 19). Each cycle will be followed by a treatment-free 
interval for 0 to 14 days depending on treatment response and recovery of blood 
counts, but may be extended as described in Section 6.2.1.1.1 after consultation 
with Sponsor.  The D5 infusion, and the D12/D19 infusions (if applicable) may be at the 
same dose as the preceding infusion or may be at a higher dose level (dose step). This 
will be based on tolerability of the lower dose level and other clinical signs, 
pharmacological and PD results and will be recommended by the DLRT. For a 
schematic description of the different dose step options see Figure 2. There is a ± 1 day 
window for dosing visits which may be implemented after consultation with Sponsor.  
For Schedule B, planned dose levels (dose per infusion) for the dose escalation 
cohorts are as follows: 72 µg, 110 µg, 160 µg, 240 µg, 360 µg and higher if MTD is 
not reached. The starting dose for the cohort 1 on Schedule B will be 72 µg 
administered as short-term IV infusions daily (QD) during the 14-day cycle 1 after 
the 72 µg target dose is found to be relatively safe and tolerable by the DLRT for Schedule 
A.  Cohort 2 and higher will include step-up doses added in each cohort 
administered in two day increments after the previous step dose up to the target 
dose in cycle 1 (eg, cohort 2 will start with 72 µg for 2 days followed by 110 µg 
administered on D3 to D14; cohort 3 will start with 72 µg for 2 days followed by 
110 µg on D3 for 2 days followed by 150 µg on D5 to D14, etc).  Cycle 2+ doses will 
be given on days 1, 4, 8 and 11 at the target dose.  See Table 3 and Section 


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6.2.1.1.2 for Schedule B dosing schema by cohort.  All subjects will be pre treated 
with an 8-mg dose of IV dexamethasone 1 hour prior to the first dose on day 1 and 
prior to each step-up dose in cycle 1 and prior to all doses in cycle 2 and beyond. 
There is no treatment free interval between cycle 1 and cycle 2.  Beyond cycle 2, a 
treatment-free interval is allowed for 0 to 14 days depending on treatment 
response and recovery of blood counts, and may be extended as described in 
Section 6.2.1.1.1 after consultation with the sponsor. Adjustments to dose level, 
dose frequency and a duration of step dosing may be considered after 
recommendation of DLRT based on review of available safety, PK, and PD data. 
Section: Study Design, Dose Escalation Cohorts 
Replace: 
Dose Escalation will be conducted in 2 stages: a single subject stage and a multiple 
subjects stage.  In the single subject cohorts, cohorts 1 and 2, single subjects will be 
enrolled at dose levels anticipated to be lower than those at which adverse events 
related to AMG 673 will be observed. Multiple subject cohorts, starting with cohort 3, will 
enroll and the cohort size will be extended to 3-4 subjects per cohort.  The Bayesian 
logistic regression model (BLRM) design will be used to guide dose escalation.   The 
actual dose selected at each dose decision may be at or below the model’s 
recommended dose as determined by the dose level review team (DLRT) after 
considering all information.  Subjects will be assessed for dose limiting toxicities (DLTs) 
for the duration of their treatment cycle ie, 2 weeks from D1 for subjects who receive 
2 doses and 4 weeks for subjects who receive 4 doses. Subjects who complete the DLT 
period may proceed to a higher dose level for the following treatment cycle once the next 
dose cohort has been deemed safe by the DLRT, after consultation with the sponsor, if 
no DLT was reported during or after the completion of the DLT period for that subject 
and no ≥ grade 3 adverse event(s), deemed treatment related by the investigator, are 
reported for that subject. 
With: 
Dose Escalation will be conducted in 2 stages: a single subject stage (Schedule A only) 
and a multiple subjects stage.  In the single subject cohorts, cohorts 1 and 2, single 
subjects will be enrolled at dose levels anticipated to be lower than those at which 
adverse events related to AMG 673 will be observed. Multiple subject cohorts, starting 
with cohort 3, will enroll and the cohort size will be extended to 3-4 subjects per cohort.  
The Bayesian logistic regression model (BLRM) design will be used to guide dose 


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escalation.  The actual dose selected at each dose decision may be at or below the 
model’s recommended dose as determined by the dose level review team (DLRT) after 
considering all information.  Subjects will be assessed for dose limiting toxicities (DLTs) 
for the duration of their first treatment cycle (ie, 2 weeks from D1 for subjects who 
receive 2 doses and 4 weeks for subjects who receive 4 doses in Schedule A and 
4 weeks from D1 for subjects in Schedule B). Subjects who complete the DLT period 
may proceed to a higher dose level for the following treatment cycle after the next dose 
level has been deemed safe by the DLRT, after consultation with Sponsor, if no DLT 
was reported for that subject and no ≥ grade 3 adverse event(s), deemed treatment 
related by the investigator, are reported for that subject. 
Section:  Study Design, Estimation of initial and target MTDs 
Replace: 
It is anticipated that 2 MTDs may be estimated, one for the initial dosing and one for the 
subsequent dosing.  Should the initial dose be limited by adverse events related to 
first dose effects, the second MTD for the target dose will be estimated after giving the 
initial dose at MTD (dose step).  Each MTD will be estimated following the dose 
escalation guided by BLRM described above.  A second dose step may also be 
implemented in a cycle if this was considered appropriate and necessary to allow further 
dose escalation.  This second dose step would be performed the same way as 
described above.  In this case, a third MTD would be estimated for the dose to be 
administered after the second dose step. 
With: 
For Schedule A, it is anticipated that at least 2 MTDs may be estimated, one for the 
initial dosing and one for the subsequent step dosing.  Should the initial dose be limited 
by adverse events related to first dose effects, the second MTD for the target dose will 
be estimated after giving the initial dose at MTD (step dose).  Each MTD will be 
estimated following the dose escalation guided by BLRM described above.  A second 
dose step may also be implemented in a cycle if this was considered appropriate and 
necessary to allow further dose escalation.  This second dose step would be performed 
the same way as described above.  In this case, a third MTD would be estimated for the 
dose to be administered after the second dose step. 
Schedule B will be initiated after preliminary safety data of AMG 673 in Schedule A 
(eg, MTD1 is estimated to be ≥72 µg) become available and may be conducted in 


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parallel with Schedule A per Sponsor’s decision.  The MTD for Schedule B will be 
estimated following the dose escalation described in Section 6.2.1.1.2 and guided 
by BLRM described above.   
Section:  Study Design, Expansion Cohort 
Replace: 
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 673.  The dose to be evaluated will be at or below the 
MTD estimated in the dose escalation cohorts.  Additional expansion cohorts may be 
covered by a protocol amendment to test alternative dose levels or biologic subsets. 
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. 
With: 
For each Schedule, upon completion of the dose escalation cohorts, additional 
subjects (up to 10) may be enrolled in a dose expansion cohort to gain further clinical 
experience, safety and efficacy data in subjects with AMG 673.  The dose to be 
evaluated will be at or below the MTD estimated in the dose escalation cohorts.  
Additional expansion cohorts may be covered by a protocol amendment to test 
alternative dose levels or biologic subsets. 
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 
each schedule. 
Section:  Sample Size 
Replace: 
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.  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. 
With: 


Product:  AMG 673   
Protocol Number:  20160377 
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It is anticipated that approximately 95 subjects will be enrolled in this study.  For 
Schedule A, 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.  For 
Schedule B, up to 40 subjects will be enrolled in the dose escalation cohorts and 
up to 10 additional subjects will be enrolled in the dose expansion cohort.  For 
ethical and operational reasons subjects who already are in the screening phase at the 
time of enrollment stop (end of expansion phase) may 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 or a schedule may be 
discontinued. 
Section:  Study Design and Treatment Schema, Treatment Phase 
Replace: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Study  
 
Treatment Phase  
AMG 673 short term infusions, up to 12 treatment cycles with 2 – 4 infusions per cycle  
DOSE ESCALATION 
First 2 cohorts are single subject 
cohorts. 
BLRM for all subsequent doses 
Number of cohorts, subjects per cohort 
and actual doses dependent on 
observation of DLTs and Dose Level 
Enrollment (Day 1) 
End of Treatment 
Safety Follow-Up 
 (4 weeks after last dose of AMG 673) 
DOSE EXPANSION 
Will begin at or below the MTD or 
highest tested dose 
n=10 
Screening  
(14 days) 


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Protocol Number:  20160377 
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With: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Phase  
AMG 673 short term infusions, up to 12 treatment cycles  
DOSE ESCALATION 
 
Schedule A*: D1/D5 on a 14 day cycle 
*First 2 cohorts are single subject cohorts 
 
Schedule B: QD on a 14 day cycle for 
cycle 1 and D1, D4, D8 and D11 for cycle 2 
and beyond  
 
Number of cohorts, subjects per cohort and 
actual doses dependent on observation of 
DLTs and Dose Level Review Team 
recommendations 
Enrollment (Day 1) 
End of Treatment 
Safety Follow-Up 
 (4 weeks after last dose of AMG 673) 
DOSE EXPANSION 
Will begin at or below the MTD or 
highest tested dose from Schedule 
A (± dose step) and/or Schedule B 
n=10 each 
End of Study  
Screening  
(14 days) 
 


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Section 5: Definitions 
 Replace: 
Treatment-Emergent Adverse Event (TEAE)  
Treatment-emergent adverse events are events categorized as Adverse Events (AEs) 
starting on or after the first dose of investigational product, as determined by the flag 
indicating if the adverse event started prior to the first dose on the Events CRF and up to 
end of study (EOS). 
Duration of Response (DOR) 
Duration of response is defined as the number of days between the date of the first 
tumor assessment indicating an objective response through to the subsequent date of 
progression as defined by revised IWG response criteria (Appendix E in the protocol) 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 tumor 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 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*).  
Time to Response (TTR)  
Time to response defined as the interval from the first administration of AMG 673 to the 
first documentation of confirmed response. 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*). Time to response is calculated as the 
number of days: (date of first response – date of study day 1 +1). 
With: 
Treatment-Emergent Adverse Event (TEAE) 
Treatment-emergent adverse events are events categorized as Adverse Events (AEs) 
including disease related events starting on or after the first dose of investigational 


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product, as determined by the flag indicating if the adverse event started prior to the first 
dose on the Events CRF and up to end of study (EOS). 
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 or death 
due to any cause, whichever occurs first. Subjects without relapse 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.  
Time to Response (TTR) 
Time to response defined as the interval from the first administration of AMG 673 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). 
Added: 
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 6.2.1.3 
Overall Response 
Overall response is defined as achieving any of the following response: CR, CRh*, 
CRi or MLFS. 
Time to Progression (Event-free Survival): 
Event-free survival (EFS) is defined as the interval from first administration of AMG 
673 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 AMG673. For non-responders, the 
event date for treatment failure is assigned as the date of first administration of 
AMG 673. 


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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 673 + 1.  
Removed: 
Dose Limiting Toxicities (DLT) 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT window. The DLT window will start on D1 (start of the administration of the first 
infusion) and last for 14 days for cohorts receiving 2 doses (i.e. Day 1 and Day 5 dose) 
and for 28 days for subjects receiving 4 doses (i.e. Days 1,5,12,19). The CTCAE will be 
used to assess toxicities/adverse events with the exception of CRS (see Table 5 in 
protocol for grading of CRS). 
Section:  7.1 Dose Level Review Team (DLRT) 
Replace: 
The DLRT will be composed of the investigators or designees, and the following Amgen 
representatives: early development leader, global safety officer or designee, clinical 
study manager, biostatistician, PK scientist (optional), and other functional area 
representatives as appropriate. The following members are responsible for DLRT 
recommendations: investigators, Amgen medical monitor, and global safety officer or 
designee.   
With: 
The DLRT will be composed of the investigators or designees, and the following Amgen 
representatives: early development leader/Medical Monitor and global safety officer, or 
their approved designees, clinical study manager, and biostatistician and PK scientist 
(optional).  Other functional area representatives may participate as appropriate. The 
following members, or their qualified designees, are responsible for DLRT 
recommendations: investigators, Amgen medical monitor, and global safety officer. 
Section7.1 Dose Level Review Team (DLRT) 
Replace: 
A quorum as defined below must be in attendance for the DLRM.  The quorum is defined 
as > 50% of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator possessing written documentation [eg e-mail] of the 


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CONFIDENTIAL  
 
 
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.   
With: 
A quorum as defined below must be in attendance for the DLRM.  The quorum is defined 
as > 50% of the responsible members or their qualified designee (ie, sub-investigator or 
research nurse or study coordinator), as well as the Amgen representatives 
responsible for DLRT recommendations listed above.  Investigators that are not 
able to participate in the meeting (eg, due to time difference) may also provide 
their vote in writing (eg, by email to Sponsor) after review of the data discussed at 
the meeting. 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.   
Section 9: General consideration: 
Replace: 
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference 
dose is 0.05.  These values were selected such that pi = 0.02 for the starting dose, and 
pi = 0.3 for dref, where 0.3 is approximately the middle of the target TPI and dref is the 
dose that is expected to be the MTD.   
With: 
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference 
dose is 0.05.  The prior distribution of BLRM for step dosing may be adjusted 
based on the accumulative data. For example, the starting dose and the reference 
dose of BLRM prior to estimate MTD2 may be based on MTD1 and the expected 
MTD for MTD2. The operating characteristics of the 2-parameter BLRM design were 
evaluated via simulation for schedule A and B separately.  
For schedule A, we evaluated the operation characteristics of the two-parameter 
BLRM design for no dose step schedule. Since it is unlikely to observe toxicity at the 
lowest dose levels, simulations use 0.45 µg as the initial dose level.  The 0.45 µg dose 


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level is anticipated to be the starting level for the multiple subject cohorts.  In addition, 
we assume that pi = 0.02 for the starting dose, and pi = 0.3 for dref, where 0.3 is 
approximately the middle of the target TPI and dref is the dose that is expected to 
be the MTD.   
 
For schedule B, simulations use 72 µg as the initial dose level and we assume 
that pi = 0.05 for the starting dose, and pi = 0.3 for dref, where 0.3 is 
approximately the middle of the target TPI and dref is the dose that is expected 
to be the MTD.   
Section:9.6.3 Laboratroty Test Results 
Replace: 
Additionally, the number and percentage of subjects experiencing 1, 2, 3 and 4 
worsening CTCAE grade shifts from baseline will be presented. The direction of the 
laboratory worsening will again be denoted. 
With: 
Additionally, the number and percentage of subjects experiencing 0,1, 2, 3 and 4 
worsening CTCAE grade shifts from baseline will be presented. The direction of the 
laboratory worsening will again be denoted. 
Removed: 
The number and percentage of subjects experiencing treatment emergent laboratory 
toxicities with worst post dose CTCAE grades of ≥1, ≥2, ≥3 and 4 will be presented. The 
direction of the laboratory worsening will be denoted. The summary will be presented for 
all laboratory parameters for which at least one subject experienced a treatment emergent 
toxicity with a worst grade ≥ 3. 
 
A listing of CTCAE grade 3 or higher laboratory toxicities will be provided. This listing will 
include all laboratory data for the subject and laboratory parameter of interest in order to 
provide proper context. A flag will indicate the grade 3 or higher toxicity.  
 
 


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Section:9.6.8 Exposure to investigational product  
Replace:  
Descriptive statistics will be produced to describe the exposure to investigational product 
by dosing schedule. The number of cycles, number of doses of investigational product 
and the total dose in μg will be summarized 
With: 
Descriptive statistics will be produced to describe the exposure to investigational product 
by dosing schedule. The number of cycles, Total Number of Non-Zero Doses, number of 
doses of investigational product and the total dose in μg will be summarized. 
 Section: Other Protocol Required Therapies 
Add: 
Time to Progression endpoint in protocol refers to Event Free Survival, to address 
the Relapse/refractory AML subjects who are already in progressive state and 
never respond. 
 
 


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Appendix A.  
Replace: 
Technical Detail and Supplemental Information Regarding Statistical Procedures 
and Programs 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant 
Medications Imputation Rules for Partial or Missing Stop Dates  
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year. If the stop date is entirely missing, assume the 
event or medication is ongoing. If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial. 
 
 
 
 
 
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. 


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 Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
With: 
The reference date for the following rules is the date of first dose [ of study drug]. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose; 2=Impute the first of the month; 3=Impute January 1 of the year; 4=Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
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 date last known to be alive is in error, set death date to the first day of the 
death year. 
If a death date is totally missing: 
Do not impute and censor the subject survival time.