Clinical trial NCT04478695
Conditions: Relapsed or Refractory Acute Myeloid Leukemia
Sponsor: Amgen
Start date: 2020-09-29; Completion date: 2020-10-23
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of AMG 330, administered in combination with pembrolizumab, in participants with relapsed or refractory acute myeloid leukemia (R/R AML).

Detailed description:
This study will assess the safety and tolerability of AMG 330 in combination with pembrolizumab and whether pembrolizumab will enhance the anti-AML activity of AMG 330. Both cohort 1 and 2 will include AMG 330 and pembrolizumab with the difference being the initiation date for pembrolizumab treatment.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AMG 330 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Continuous intravenous (IV) infusion. intervention 2: Intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 330 + Pembrolizumab 
Protocol Number:  20170646  
Date:  04 May 2020 
Page 1 of 136 
CONFIDENTIAL 
Title Page 
Protocol Title: 
A Phase 1b Study Assessing Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and 
Efficacy of AMG 330 cIV in Combination With 
Pembrolizumab in Adult Subjects With Relapsed 
or Refractory Acute Myeloid Leukemia 
Short Protocol Title: 
A Phase 1b Study of AMG 330 in Combination 
With Pembrolizumab in Adult Subjects with 
Relapsed or Refractory Acute Myeloid Leukemia 
Protocol Number: 
20170646 
Investigational Product: 
AMG 330 + Pembrolizumab 
Trade Name: 
N/A 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+1-805-447-1000
Protocol 
Approver 
Name: 
, MD, PhD 
Function: 
VP Early Development, TA Head Hematology & 
Oncology 
Key 
Sponsor 
Contact 
Name: 
, MD, PhD 
Address: 
One Amgen Center Drive, Thousand Oaks, CA 
91320 
Telephone Number: 
Direct:
Cellular: 
Email Address: 
EudraCT Number: 
Not applicable 
NCT Number: 
Not available 
Protocol Version Date: 
Document Version 
Date 
Original 
04 May 2020 
Data Elements Standards 
Version: 
6 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 
Approved
NCT Number: NCT04478695
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
Page 2 of 136 
CONFIDENTIAL  
 
 
Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000.f 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
Page 3 of 136 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1b Study Assessing Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 330 cIV in 
Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia, dated 04 May 2020, and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, 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) and my 
subinvestigators (including, if applicable, their spouses or legal partner 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 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
Page 4 of 136 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 14 
1.3 
Schedule of Activities (SoA) ...................................................................... 17 
2. 
Introduction ........................................................................................................... 27 
2.1 
Study Rationale ......................................................................................... 27 
2.2 
Background ............................................................................................... 28 
2.2.1 
Disease ..................................................................................... 28 
2.2.2 
Amgen Investigational Product Background:  AMG 
330 ............................................................................................ 29 
2.2.2.1 
Nonclinical Pharmacology:  AMG 330 ..................... 30 
2.2.2.2 
Nonclinical Pharmacokinetics:  AMG 330 ................ 30 
2.2.2.3 
Nonclinical Toxicology:  AMG 330 ........................... 31 
2.2.3 
Non-Amgen Investigational Product Background:  
Pembrolizumab ......................................................................... 31 
2.3 
Benefit/Risk Assessment ........................................................................... 33 
3. 
Objectives and Endpoints ..................................................................................... 35 
4. 
Study Design ........................................................................................................ 36 
4.1 
Overall Design .......................................................................................... 36 
4.1.1 
Cohort 1 Design ........................................................................ 37 
4.1.2 
Cohort 2 Design ........................................................................ 39 
4.2 
Number of Subjects ................................................................................... 40 
4.2.1 
Replacement of Subjects ........................................................... 40 
4.2.2 
Number of Sites ......................................................................... 41 
4.3 
Justification for Investigational Product Dose ............................................ 41 
4.3.1 
Justification for Non-investigational Product Dose ..................... 43 
4.4 
End of Study ............................................................................................. 43 
4.4.1 
End of Study Definition .............................................................. 43 
4.4.2 
Study Duration for Subjects ....................................................... 44 
4.5 
Patient Input on Study Design ................................................................... 44 
5. 
Study Population .................................................................................................. 44 
5.1 
Inclusion Criteria ....................................................................................... 44 
5.2 
Exclusion Criteria ...................................................................................... 46 
5.3 
Subject Enrollment .................................................................................... 48 
5.4 
Screen Failures ......................................................................................... 49 
5.5 
Washout Period/Run-in Period/Invasive Procedure(s) ............................... 49 
6. 
Treatments ........................................................................................................... 49 
6.1 
Treatment(s) Administered ........................................................................ 50 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
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CONFIDENTIAL  
 
 
6.1.1 
Investigational Products ............................................................ 50 
6.1.1.1 
AMG 330 Dosage, Administration, and 
Schedule ................................................................. 51 
6.1.1.2 
AMG 330 Inpatient Dosing ...................................... 52 
6.1.1.3 
AMG 330 Outpatient Dosing .................................... 53 
6.1.1.4 
Pembrolizumab Dosage, Administration, 
and Schedule .......................................................... 54 
6.1.2 
Non-investigational Products ..................................................... 55 
6.1.3 
Medical Devices ........................................................................ 55 
6.1.4 
Other Protocol-required Therapies ............................................ 55 
6.1.5 
Other Treatment Procedures ..................................................... 56 
6.1.6 
Product Complaints ................................................................... 56 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 57 
6.2 
Dose Modification ...................................................................................... 58 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules, Dose-Limiting Toxicities (DLTs) ....................... 58 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 60 
6.2.2.1 
Amgen Investigational Product:  AMG 330 .............. 60 
6.2.2.2 
Non-Amgen Investigational Product(s):  
Pembrolizumab ....................................................... 65 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 71 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 71 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 71 
6.4.1 
Method of Treatment Assignment .............................................. 71 
6.4.2 
Blinding ..................................................................................... 71 
6.5 
Treatment Compliance .............................................................................. 71 
6.6 
Treatment of Overdose ............................................................................. 71 
6.7 
Prior and Concomitant Treatment ............................................................. 72 
6.7.1 
Prior Treatment ......................................................................... 72 
6.7.2 
Concomitant Treatment ............................................................. 72 
6.8 
Specific Recommendations for Cytokine Release Syndrome, 
Tumor Lysis Syndrome, and Infection Prophylaxis .................................... 73 
7. 
Discontinuation Criteria ......................................................................................... 76 
7.1 
Discontinuation of Study Treatment........................................................... 77 
7.2 
Discontinuation From the Study ................................................................ 78 
7.2.1 
Reasons for Removal From Study ............................................. 78 
7.3 
Lost to Follow-up ....................................................................................... 78 
8. 
Study Assessments and Procedures .................................................................... 79 
8.1 
General Study Periods .............................................................................. 79 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 79 
8.1.2 
Treatment Period ....................................................................... 80 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
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Date:  04 May 2020 
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CONFIDENTIAL  
 
 
8.1.3 
Safety Follow-up ........................................................................ 80 
8.1.4 
Long-term Follow-up .................................................................. 80 
8.1.5 
End of Study .............................................................................. 80 
8.2 
Description of General Study Assessments and Procedures ..................... 80 
8.2.1 
General Assessments ............................................................... 81 
8.2.1.1 
Informed Consent .................................................... 81 
8.2.1.2 
Demographics ......................................................... 81 
8.2.1.3 
Medical History ........................................................ 81 
8.2.1.4 
Physical Examination .............................................. 81 
8.2.1.5 
Physical Measurements .......................................... 81 
8.2.1.6 
Performance Status................................................. 81 
8.2.2 
Efficacy Assessments ................................................................ 81 
8.2.2.1 
Disease Response .................................................. 81 
8.2.4 
Safety Assessments .................................................................. 82 
8.2.4.1 
Vital Signs ............................................................... 82 
8.2.4.2 
Electrocardiograms (ECGs) ..................................... 83 
8.2.4.3 
Vital Status .............................................................. 83 
8.2.4.4 
Other Safety ............................................................ 83 
8.2.5 
Adverse Events and Serious Adverse Events ............................ 83 
8.2.5.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 83 
8.2.5.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 85 
8.2.5.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 85 
8.2.5.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 86 
8.2.5.5 
Safety Monitoring Plan ............................................ 86 
8.2.5.6 
Pregnancy and Lactation ......................................... 86 
8.2.6 
Clinical Laboratory Assessments ............................................... 87 
8.2.7 
Pharmacokinetic Assessments .................................................. 87 
8.2.8 
Pharmacodynamic Assessments ............................................... 88 
8.2.10 
Antibody Testing Procedures ..................................................... 88 
9. 
Statistical Considerations ...................................................................................... 91 
9.1 
Statistical Hypotheses ............................................................................... 91 
9.2 
Sample Size Determination ....................................................................... 91 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 91 
9.3.1 
Analysis Sets ............................................................................. 91 
Approved 
 
 


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Date:  04 May 2020 
Page 7 of 136 
CONFIDENTIAL  
 
 
9.3.2 
Covariates ................................................................................. 92 
9.3.3 
Subgroups ................................................................................. 92 
9.3.4 
Handling of Missing and Incomplete Data .................................. 92 
9.4 
Statistical Analyses ................................................................................... 92 
9.4.1 
Planned Analyses ...................................................................... 92 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 92 
9.4.1.2 
Primary Analysis ..................................................... 92 
9.4.1.3 
Final Analysis .......................................................... 92 
9.4.2 
Methods of Analyses ................................................................. 93 
9.4.2.1 
General Considerations ........................................... 93 
9.4.2.2 
Efficacy Analyses .................................................... 93 
9.4.2.3 
Safety Analyses ...................................................... 93 
9.4.2.4 
Other Analyses ........................................................ 94 
10. 
References ........................................................................................................... 95 
11. 
Appendices ........................................................................................................... 98 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 99 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 102 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 103 
Regulatory and Ethical Considerations .................................................... 104 
Informed Consent Process ...................................................................... 105 
Data Protection/Subject Confidentiality ................................................... 106 
Publication Policy .................................................................................... 107 
Investigator Signatory Obligations ........................................................... 108 
Data Quality Assurance ........................................................................... 108 
Source Documents .................................................................................. 109 
Study and Site Closure............................................................................ 110 
Compensation ......................................................................................... 110 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 111 
Definition of Adverse Event ..................................................................... 111 
Definition of Serious Adverse Event ........................................................ 112 
Recording Adverse Events and Serious Adverse Events ........................ 113 
Evaluating Adverse Events and Serious Adverse Events ........................ 114 
Reporting of Serious Adverse Event ........................................................ 115 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 119 
Definition of Females of Childbearing Potential ....................................... 119 
Collection of Pregnancy Information ........................................................ 121 
Collection of Lactation Information .......................................................... 122 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 125 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
Page 8 of 136 
CONFIDENTIAL  
 
 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 127 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................. 127 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 128 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 129 
11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 131 
11.9 
Appendix 9.  Eastern Cooperative Oncology Group (ECOG) 
Performance Status ................................................................................ 132 
11.10 Appendix 10.  World Health Organization Classification for Acute 
Myeloid Leukemias ................................................................................. 133 
11.11 Appendix 11.  European LeukemiaNet (ELN) Response Criteria 
in Acute Myeloid Leukemia (2017) .......................................................... 135 
 
List of Tables 
Table 1-1.  Schedule of Activities for Cohort 1, Cycle 1 ................................................. 17 
Table 1-2.  
Collection Schedule for Cohort 1, Cycle 1 ................................... 19 
Table 1-3.  Schedule of Activities for Cohort 1, Cycles 2 and beyond ............................ 20 
Table 1-4.  
 Collection Schedule for Cohort 1, Cycle 2 and beyond ............... 22 
Table 1-5.  Schedule of Activities for Cohort 2 (all cycles) ............................................. 23 
Table 1-6.  
Collection Schedule for Cohort 2, All Cycles ............................... 25 
Table 1-7.  Schedule of Activities for Each AMG 330 Dose Step of a Repeat 
Cycle (Any Cohort) ................................................................................. 26 
Table 4-1.  Dosing for Cohort 1 (Cycle 1) ...................................................................... 38 
Table 4-2.  Dosing for Cohort 1 (Cycle 2 and Beyond) ................................................... 39 
Table 4-3.  Dosing for Cohort 2 (All Cycles) ................................................................... 40 
Table 5-1.  Adequate Organ Function Laboratory Values .............................................. 45 
Table 6-1.  Study Treatments ........................................................................................ 50 
Table 6-2.  Trial Treatment ............................................................................................ 54 
Table 6-3.  Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated With 
Pembrolizumab ....................................................................................... 67 
Table 6-4.  Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines ............................................................................. 70 
Table 6-5.  Grading and Management of Cytokine Release Syndrome.......................... 74 
Table 11-1.  Analyte Listing ......................................................................................... 102 
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Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 128 
Table 11-3.  2016 WHO Classification for AML ............................................................ 133 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 14 
Figure 1-2.  Combination Regimen Schema for Cohort 1, Cycle 1 ................................. 15 
Figure 1-3.  Combination Regimen Schema for Cohort 1, Cycle 2 and beyond ............. 15 
Figure 1-4.  Combination Regimen Schema for Cohort 2, Cycles 1, 2, and 3 ................ 16 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 116 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 123 
Approved 
 
 


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Protocol Number:  20170646  
Date:  04 May 2020 
Page 10 of 136 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1b Study Assessing Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of AMG 330 cIV in Combination With Pembrolizumab 
in Adult Subjects With Relapsed or Refractory Acute Myeloid Leukemia 
Short Protocol Title:  A Phase 1b Study of AMG 330 in Combination With 
Pembrolizumab in Adult Subjects with Relapsed or Refractory Acute Myeloid Leukemia 
Study Phase:  Phase 1b 
Indication:  Adult Subjects with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
Rationale 
 
AMG 330 is a canonical bispecific cluster of differentiation (CD)33/CD3 T-cell 
engager (BiTE®) molecule in development for myeloid malignancies. 
 
AMG 330 targets CD33 which is expressed on the cell surface of AML blasts from 
> 95% of AML cases. 
 
AMG 330 lead indication is relapsed or refractory AML (R/R AML), and this patient 
population is characterized by a poor prognosis, whose 5-year survival remains 
about 10%. 
 
CD33 represents a validated target in AML with development and approval of 
Mylotarg (gemtuzumab ozogamicin) that demonstrated clinical benefit in select AML 
patient populations. 
 
Preliminary efficacy has been demonstrated for AMG 330.  During the ongoing 
phase 1a dose escalation study, 5 patients with R/R AML treated with 
, and 
 µg target doses achieved complete remission (CR)/incomplete recovery (CRi). 
 
AMG 330 dose levels from 
to 
 µg have been assessed in the phase 1a 
monotherapy dose escalation study, considered safe and tolerable and will be tested 
in combination with pembrolizumab.  Higher doses of AMG 330 have not been tested 
as monotherapy and will not be included in this study. 
 
Up-regulation of the programmed cell death 1 (PD-1) receptor and programmed cell 
death ligand 1 (PD-L1) immune checkpoint has been established in ex vivo 
cytotoxicity models as a key mediator of acquired resistance to AMG 330 therapy 
(Krupka et al, 2016).  AMG 330-induced T-cell activation resulted in upregulation of 
PD-L1 on primary AML cells. 
 
Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis, T-cell 
proliferation and interferon (IFN)-gamma secretion were significantly enhanced in 
vitro (Krupka et al, 2016). 
 
Preliminary assessment of T cells from patients treated with AMG 330 shows 
up-regulation of PD-1 expression. 
 
The hypothesis is that co-administration with a PD-1 immune checkpoint inhibitor will 
further augment AMG 330 activity, produce deeper and more durable remissions, 
and prevent and/or delay acquired resistance to AMG 330 therapy. 
 
Pembrolizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody with 
high specificity and high affinity of binding to PD-1, thus blocking its interaction with 
PD-L1 and PD-L2.  Pembrolizumab has an acceptable clinical safety profile, is 
indicated for the treatment of patients across a number of malignancies, and is in 
clinical development as an intravenous (IV) immunotherapy for additional advanced 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646  
Date:  04 May 2020 
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CONFIDENTIAL  
 
 
tumors.  For more details on specific indications for Keytruda® (pembrolizumab) refer 
to the Investigator’s Brochure. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 330 administered in 
combination with pembrolizumab in 
subjects with relapsed or refractory 
acute myeloid leukemia (R/R AML) 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent adverse events 
(TEAEs), treatment-related adverse events 
(TRAEs), and changes in vital signs, 
electrocardiograms (ECGs), and clinical 
laboratory tests 
Secondary 
 
Evaluate the anti-leukemia activity of 
AMG 330 administered in 
combination with pembrolizumab in 
R/R AML patients 
 
Responses to treatment with AMG 330 
administered in combination with 
pembrolizumab.  Response is defined as any 
of the following:  complete remission without 
mininum residual disease (CRMRD-), complete 
remission (CR), CR with incomplete recovery 
(CRi), or morphological leukemia-free state 
(MLFS), or partial remission (all according to 
the 2017 European LeukemiaNet (ELN) 
criteria (Döhner et al, 2017). 
 
Duration of response 
 
Evaluate the pharmacokinetics (PK) 
of AMG 330 when AMG 330 and 
pembrolizumab are administered in 
combination 
 
Descriptive statistics of AMG 330 
concentrations and PK parameters. 
 
Evaluate the immunogenicity of 
AMG 330 when administered in 
combination with pembrolizumab 
 
Incidence of anti-AMG 330 antibody formation 
 
Overall Design 
This is a phase 1b study assessing safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics, and efficacy of AMG 330 administered as continuous intravenous 
(cIV) infusion in combination with pembrolizumab in adult subjects with R/R AML.   
The study is a non-randomized study and will consist of 2 sequential dosing cohorts.  
Both cohorts will include AMG 330 and pembrolizumab with the difference being the 
initiation date for pembrolizumab treatment. 
This study will use a staggered enrollment approach.  Subject enrollment will start with 
cohort 1.  The first subject dosed in cohort 1 will serve as the sentinel subject.  
Subsequent subjects dosed in cohort 1 will start AMG 330 (
 µg/day) administration 
once sentinel subject has cleared study day 21 (AMG 330 monotherapy at 
 µg/day).  
Per sponsor determination, if the sentinel subject does not experience a dose-limiting 
toxicity (DLT) during days 15 to 21 after pembrolizumab is administered, the other 
subjects in cohort 1 will be allowed to continue the planned treatment schedule.  
Investigators and sponsor will meet after all subjects in cohort 1 have completed study 
day 28 (ie, AMG 330 
 µg/day dose level in combination with pembrolizumab) to 
assess the safety profile.  If the safety data from cohort 1 is acceptable per the 
Approved 
 
 


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Date:  04 May 2020 
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pre-specified DLT criteria, subjects enrolled in cohort 2 may proceed with the treatment 
schedule.  Similar to cohort 1, the first subject dosed in cohort 2 will serve as the sentinel 
subject.  Per sponsor determination, if the sentinel subject does not experience a DLT 
during the first 7 days, the other subjects in cohort 2 will be allowed to continue the 
planned treatment schedule. 
Safety data will be continuously monitored throughout the whole treatment period.  Study 
team in consultation with investigators may reconvene to make appropriate safety 
measures and adjustments as needed. 
Cohort 1 Design: 
Cycle 1 is 77 days in duration and subsequent cycles are 57 days in duration.  
Treatment will start with AMG 330 on day 1.  AMG 330 will be administered at a starting 
dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 
7 days.  If the subject has not experienced a DLT by day 14, they will receive 
pembrolizumab on day 15.  Pembrolizumab will be administered at a dose of 200 mg 
(Q3W) by a 30-minute IV infusion.  The subject will remain at an AMG 330 dose level of 
 µg/day for an additional 7 days.  Thereafter, AMG 330 dosing will continue as per 
Table 4-1, increasing dose levels up to 
 µg/day as tolerated by subjects.  
Pembrolizumab dosing will continue every 21 days starting from day 15. 
Cohort 2 Design: 
All cycles are 57 days in duration.  Subjects in cohort 2 will receive both AMG 330 and 
pembrolizumab on day 1.  Pembrolizumab will be administered at a dose of 200 mg 
(Q3W) by a 30-minute IV infusion.  If the subject does not develop a ≥ grade 2 infusion 
reaction, or if the infusion reaction is reversible after a 1-hour observation period, the 
subject will start AMG 330 at a starting dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 7 days, and continue dosing as per 
Table 4-3, increasing dose levels every 7 days up to 
 µg/day as tolerated by 
subjects.  Pembrolizumab will be administered at 200 mg IV once every 3 weeks. 
Cohorts 1 and 2: 
Subjects in both cohort 1 and cohort 2 may continue with cycle 2 and beyond of 
AMG 330 and pembrolizumab up to 6 months if the combination regimen remains 
tolerable and is deriving clinical benefit in the opinion of the investigator.  In both 
cohorts 1 and 2, subjects continuing with cycle 2 and beyond may be permitted to 
shorten the duration of AMG 330 step dose levels to 2 to 5 days based on individual 
clinical experience from cycle 1 and based on the clinical judgement of the investigator 
and in consultation and agreement with the sponsor.  The duration of the combination 
treatment period for individual subjects may be extended up to 1 year if the subject is 
deriving clinical benefit in the opinion of the investigator and in consultation with the 
sponsor.  If AMG 330 is discontinued, pembrolizumab may be continued as a 
monotherapy until disease progression for a maximum of 35 cycles (approximately 
2 years).  If pembrolizumab is discontinued, AMG 330 may be continued as a 
monotherapy. 
Number of Subjects 
It is anticipated that approximately 20 subjects will be enrolled in this study, with at least 
6 DLT evaluable subjects in each cohort.  With 6 evaluable subjects in 1 cohort, there is 
an 82% chance of observing at least 1 DLT if the true DLT rate is 25%. 
Summary of Subject Eligibility Criteria 
This study will enroll adult subjects with relapsed/refractory AML. 
For a full list of eligibility criteria, please refer to Section 5.1 and Section 5.2. 
Approved 
 
 


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CONFIDENTIAL  
 
 
Treatments 
AMG 330 and the intravenous solution stabilizer (IVSS) will be manufactured and 
packaged by Amgen Inc.  KEYTRUDA® (pembrolizumab) solution for infusion will be 
manufactured and packaged by Merck & Co Inc.  Both products will be distributed using 
Amgen clinical study drug distribution procedures.  AMG 330 is supplied as a sterile, 
single-use, powder for solution in a vial containing 
 mg of AMG 330.  The drug 
product is formulated with potassium phosphate, captisol, sucrose, polysorbate 80, 
pH 
.  The final container is a 5 cc glass vial and contains 1 mL deliverable volume of 
AMG 330.  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 (
 
, pH 
).  The IVSS is intended for pre-treatment of IV bags prior to 
dilution of AMG 330 drug product.  KEYTRUDA® (pembrolizumab) will be supplied as 
two 100 mg/4 mL (25 mg/mL), single-dose vials. 
Procedures 
After written informed consent has been obtained, all screening tests and procedures will 
be performed within the 14 days preceding administration of the first dose of (day 1), 
unless otherwise noted.  Subjects will be seen in clinic where evaluations will be 
performed including physical examination, vital signs, clinical laboratory tests, 
electrocardiogram (ECGs), PK, and 
 sample collections. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Table 1-1, Table 1-3, and Table 1-5. 
Statistical Considerations 
All subjects who are enrolled and receive at least 1 administration of the investigational 
product (AMG 330 and pembrolizumab) will be included in the analysis, unless otherwise 
specified.   
The primary analysis will occur when all subjects complete end of study.  Descriptive 
statistics will be provided for selected demographics, safety, efficacy, PK, 
, and 
data overall and by cohort 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 (TEAEs) and treatment-related adverse events will be tabulated.  The number of 
percentage of subjects reporting DLTs will be summarized for DLT evaluable subjects.  
Additional safety parameters including clinical laboratory test, ECG, and vital sign data 
may be summarized as data over time and/or changes from baseline over time.   
The proportion of responding subjects (defined as any of the following:  complete 
remission without mininum residual disease (CRMRD-), CR, CRi, morphologic 
leukemia-free state (MLFS), or partial remission (PR) per 2017 European LeukemiaNet 
(ELN) response criteria will be tabulated.  Duration of response will be presented per 
subject and Kaplan-Meier estimates may also be further presented if data allows.  For a 
full description of statistical analysis methods, please refer to Section 9.  Details of the 
statistical analysis will also be described in the statistical analysis plan. 
Statistical Hypotheses 
This is a phase 1 study and no formal statistical hypothesis will be tested. 
Sponsor Name:  Amgen Inc. 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 14 of 136 
CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
 
cIV = continuous intravenous; IV = intravenous 
 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
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Date:  04 May 2020 
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Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 16 of 136 
CONFIDENTIAL  
 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 17 of 136 
CONFIDENTIAL  
 
 
1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities for Cohort 1, Cycle 1 
CD = cluster of differentiation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = end of treatment; 
 PK = pharmacokinetic; SCR = screening; SFU = safety follow-up 
a If the investigator determines that the subject has derived treatment benefit, they may proceed to cycle 2 (Table 1-3).  If the subject does not proceed to receive 
additional treatment cycles, they will proceed to end of study assessment on day 107 (30 days after last dose of investigational product). 
 
SCR 
Treatment Period 
Infusion-free perioda 
Pembrolizum
ab 
monotherapy  
Cycles 2-35b 
EOT 
SFUc 
Cycle 1 Day: 
 
1 
2 3 4 8 15 22 29 36 43 50 57 64 71 
78 
79 80-84 
 
 
Hours 
 
Pre-dose 0.5 1 
2 3 4 6 8 12 16 20  
 
 
 
 
 
 
 
 
 
 
 
 
EOI 0.5 2 4 8 
 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationd 
 
X 
X X X X X X X X 
X X X X X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
=============================================================================================== 
Serious adverse events 
 
=============================================================================================== 
Adverse eventse 
 
 
 
===================================================================================== 
Clinical Evaluationf 
X 
X 
 
 
 
 
 
 
 
 
 
 X X X X X X X X 
X X X X X X 
 
 
 
 
 
 
X 
X 
X 
Vital signs, pulse oximetryg 
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 
12-lead ECGh 
X 
X 
X 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
LABORATORY ASSESSMENTS 
Highly sensitive pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulationj 
X 
X 
 
 
 
 
 
 X 
 
 
 X X X X X X X X 
X X X X X X 
 
 
 
 
 
 
X 
X 
X 
Hematology, Chemistryj 
X 
X 
 
 
 
 
 
 X 
 
 
 X X X X X X X X 
X X X X X X 
 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 X  X X X X X 
X X X X X X 
 
 
 
 
 
 
 
X 
X 
Hepatitis Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Testsl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Anti-AMG 330-antibodym 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
X X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Anti-Pembrolizumab-antibodym 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Xb 
 
 
GENERAL AND SAFETY ASSESSMENTS 
PK ASSESSMENTS 
AMG 330 PK Collectionn  
 
X 
 
 
 
 
 X  
 
 
 
 X X X X X X X 
X X X X X X 
X X X X X 
 
 
 
 
Pembrolizumab PK Collection (predose)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab PK Collection (post dose)p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENTS 
Bone marrow aspirate/biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Xr 
 
X 
 
 Xr  
X 
 
 
 
 
 
 
X q 
 
Xs 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 18 of 136 
CONFIDENTIAL  
 
 
b If AMG 330 is discontinued, pembrolizumab may be continued as a monotherapy until disease progression, administered every 21 days, for a maximum of 35 cycles 
(approximately 2 years). 
c Two safety follow-up visits should be performed:  30 days (+ 7 days) after the last dose of AMG 330 and 30 days (+ 7 days) after the last dose of pembrolizumab.  If 
the 2 safety follow-up periods overlap, the 2 safety follow-up visits can be combined into one.  
d Hospitalization will be required at the start of study day 1 and for a minimum of 72 hours following initiation of AMG 330, after each AMG 330 dose level increase and 
after each pembrolizumab administration.  
e Adverse events will be collected from start of AMG 330 infusion on study day 1. 
f Clinical evaluations will include physical exam, ECOG, and weight.  Screening only:  demographics, medical history, and height will also be obtained. 
g Vital signs will be obtained after start of AMG 330 infusion on study day 1 and after AMG 330 dose level increases.  Vital signs will also be assessed prior to subject`s 
discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
h Measurements to be taken in triplicate. 
i A highly sensitive (serum or urine) pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal. 
j Coagulation, hematology, and chemistry to be collected 8 hours after start of AMG 330 infusion on study day 1.  
k Hepatitis serologies include hepatitis B surface antigen (HBsAg) or quantifiable hepatitis B virus (HBV) viral load, hepatitis C antibody or RNA.  
l Thyroid function testing every 6 weeks while on treatment.  Thyroid panel should include:  triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), 
thyroid-stimulating hormone (TSH).  
m Anti-AMG 330 antibody and anti-pembrolizumab antibody samples will be collected at the indicated time points during the study, and on days when both AMG 330 
and pembrolizumab are to be administered, anti-AMG 330 antibody and anti-pembrolizumab antibody samples will be collected before administration of 
pembrolizumab and before administration of AMG 330 step-dose on that day at the indicated time points throughout the treatment period. 
p Pembrolizumab PK samples will be collected 30 minutes post infusion of pembrolizumab (on day 15, 36, 57, and 78). 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 19 of 136 
CONFIDENTIAL  
 
 
Table 1-2.  
 Collection Schedule for Cohort 1, Cycle 1 
AMG 330 dose level (cIV) 
AMG 330 days 
administered 
Pembrolizumab days 
administered (IV infusion) 
 µg/day 
D1-3 
  
 µg/day 
D4-7 
  
 µg/day 
D8-14, D15-21 
D15 
 µg/day 
D22-28 
  
 µg/day 
D29-35; D36-42 
D36 
 µg/day 
D43-49 
 
 µg/day 
D50-56; D57-63 
D57  
 µg/day 
D64-77 
  
 µg/day 
(infusion free period) 
D78-85 
D78 
 
cIV = continuous intravenous; CXDX = cycle X day X; D = day; EOI = end of infusion; HR = hour; IV = intravenous 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 20 of 136 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities for Cohort 1, Cycles 2 and beyond 
 
Treatment Period 
1 week infusion free interval a 
Pembrolizuma
b monotherapy  
Cycles 3-35b 
EOT 
SFU
c 
Cycle Day: 
1 
2 3 4 8 
1
5 
2
2 
2
9 
3
6 
4
3 
5
0 
57 
5
8 
59-
63 
 
 
 
Pre-
dose 
0.
5 
1 
2 
3 
4 
6 
8 
1
2 
1
6 
2
0 
 
 
 
 
 
 
 
 
 
 
EO
I 
0.
5 
2 
4 
8 
 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalizationd 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
=============================================================================================== 
Serious adverse events 
 
=============================================================================================== 
Adverse eventse 
 
=============================================================================================== 
Clinical Evaluationf 
X 
 
 
 
 
 
 
 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Vital signs, pulse oximetryg 
X 
 
X X X X X X X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
 
12-lead ECGh 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
LABORATORY ASSESSMENTS 
Highly sensitive pregnancy testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulationj 
X 
 
 
 
 
 
 
X 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology, Chemistryj 
X 
 
 
 
 
 
 
X 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Thyroid Function Testsk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Anti-AMG 330-antibodyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
 
X 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Xb 
 
 
GENERAL AND SAFETY ASSESSMENTS 
PK ASSESSMENTS 
AMG 330 PK Collectionm  
X 
 
 
 
 
 
X 
 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X X X X 
 
 
 
 
DISEASE ASSESSMENTS 
Bone marrow aspirate/biopsy 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Xn 
 
Xp 
CD = cluster of differentiation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = end of treatment; 
PK = pharmacokinetic; SFU = safety follow-up 
a If the investigator determines that the subject has derived treatment benefit, they may proceed to the next cycle (Table 1-3).  If the subject does not proceed to 
receive additional treatment cycles, they will proceed to end of study assessment on day 107 (30 days after last dose of investigational product). 
b If AMG 330 is discontinued, pembrolizumab may be continued as a monotherapy until disease progression, administered every 21 days, for a maximum of 35 cycles 
(approximately 2 years). 
c Two safety follow-up visits should be performed:  30 days (+ 7 days) after the last dose of AMG 330 and 30 days (+ 7 days) after the last dose of pembrolizumab.  If 
the 2 safety follow-up periods overlap, the 2 safety follow-up visits can be combined into one.  
d Hospitalization will be required at the start of study day 1 and for a minimum of 72 hours following initiation of AMG 330, after each AMG 330 dose level increase.  
e Adverse events will be collected from the start of AMG 330 infusion on study day 1. 
f Clinical evaluations will include physical exam, ECOG, and weight. 
g Vital signs will be obtained after start of AMG 330 infusion on study day 1 and after AMG 330 dose level increases.  Vital signs will also be assessed prior to subject`s 
discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
h Measurements to be taken in triplicate. 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 21 of 136 
CONFIDENTIAL  
 
 
i A highly sensitive (serum or urine) pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal. 
j Coagulation, hematology, and chemistry to be collected 8 hours after start of AMG 330 infusion on study day 1.  
k Thyroid function testing every 6 weeks while on treatment.  Thyroid panel should include:  triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), 
thyroid-stimulating hormone (TSH).  
l Anti-AMG 330 antibody samples will be collected at the indicated time points during the study, and on days when both AMG 330 and pembrolizumab are to be 
administered, anti-AMG 330 antibody samples will be collected before administration of pembrolizumab and before administration of AMG 330 step-dose on that day 
at the indicated time points throughout the treatment period. 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 22 of 136 
CONFIDENTIAL  
 
 
Table 1-4.  
 Collection Schedule for Cohort 1, Cycle 2 and beyond 
AMG 330 dose level (cIV) 
AMG 330 days 
administered 
Pembrolizumab days 
administered (IV infusion)  
 µg/day 
D1-3 
 
 µg/day 
D4-7 
 
 µg/day 
D8-14 
 
 µg/day 
D15-21 
D15 
 µg/day 
D22-28 
 
 µg/day 
D29-35 
 
 µg/day 
D36-42 
D36 
 µg/day 
D43-56  
 
 µg/day 
(infusion free period) 
D57-64  
D57 
cIV = continuous intravenous; CXDX = cycle X day X; D = day; HR = hour; IV = intravenous 
 
 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 23 of 136 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities for Cohort 2 (all cycles) 
 
SCR 
(C1 
only) 
 
Treatment Period 
1 week infusion free intervala 
Pembrolizumab 
monotherapy  
Cycles 2-35b 
EOT 
SFUc 
Cycle Day: 
 
 
1 
2 3 4 8 15 22 29 
36 
43 50 
57 
58 
59-63 
 
 
 
 
Pre-
dos
e 
0.
5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
 
 
 
 
 
 
 
 
 
 
EOI 
0.
5 
2 
4 
8 
 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
====================================================================================================== 
Serious adverse events 
 
====================================================================================================== 
Adverse eventse 
 
====================================================================================================== 
Clinical Evaluationf 
X 
X 
 
 
 
 
 
 
 
 
 
 
X X X X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Vital signs, pulse oximetryg 
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 
12-lead ECGh 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Highly sensitive pregnancy 
testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulationj 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X X X X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology, Chemistryj 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X X X X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Hepatitis Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Testsl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Anti-AMG 330-antibodym 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
Anti-pembrolizumab-
antibody (C1 only)m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL PRODUCT DOSING 
AMG 330 
 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Xq 
 
 
GENERAL AND SAFETY ASSESSMENTS 
PK ASSESSMENTS 
AMG 330 PK Collectionn  
 
X 
 
 
 
 
 
X 
 
 
 
 
X X X X 
X 
X 
X 
X 
X 
 
X 
X 
X X 
X 
X 
 
 
 
 
Pembrolizumab PK 
Collection (predose) (C1 
only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab PK 
Collection (post dose) (C1 
only)p 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 24 of 136 
CONFIDENTIAL  
 
 
 
SCR 
(C1 
only) 
 
Treatment Period 
1 week infusion free intervala 
Pembrolizumab 
monotherapy  
Cycles 2-35b 
EOT 
SFUc 
Cycle Day: 
 
 
1 
2 3 4 8 15 22 29 
36 
43 50 
57 
58 
59-63 
 
 
 
 
Pre-
dos
e 
0.
5 
1 
2 
3 
4 
6 
8 
12 
16 
20 
 
 
 
 
 
 
 
 
 
 
EOI 
0.
5 
2 
4 
8 
 
 
 
 
DISEASE ASSESSMENTS 
Bone marrow 
aspirate/biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Xq 
 
Xr 
CD = cluster of differentiation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = end of treatment; 
 PK = pharmacokinetic; SCR = screening; SFU = safety follow-up 
a If the investigator determines that the subject has derived treatment benefit, they may proceed to cycle 2 (Table 1-5).  If the subject does not proceed to receive 
additional treatment cycles, they will proceed to end of study assessment on day 107 (30 days after last dose of investigtational product). 
b If AMG 330 is discontinued, pembrolizumab may be continued as a monotherapy until disease progression, administered every 21 days, for a maximum of 35 cycles 
(approximately 2 years). 
c Two safety follow-up visits should be performed:  30 days (+ 7 days) after the last dose of AMG 330 and 30 days (+ 7 days) after the last dose of pembrolizumab.  If 
the 2 safety follow-up periods overlap, the 2 safety follow-up visits can be combined into one.  
d Hospitalization will be required at the start of study day 1 and for a minimum of 72 hours following initiation of AMG 330, after each AMG 330 dose level increase.  
e Adverse events will be collected from start of AMG 330 infusion on study day 1. 
f Clinical evaluations will include physical exam, ECOG, and weight.  Screening only:  demographics, medical history, and height will also be obtained. 
g Vital signs will be obtained at hour 1, 2, 3, 4, 6, 8, 12, 16, and 20 after start of AMG 330 infusion on study day 1 and after AMG 330 dose level increases.  Vital signs 
will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
h Measurements to be taken in triplicate. 
i A highly sensitive (serum or urine) pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal. 
j Coagulation, hematology, and chemistry to be collected 8 hours after start of AMG 330 infusion on study day 1.  
k Hepatitis serologies include hepatitis B surface antigen (HBsAg) or quantifiable hepatitis B virus (HBV) viral load, hepatitis C antibody or RNA.  
l Thyroid function testing every 6 weeks while on treatment.  Thyroid panel should include:  triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), 
thyroid-stimulating hormone (TSH).  
m Anti-AMG 330 antibody and anti-pembrolizumab antibody samples will be collected at the indicated time points during the study, and on days when both AMG 330 
and pembrolizumab are to be administered, anti-AMG 330 antibody and anti-pembrolizumab antibody samples will be collected before administration of 
pembrolizumab and before administration of AMG 330 step-dose on that day at the indicated time points throughout the treatment period.  Anti-pembrolizumab 
antibody samples are only collected during cycle 1. 
o Pembrolizumab PK samples will be collected pre-dose (within 24 hours) before each infusion of pembrolizumab on cycle 1 only. 
p Pembrolizumab PK samples will be collected 30 minutes post infusion of pembrolizumab on cycle 1 only.  
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 25 of 136 
CONFIDENTIAL  
 
 
Table 1-6.  
Collection Schedule for Cohort 2, All Cycles 
AMG 330 dose level 
(cIV) 
AMG 330 days 
administered 
Pembrolizumab days 
administered (IV infusion)  
 
Cycle 1 
Cycle 2-3 
 µg/day 
D1-3 
D1 
 µg/day 
D4-7 
  
 µg/day 
D8-14 
 µg/day 
D15-21 
  
 µg/day 
D22-28 
D22  
 µg/day 
D29-35 
 µg/day 
D36-42 
  
 µg/day 
D43-56  
D43  
 µg/day 
(infusion free period) 
D57-64 
 
 
cIV = continuous intravenous; CXDX = cycle X day X; D = day; EOI = end of infusion; HR = hour; IV = intravenous  
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab  
Protocol Number:  20170646 
Date:  04 May 2020 
Page 26 of 136 
CONFIDENTIAL  
 
 
Table 1-7.  Schedule of Activities for Each AMG 330 Dose Step of a Repeat Cycle (Any Cohort) 
Day (relative to dose step) 
1 
2e 
3e 
4e 
Hours 
prior to step 
relative to start of dose step 
0.5 
1 
2 
4 
6 
8 
12 
16 
20 
24 
48 
72 
GENERAL AND SAFETY ASSESSMENTS 
Hospitalization 
Xb 
Clinical evaluationa 
X 
  
  
  
  
  
  
  
  
  
X 
X 
X 
Vital signs, pulse oximetryc 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG triplicate measurement 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
LABORATORY ASSESSMENTS 
Coagulation 
X 
  
  
  
  
  
 X 
  
  
  
X 
X 
X 
Hematology, chemistry 
X 
  
  
  
  
  
 X 
  
  
  
X 
X 
X 
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
PK ASSESSMENTS 
AMG  330 PK collectiond 
Xe 
  
X 
X 
  
X 
X 
  
  
  
X  
X 
  
Pembrolizumab PK collection (C1 only) 
X 
 X 
 
 
 
 
 
 
 
 
 
 
  
C = cycle; CD = cluster of differentiation; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PK = pharmacokinetic 
a Clinical evaluations will include physical exam, ECOG, and weight. 
b Hospitalization after dose step will be for a minimum of 72 hours.   
c Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.   
 
Approved 
 
 


Product:  AMG 330 + Pembrolizumab 
Protocol Number:  20170646  
Date:  04 May 2020 
Page 27 of 136 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
Cluster of differentiation (CD)33 is a promising cell surface target for treatment of acute 
myeloid leukemia (AML), as it is expressed on the cell surface of more than 90% of 
leukemia isolates from patients with AML with a very high average antigen density 
(Krupka et al, 2014).  CD33 was also found cell surface of virtually all AML patient 
samples (Krupka et al, 2014) and CD33 expression is restricted to the hematopoietic 
system (La Russa et al, 1992; Andrews et al, 1989; Andrews et al, 1986).  AMG 330 is a 
bispecific T-cell engager (BiTE®) construct that binds both CD33 and CD3, and redirects 
T cells toward CD33+ cells.  With the induced proximity, AMG 330 mediates T-cell 
cytotoxicity against AML blasts.  Anti-AML activity of AMG 330 and other CD33/CD3 
BiTE molecules has been previously reported (Westervelt et al, 2018; Ravandi et al, 
2018).  Recent assessment of preliminary efficacy demonstrated that 5 (10%) out 
50 treated patients experienced complete remission (CR)/CR with incomplete recovery 
(CRi), while approximately 50% of treated patients experienced only a transient 
decrease in the number of AML blasts in bone marrow.  This finding is in line with the 
current view that in AML, tumor-reactive T cell responses can be strongly impeded by 
various immune resistance including up-regulation of inhibitory checkpoints such as 
programmed cell death 1 (PD-1) receptor (Alfayez and Borthakur, 2018; Hobo et al, 
2018).  Indeed, pre-clinical findings demonstrate that the response to AMG 330 
monotherapy may be suboptimal due to engagement of resistance mechanisms 
including up-regulation of PD-1 on T cells (Krupka et al, 2016).  Current experience with 
AMG 330 shows upregulation of PD-1 expression in treated subjects with relapsed or 
refractory (R/R) AML (Amgen, data on file) providing a rationale for combining AMG 330 
with PD-1 blockers to overcome the resistance.  PD-1 expression on CD4+ and CD8+ 
lymphocytes appears to be AMG 330 dose-dependent and trends higher in 
non-responders (Amgen, data on file).  Pembrolizumab is a humanized immunoglobulin 
G4 (IgG4) monoclonal antibody with high specificity and potency of binding the PD-1 
receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2) and is indicated for the treatment of patients 
across a number of indications.  However, PD-1 inhibition demonstrated limited single 
agent efficacy in paients with R/R AML suggesting a need for rationally designed 
combinations of PD-1 inhibitors with other immuno-oncology therapies aiming to improve 
T cell mediated cytotoxicity and surveillance (Boddu et al, 2017).  
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This study is will assess the safety and tolerability of the combination of AMG 330 with 
pembrolizumab and whether the inhibition of the PD-1/PD-L1 pathway by 
pembrolizumab will enhance the anti-AML activity of AMG 330.  In cohort 1, subjects will 
be treated first with AMG 330 and then pembrolizumab will be subsequently 
administered to block PD-1 that became up-regulated in response to AMG 330.  In 
cohort 2, pembrolizumab will be administered immediately prior to AMG 330 
administration to block PD-1 that is expressed at baseline and any PD-1 up-regulated in 
response to AMG 330. 
2.2 
Background 
2.2.1 
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 2014, an estimated 18 860 new cases of 
AML were expected in the US with approximately 10 460 deaths from this disease 
(American Cancer Society, 2014). 
Outcomes for most patients with AML remain poor (Burnett et al, 2011).  In particular, 
relapsed disease is associated with unsatisfactory outcomes in the majority of patients 
(Ravandi, 2013).  Although the majority of patients with AML initially achieve CR, over 
60% will eventually relapse after a variable period of remission.  Using the traditional 
cytotoxic chemotherapy regimens, the likelihood of achieving a second CR is low 
especially if the first CR was short in duration, particularly if less than 1 year (Estey et al, 
1996).   
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 90% of leukemia 
isolates from patients with AML with a very high average antigen density (Krupka et al, 
2014; Tanimoto et al, 1989; Scheinberg et al, 1989).  It is not expressed on tissues other 
than the hematopoietic system. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) 
and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to 
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negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2) (Greenwald et al, 2005; Okazaki et al, 2001).  Therapeutic studies in 
mouse models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment 
modalities (Spranger et al, 2014; Curran et al, 2010; Pilon-Thomas et al, 2010; 
Weber, 2010; Hirano et al, 2005; Blank et al, 2004; Strome et al, 2003).  Anti-mouse 
PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses in 
models of squamous cell carcinoma, pancreatic carcinoma, melanoma, AML and 
colorectal carcinoma (Curran et al, 2010; Pilon-Thomas et al, 2010; Zhang et al, 2009; 
Nomi et al, 2007; Strome et al, 2003).  In such studies, tumor infiltration by CD8+ T cells 
and increased interferon (IFN)-gamma, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD-1 
checkpoint inhibition involved local infiltration and activation of effector T cell function in 
vivo (Curran et al, 2010).  Experiments have confirmed the in vivo efficacy of anti-mouse 
PD-1 antibody as a monotherapy, as well as in combination with chemotherapy, in 
syngeneic mouse tumor models (see the Investigator’s Brochure ). 
2.2.2 
Amgen Investigational Product Background:  AMG 330 
BiTEs® 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.   
AMG 330, targeting the surface antigen CD33, is a novel BiTE® which is being 
developed with the intent to treat patients with AML.  Other CD33 expressing myeloid 
diseases, myelodysplastic syndrome and chronic myeloid leukemia, may be evaluated 
later in clinical development.   
AMG 330 is currently being evaluated in the ongoing phase 1 dose escalation study in 
subjects with R/R AML (NCT02520427).  One of the most frequent adverse events 
observed during the dose escalation study is cytokine release syndrome (CRS).  An 
onset of grade 3 CRS during dose escalation led to an introduction of dose steps 
resulting in ameliorating frequency and severity of CRS.  Subsequently, maximum 
tolerated dose (MTD) in the ongoing first-in-human phase 1a dose escalation study has 
not been reached.  A detailed description of the chemistry, pharmacology, safety and 
efficacy of AMG 330 is provided in the Investigator’s Brochure. 
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2.2.2.1 
Nonclinical Pharmacology:  AMG 330 
In vitro Pharmacology: 
AMG 330 is a highly potent molecule selectively mediating redirected lysis of 
CD33+ cells, while viability of target-negative cells remains unaltered.  The cytotoxic 
effect of AMG 330 is time- and dose-dependent, with mean concentrations inducing 
half-maximal target cell lysis ranging from 24 to 200 pg/mL (0.4 to 3.7 pM) with human 
effector cells. 
In the presence of target cells, AMG 330 induced a polyclonal activation of T cells, which 
resulted in an up-regulation of the T cell activation markers CD25 and CD69, induction of 
granzyme B and perforin synthesis, T cell proliferation and release of cytokines like 
interferon-, tumor necrosis factor (TNF), interleukin (IL)-2, IL-10 and IL-6. 
In primary AML samples AMG 330 induced an expansion of residual autologous memory 
T cells and an efficient elimination of AML blasts even at low effector cell:  target cell 
ratios. 
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 330-mediated redirected lysis of target cells and concomitant upregulation of 
CD25. 
In vivo Pharmacology 
Antitumor activity of AMG 330 was evaluated in AML xenograft models. 
Intravenous treatment of non-obese diabetic/severe combined immunodeficiency 
disease (NOD/SCID) mice bearing subcutaneous EOL-1 tumors with AMG 330 
(1, 10, and 100 µg/kg/day) resulted in a statistically significant and dose-dependent 
tumor growth delay. 
In an orthotopic AML model NOD/SCID mice were intravenously injected with 
MOLM-13 tumor cells.  Administration of AMG 330 (2, 20, and 200 µg/kg/day) resulted in 
a significant prolonged survival even at a dose of 2 µg/kg/day AMG 330.  In animals 
which survived until study termination on day 111, no CD33-positive target cells were 
detectable in blood, spleen and bone marrow.   
2.2.2.2 
Nonclinical Pharmacokinetics:  AMG 330 
After single intravenous (IV) administration, AMG 330 clearance (CL) was higher in 
mouse (53.5 mL/hour/kg) than in monkey (32 mL/hour/kg).  The mean terminal half-life 
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(T1/2,z) of AMG 330 after a single IV bolus in mouse and 7 or 28 days of subcutaneous 
dosing in monkey was similar between these 2 species (4 to 8 hours); after 28 days of 
continuous intravenous (cIV) dosing t1/2,z of AMG 330 was 1.6 to 2.7 hours.  The 
bioavailability of AMG 330 after subcutaneous dosing was 22% and ~40% in mouse and 
monkey, respectively.  Dose proportionality was observed for exposure in both species 
after a single IV bolus injection in mouse and 7 days of cIV dosing in monkey; loss of 
exposure was observed after 28 days of cIV dosing due to the formation of anti-drug 
antibodies.   
2.2.2.3 
Nonclinical Toxicology:  AMG 330 
The potential toxicity of AMG 330 was evaluated in a Good Laboratory Practice 
(GLP)-compliant 28-day cynomolgus monkey toxicology study.  AMG 330 was 
administered daily by cIV at 0, 3, 10, or 30 µg/kg or subcutaneously (SC) at 25 µg/kg.  
Two 30 µg/kg-cIV females were euthanized on days 10 and 11 due to infections along 
the catheter port tract and/or at the skin contact points of the infusion jacket.  The 
infections were considered secondary to AMG 330-related decreases in mature myeloid 
cells in the bone marrow and in circulating leukocytes.  Other AMG 330-related findings 
were consistent with its expected pharmacology and included decreased leukocytes, 
which correlated with decreased T-lymphocytes, along with expected increased 
activated T-lymphocytes, and increased cytokine levels in all dose groups.  Some 
animals at 30 µg/kg cIV and 25 µg/kg SC had clinical signs associated with 
inflammation/infection at the dose administration site that resolved after topical 
antimicrobial application and were able to complete the intended 28-day dose 
administration.  In animals that survived to scheduled termination, there were no 
AMG 330-related macroscopic, organ weight or light microscopic changes.  The 
changes observed in this study were consistent with the expected pharmacology of 
AMG 330.  The highest non-severely toxic dose (HNSTD) was considered to be 
10 µg/kg/day cIV and 25 µg/kg/day SC. 
No combination toxicology studies have been conducted with AMG 330 and 
pembrolizumab. 
2.2.3 
Non-Amgen Investigational Product Background:  Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high specificity of 
binding to the PD-1, thus inhibiting its interaction with PD-L1 and PD-L2.  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
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clinical development as an IV immunotherapy for advanced malignancies.  Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the Investigator’s Brochure. 
Refer to the Investigator’s Brochure/approved labeling for detailed background 
information on pembrolizumab. 
Therapeutic studies of pembrolizumab in mouse models have shown that administration 
of antibodies blocking PD-1/PD-L1 interaction enhances infiltration of tumor-specific 
CD8+ T cells and ultimately leads to tumor rejection, either as a monotherapy or in 
combination with other treatment modalities (Spranger et al, 2014; Curran et al, 2010; 
Pilon-Thomas et al, 2010; Weber, 2010; Hirano et al, 2005; Blank et al, 2004; Strome et 
al, 2003).  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, AML and colorectal carcinoma (Curran et al, 2010; Pilon-Thomas et al, 2010; 
Nomi et al, 2007; Zhang et al, 2004; Strome et al, 2003).  In such studies, tumor 
infiltration by CD8+ T-cells and increased IFN-gamma, granzyme B and perforin 
expression were observed, indicating that the mechanism underlying the antitumor 
activity of PD-1 checkpoint inhibition involved local infiltration and activation of effector 
T cell function in vivo (Curran et al, 2010).  Experiments have confirmed the in vivo 
efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination with 
chemotherapy, in syngeneic mouse tumor models (see the pembrolizumab Investigator’s 
Brochure). 
The importance of intact immune surveillance function in controlling outgrowth of 
neoplastic transformations has been known for decades (Disis et al, 2010).  
Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in 
cancer tissue and favorable prognosis in various malignancies.  In particular, the 
presence of CD8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory 
T cells (T-regs) correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma (Hunder et al, 2008; Dudley et al, 2005). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
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responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic CTLA-4 that has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2) (Greenwald et al, 2005; Okazaki et al, 2001).  The structure of murine 
PD-1 has been resolved (Zhang et al, 2004). 
PD-1 and its family members are type I transmembrane glycoproteins containing an Ig 
variable-type (IgV-type) domain responsible for ligand binding and a cytoplasmic tail 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, and an immunoreceptor tyrosine-based switch motif.  
Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to 
the dephosphorylation of effector molecules, such as CD3 zeta (CD3ζ), protein kinase 
C-theta (PKCθ) and zeta-chain-associated protein kinase (ZAP)70, which are involved in 
the CD3 T cell signaling cascade (Riley, 2009; Chemnitz et al, 2004; Sheppard et al, 
2004; Okazaki, et al, 2001).  The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from that of CTLA-4 because both molecules regulate 
an overlapping set of signaling proteins (Francisco et al, 2010; Parry et al, 2005).  As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention 
in cancer. 
2.3 
Benefit/Risk Assessment 
As of 17 June 2019, 49 patients have received AMG 330 in the ongoing first in human 
study.  Based on the mode of action targeting CD33 which is expressed on myeloid 
cells, myelosuppression and particularly neutropenia is expected.  In addition, infections 
may be observed based on the myelosuppressive effect.  Neutropenia and infections are 
conditions that are not unexpected in the setting of AML given the nature of this bone 
marrow disease. 
Cytokine release syndrome (CRS) is an identified risk for AMG 330 and respective signs 
and symptoms were observed in 67% of subjects treated in the study so far. 
Checkpoint inhibition may potentially increase the risk for increased frequency and 
severity of CRS.  This risk is mitigated by the requirement for the administration of 
dexamethasone prior to each step dose of AMG 330.  In addition, in cycle 1 of cohort 1, 
pembrolizumab is introduced 7 days following the step dose of AMG 330 which may 
reduce the likelihood or severity of CRS.  Lastly, treatment with both dexamethasone 
and tocilizumab will be available for the treatment of clinically significant CRS. 
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Pembrolizumab has an acceptable clinical safety profile, is indicated for the treatment of 
patients across a number of malignancies and is in clinical development as an IV 
immunotherapy for additional advanced tumors.  In patients with a history of allogeneic 
hematopoietic stem cell transplantation (HSCT), acute Graft versus Host Disease 
(GVHD), including fatal GVHD, has been reported after treatment with pembrolizumab.  
Based on the benefit of pembrolizumab treatment vs the risk of GVHD assessment, 
subjects undergone allogenic HSCT within 5 years prior to the study will be excluded. 
One of the most frequent adverse events observed during the phase 1a AMG 330 dose 
escalation study is CRS associated with a release of several potent cytokines including 
pro-inflammatory IL-6 (Amgen, data on file).  Up-regulation of PD-1 expression is a 
natural pathway employed by immune system to control the inflammation (de la Fuente, 
2012), and there is a risk that blocking PD-1 may potentially interfere with the 
endogenous protective mechanisms and further aggravate the inflammatory cascade 
leading to higher grades of CRS in subjects treated with the combination regimen.  Thus, 
PD-1/PD-L1 axis may play a dual role:  protect from inflammation and to enable the 
resistance mechanisms.  To mitigate this risk associated with inflammation, the following 
strategy will be used:  administration of dexamethasone prior to each step dose of 
AMG 330, small step doses to reduce T cell challenge and 7-day duration of each step 
dose to allow prompt mitigation of potential inflammatory reactions.  The potential benefit 
is to disable the resistance mechanisms to allow improved efficacy.   
There is limited potential for other overlapping toxicities because more adverse events 
associated with pembrolizumab occur later during the treatment whereas AMG 330 
related toxicities are acute and observed shortly after dose increase.  
The above benefit risk assessment supports the conduct of this clinical study.  See the 
AMG 330 Investigator’s Brochure for further data on AMG 330 and Prescribing 
Information and the pembrolizumab Investigator’s Brochure for further data on 
pembrolizumab. 
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 330 administered in 
combination with pembrolizumab in 
subjects with relapsed or refractory 
acute myeloid leukemia (R/R AML) 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent adverse events 
(TEAEs), treatment-related adverse events 
(TRAEs), and changes in vital signs, 
electrocardiograms (ECGs), and clinical 
laboratory tests 
Secondary 
 
Evaluate the anti-leukemia activity of 
AMG 330 administered in 
combination with pembrolizumab in 
R/R AML patients 
 
Responses to treatment with AMG 330 
administered in combination with 
pembrolizumab.  Response is defined as any 
of the following:  complete remission without 
mininum residual disease (CRMRD-), complete 
remission (CR), CR with incomplete recovery 
(CRi), or morphological leukemia-free state 
(MLFS), or partial remission (all according to 
the 2017 European LeukemiaNet (ELN) 
criteria (Döhner et al, 2017). 
 
Duration of response 
 
Evaluate the pharmacokinetics (PK) 
of AMG 330 when AMG 330 and 
pembrolizumab are administered in 
combination 
 
Descriptive statistics of AMG 330 
concentrations and PK parameters. 
 
Evaluate the immunogenicity of 
AMG 330 when administered in 
combination with pembrolizumab 
 
Incidence of anti-AMG 330 antibody formation 
 
 
Exploratory 
 
Evaluate the pharmacokinetics (PK) 
of pembrolizumab when AMG 330 
and pembrolizumab are administered 
in combination 
 
Descriptive statistics of pembrolizumab 
concentrations. 
 
Evaluate the immunogenicity of 
pembrolizumab when AMG 330 and 
pembrolizumab are administered in 
combination 
 
Incidence of anti-pembrolizumab antibody 
formation  
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 
Evaluate the relationship between 
AMG 330 and pembrolizumab 
exposure and response to treatment 
 
Correlate the serum levels AMG 330 and 
pembrolizumab with changes in tumor burden 
(exposure/efficacy) and with adverse event 
incidence (exposure/safety) 
 
 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 1b study assessing safety, tolerability, PK, pharmacodynamics, and 
efficacy of AMG 330 administered as cIV infusion in combination with pembrolizumab in 
adult subjects with R/R AML. 
The study is a non-randomized study and will consist of 2 sequential dosing cohorts.  
Both cohorts will include AMG 330 and pembrolizumab with the difference being the 
initiation date for pembrolizumab treatment. 
This study will use a staggered enrollment approach.  Subject enrollment will start with 
cohort 1 (Section 4.1.1).  The first subject dosed in cohort 1 will serve as the sentinel 
subject.  Subsequent subjects dosed in cohort 1 will start AMG 330 (
 µg/day) 
administration once sentinel subject has cleared the study day 21 dose (AMG 330 
monotherapy at 
 µg/day).  Per sponsor determination, if the sentinel subject does not 
experience a dose-limiting toxicity (DLT) on days 15 to 21 after pembrolizumab is 
administered, the other subjects in cohort 1 will be allowed to continue the planned 
treatment schedule.  If the sentinel subject experiences a DLT during days 15 to 21, the 
dose level review team (DLRT) will discuss the case and the decision will be made by 
the sponsor based on clinical assessments of the adverse event and potential decisions 
by the sponsor may include stopping AMG 330 and/or pembrolizumab, dose 
de-escalation of AMG 330, or continuing therapy at full dose.  Investigators and sponsor 
will meet after all subjects in cohort 1 have completed study day 28 (ie, AMG 330 
 µg/day dose level in combination with pembrolizumab) to assess the safety profile.  
If pre-specified safety criteria are met (≤ 3 out of 10 treated subjects in cohort 1 
experienced DLT by day 28), subjects enrolled in cohort 2 (Section 4.1.2) may proceed 
with the treatment schedule.  Similar to cohort 1, the first subject dosed in cohort 2 will 
serve as the sentinel subject.  Per sponsor determination, if the sentinel subject does not 
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experience a DLT during the first 7 days, the other subjects in cohort 2 will be allowed to 
continue the planned treatment schedule. 
Safety data will be continuously monitored throughout the whole treatment period.  
Sponsor in consultation with investigators may reconvene to make appropriate safety 
measures and adjustments as needed. 
Subjects in both cohort 1 and cohort 2 may continue with cycle 2 and beyond of 
AMG 330 and pembrolizumab up to 6 months if the combination regimen remains 
tolerable and is deriving clinical benefit in the opinion of the investigator.  In both 
cohorts 1 and 2, subjects continuing with cycle 2 and beyond may be permitted to 
shorten the duration of AMG 330 step dose levels to 2 to 5 days based on individual 
clinical experience from cycle 1 and based on the clinical judgement of the investigator 
and in consultation and agreement with the sponsor.  The duration of the combination 
treatment period for individual subjects may be extended up to 1 year if the subject is 
deriving clinical benefit in the opinion of the investigator and in consultation with the 
sponsor.  If AMG 330 is discontinued, pembrolizumab may be continued as a 
monotherapy until disease progression for a maximum of 35 cycles (approximately 
2 years).  If pembrolizumab is discontinued, AMG 330 may be continued as a 
monotherapy. 
4.1.1 
Cohort 1 Design 
Cycle 1 is 77 days in duration and subsequent cycles are 57 days.  Treatment will start 
with AMG 330 on day 1.  Dexamethasone 8 mg will be given to subjects 1 hour prior to 
each step dose of AMG 330.  AMG 330 will be administered at a starting dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 7 days.  
If the subject experiences DLT during these first 7 days of treatment with AMG 330 at 
 µg/day, this subject will be replaced.  If the subject has not experienced a DLT by 
day 14, they will receive pembrolizumab on day 15.  Pembrolizumab will be administered 
at a dose of 200 mg (Q3W) by a 30-minute IV infusion.  The subject will remain at an 
AMG 330 dose level of 
 µg/day for additional 7 days. 
Thereafter, AMG 330 dosing will continue as per Table 4-1, increasing dose levels to 
 µg/day for 7 days followed by 
 µg/day for 7 days.  If the subject has not 
experienced a DLT at the 
 µg/day dose level of AMG 330 between days 29 to 35, 
they will receive pembrolizumab on day 36 and remain on the AMG 330 
 µg/day 
dose for an additional 7 days.  AMG 330 dosing will further increase to 
 µg/day for 
7 days followed by 
 µg/day for 7 days.  If the subject has not experienced a DLT at 
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the 
 µg/day dose level of AMG 330 between days 
 to 
, they will receive 
pembrolizumab on day 57 and remain on the 
 µg/day dose for additional 7 days.  To 
complete cycle 1, a final dose level increase to 
 µg/day AMG 330 for an additional 
14 days will be administered. 
Cycle 1 will be followed by a 1-week interval without AMG 330 administration and 
administration of pembrolizumab will continue non-interrupted on the Q3W schedule.  
The AMG 330-infusion free interval may be extended up to 4 weeks (depending on 
safety, treatment response, and in case of prolonged marrow aplasia and cytopenia in 
aleukemic subjects) after consultation with the sponsor. 
Table 4-1.  Dosing for Cohort 1 (Cycle 1) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
 
D4-7 
 
D8-14, D15-21 
D15 
D22-28 
 
D29-35; D36-42 
D36 
D43-49 
 
D50-56; D57-63 
D57 
D64-77 
 
(infusion-free period) 
D78-85 
D78 
cIV = continuous intravenous; D = day; IV = intravenous 
Cycle 2 will start with the initiation of AMG 330 administration and include the same step 
dose levels and duration as in cycle 1 with the exception of the 
 and 
 µg/day 
dose levels, which will be shortened from 14 days to 7 days (Table 4-2).  The duration of 
AMG 330 step dose levels in cycle 2 and beyond can be shortened to 2 to 5 days if a 
subject tolerated the investigational product in cycle 1 and based on the discussion and 
agreement between the investigator and the sponsor.  All subsequent cycles will be 
conducted similarly to cycle 2. 
On days when pembrolizumab administration and an AMG 330 dose level increase will 
occur, the subject will receive dexamethasone 8 mg at the conclusion of the 
pembrolizumab infusion.  Dexamethasone will be given 1 hour prior to increasing the 
AMG 330 dose.  If the subject does not develop a ≥ grade 2 infusion reaction, or if the 
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infusion reaction is reversible after the 1-hour observation period, AMG 330 may be 
increased to the next dose level, as shown in Table 4-2. 
Table 4-2.  Dosing for Cohort 1 (Cycle 2 and Beyond) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
 
D4-7 
 
D8-14 
 
D15-21 
D15 
D22-28 
 
D29-35 
 
D36-42 
D36 
D43-56 
 
(infusio
period) 
D57-64 
D57 
cIV = continuous intravenous; D = day; IV = intravenous 
4.1.2 
Cohort 2 Design 
Subjects in cohort 2 will receive both AMG 330 and pembrolizumab on day 1.  All cycles 
are 57 days in duration.  Pembrolizumab will be administered at a dose of 200 mg 
(Q3W) by a 30-minute IV infusion.  The subject will then receive dexamethasone 8 mg.  
Dexamethasone will be given 1 hour prior to each step dose of AMG 330.  If the subject 
does not develop a ≥ grade 2 infusion reaction, or if the infusion reaction is reversible 
after the 1-hour observation period, the subject will start AMG 330 at a starting dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 7 days, 
and continue dosing as per Table 4-3, increasing dose levels every 7 days up to 
 µg/day as tolerated by subjects.  Pembrolizumab will be administered at 200 mg IV 
once every 3 weeks.  Subjects will continue 
 µg/day of AMG 330 and pembrolizumab 
for 14 days.  Cycle 1 will be followed by a 1-week interval without AMG 330 
administration, and administration of pembrolizumab will continue non-interrupted on 
Q3W schedule.  The AMG 330-infusion free interval may be extended up to 4 weeks 
(depending on safety, treatment response, and in case of prolonged marrow aplasia and 
cytopenia in aleukemic subjects) after consultation with the sponsor.  Cycle 2 and all 
subsequent cycles will start with the initiation of AMG 330 administration and include the 
same step dose levels and duration as in cycle 1.  The duration of AMG 330 step dose 
levels in cycle 2 and beyond can be shortened to 2 to 5 days if a subject tolerated the 
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investigational product in cycle 1 and based on the discussion and agreement between 
the investigator and the sponsor. 
Table 4-3.  Dosing for Cohort 2 (All Cycles) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
D1 
D4-7 
 
D8-14 
 
D15-21 
 
D22-28 
D22  
D29-35 
 
D36-42 
 
D43-56 
D43 
(infusion-free period) 
D57-64 
 
cIV = continuous intravenous; D = day; IV = intravenous 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
It is anticipated that approximately 20 subjects will be enrolled in the study, with at least 
6 DLT evaluable subjects in each cohort.  With 6 evaluable subjects in 1 cohort, there is 
an 82% chance of observing at least 1 DLT if the true DLT rate is 25%.  For cohort 1, at 
least 10 subjects will be dosed through study day 28. 
Participants in this clinical investigation shall be referred to as “subjects”.  For the 
sample size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Ineligible subjects (ie, subjects who were exposed to AMG 330 or pembrolizumab, but 
post hoc were found to be ineligible) may be replaced.  Subjects who do not meet the 
DLT evaluable criteria (see Section 6.2.1) may be replaced until at least 6 subjects 
become DLT evaluable in each cohort or at least 10 subjects in cohort 1 have been 
dosed through study day 28.  If a sentinel subject in cohort 1 experiences a DLT at 
 µg/day, 
 µg/day or 
 µg/day of AMG 330 during the first 14 days of monotherapy 
treatment in cycle 1, this subject will be defined as DLT evaluable and will not proceed 
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with the combination regimen.  The sentinel role will be re-assigned to the next available 
subject. 
4.2.2 
Number of Sites 
Approximately 5 investigative sites in the United States will be included in the study.  
Sites that do not enroll subjects within 6 months of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
Justification for AMG 330 Dose 
The planned dosing schedule for AMG 330 will evaluate doses that have been tested in 
the ongoing first-in-human study (Amgen Study 20120252) in subjects with R/R AML.  
Planned dose levels for step dose escalation will be as follows:  
 
 and 
 µg/day.  The rationale for selecting these dose levels for the 
combination study includes following findings generated during the phase 1 dose 
escalation study:  each of the proposed doses has been tested as a monotherapy and 
deemed safe and tolerable, and proposed dose levels include efficacious doses (CR/CRi 
have been reported at 
 and 
 µg dose levels). 
As of 17 June 2019, treatment-emergent adverse events (TEAEs) were reported for 
47 (95.9%) of 49 subjects.  Forty subjects (81.6%) had grade ≥ 3 adverse events, 
33 subjects (67.3%) had serious adverse events, and 2 subjects (4.1%) had fatal 
adverse events.  Six subjects (12.2%) had adverse events that led to discontinuation of 
AMG 330.  Dose-limiting toxicities (DLTs) were reported for 6 subjects.  The most 
frequently reported adverse event by preferred term was CRS (31 subjects, 63.3%).  
Adverse events considered by the investigator to be related to AMG 330 were reported 
for 43 subjects (87.8%), the most frequently reported treatment-related adverse events 
(subject incidence ≥ 20%) were CRS (63.3%), rash (30.6%), febrile neutropenia (22.4%), 
and nausea (20.4%). 
CRS mitigation approach developed for AMG 330 and implemented into the ongoing first 
in human study allows resolution of CRS within 7 days.  Thus, the duration of each step 
dose is defined as at least 7 days to allow monitoring the frequency, severity and 
resolution dynamics of CRS in subjects treated with the combination regimen.  An 
exception is given for first 2 lower doses (
 µg/day and 
 µg/day), duration for which 
will be 3 and 4 days respectively, since the occurrence of CRS is rare at these doses 
due to the current CRS mitigation approach (ie, premedication with dexamethasone 
8 mg 1 hour prior to each step dose of AMG 330). 
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As of the 17 June 2019 data snapshot date, 5 of 39 evaluable subjects had a response.  
One subject (cohort 11 [
 µg/day]) achieved CR, 3 subjects (1 each in cohort 8 
[
 µg/day], cohort 9 [
 µg/day], and cohort 12 [
 µg/day]) achieved 
CRi, and 1 subject (cohort 2 [
 µg/day]) achieved morphologic leukemia-free state 
(MLFS).  The objective response rate based on subjects who achieved either a CR, CRi, 
CR with partial hematologic recovery (CRh), partial remission (PR), or MLFS was 12.8% 
(80% CI:  6.4%, 22.5%).  Two additional subjects in cohort 15 (
 µg/day) 
achieved CR (1 subject) and CRi (1 subject) after the data snapshot date of 
17 June 2019. 
Refer to the AMG 330 Investigational Brochure for further information. 
Justification for Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  
Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type.  As outlined below, this dose is justified by: 
 
Clinical data from 8 randomized studies demonstrating flat dose and 
exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks 
(Q2W),  
 
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
 
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically-based PK analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer, covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and 
different treatment settings (monotherapy and in combination with chemotherapy).  Five 
studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 
Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2, and KN006).  All of these studies 
demonstrated flat dose and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied.  
Subsequently, flat dose and exposure-response relationships were also observed in 
other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
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classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type.  These findings are consistent with the mechanism of 
action of pembrolizumab, which acts by interaction with immune cells, and not via direct 
binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, 
PK data in KN001 evaluating target-mediated drug disposition conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 
200 mg Q3W.  Second, a physiologically-based PK analysis was conducted to predict 
tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression.  
This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the 
fixed-dosing provides similar control of PK variability as weight-based dosing, with 
considerable overlap in the distribution of exposures from the 200 mg Q3W fixed dose 
and 2 mg/kg Q3W dose.  Supported by these PK characteristics and given that 
fixed-dose has advantages of reduced dosing complexity and reduced potential of 
dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation across all 
pembrolizumab protocols. 
4.3.1 
Justification for Non-investigational Product Dose 
Not applicable 
4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
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 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
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subject last visit), following any additional parts in the study (eg, long-term follow-up, 
additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
The expected study duration for subjects will be approximately 121 days, including up to 
14 days for screening activities, 77 (cohort 1) or 56 (cohort 2) days for treatment with 
AMG 330 in combination with pembrolizumab, and 30 days for safety follow-up.  
Subjects in both cohort 1 and cohort 2 may continue to repeat cycles of AMG 330 and 
pembrolizumab up to 6 months if the dose of the combination regimen remains tolerable 
and the subject is deriving benefit in the opinion of the investigator.  The duration of the 
combination treatment period for individual subjects may be extended up to 1 year if the 
subject is deriving benefit in the opinion of the investigator and after consultation with 
sponsor.  If AMG 330 is discontinued, pembrolizumab may be continued as a 
monotherapy until disease progression for a maximum of 35 cycles (approximately 
2 years).  If either study drug is discontinued, the other may be continued as a 
monotherapy. 
4.5 
Patient Input on Study Design 
Not applicable 
5. 
Study Population 
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). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Age ≥ 18 years on day of signing informed consent. 
103 
AML as defined by the WHO Classification (Section 11.10) persisting or recurring 
following 1 or more treatment courses.  Exception:  promyelocytic leukemia 
(APML) is excluded from the study. 
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104 
More than 5% blasts in bone marrow. 
105 
Eastern Cooperative Oncology Group (ECOG, Section 11.9) Performance Status 
of ≤ 1. 
106 
Have adequate organ function as defined in Table 5-1.  Specimens must be 
collected within 14 days prior to study day 1. 
Table 5-1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Renal 
Measured or calculateda creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≥ 30 mL/min for participant with creatinine 
levels > 1.5 x institutional ULN 
Hepatic 
Total bilirubin 
≤ 1.5 xULN OR direct bilirubin ≤ ULN for 
participants with total bilirubin levels 
> 1.5 x ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 x ULN  
Coagulation 
International normalized ratio (INR) 
OR prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤ 1.5 x ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR = glomerular filtration rate; ULN = upper limit of normal. 
a Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note:  This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and guidelines 
for the administration of specific chemotherapies. 
107 
A male participant must agree to use contraception during the treatment period 
and for at least 120 days after receiving the last dose of study drug (AMG 330 or 
pembrolizumab). 
- 
Acceptable methods of highly effective birth control include sexual 
abstinence; vasectomy; or a condom with spermicide (men) in combination 
with hormonal birth control or intrauterine device (IUD) (women). 
- 
Males will not be allowed to donate sperm during this period.  
108 
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) 
- 
A WOCBP who agrees to follow contraceptive guidance during the treatment 
period and for at least 120 days after the last dose of study treatment 
(AMG 330 or pembrolizumab) 
- 
Acceptable methods of highly effective birth control include sexual 
abstinence; bilateral tubal ligation/occlusion; or a condom with spermicide 
(men) in combination with hormonal birth control or IUD (women). 
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5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Active extramedullary AML in the central nervous system (CNS). 
Other Medical Conditions 
202 
Prior malignancy (other than in situ cancer) unless treated with curative intent and 
without evidence of disease for > 2 years before screening. 
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that 
have undergone potentially curative therapy are not excluded. 
203 
History or evidence of significant cardiovascular risk including any of the following:  
symptomatic congestive heart failure, unstable angina, clinically significant 
arrhythmias (eg, ventricular fibrillation, ventricular tachycardia etc.), recent 
coronary angioplasty, intra-cardiac defibrillators or any clinically relevant 
concurrent disorder that may pose a risk to subject safety or interfere with study 
evaluation, procedures, or completion. 
204 
History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
12 months. 
205 
Active infection requiring IV antibiotics within 1 week of study enrollment (day 1). 
206 
Known positive test for human immunodeficiency virus (HIV). 
207 
History of chronic or active hepatitis B (known to be positive for hepatitis B surface 
antigen [HBsAg] or quantifiable hepatitis B virus [HBV] viral load).  Positive for 
hepatitis B, and/or history of hepatitis B infections, or known to be positive for 
HBsAg/HBV DNA. 
208 
History of chronic or active hepatitis C.  Active hepatitis C is defined by a known 
positive hepatitis C antibody result and known quantitative hepatitis C virus RNA 
results greater than the lower limits of detection of the assay. 
209 
Unresolved toxicities from prior antitumor therapy, defined as not having resolved 
to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 grade 
1 or to levels dictated in the eligibility criteria.  Exception:  myelosuppression (eg, 
neutropenia, anemia, thrombocytopenia), 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.  Participants with ≤ grade 2 neuropathy may be eligible. 
210 
Current or recent (within 3 months of study drug administration) gastrointestinal 
disease such as chronic or intermittent diarrhea, or uncontrolled disorders that 
increase risk of diarrhea, such as inflammatory bowel disease.  
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Exception:  non-chronic conditions (eg, infectious diarrhea) that are completely 
resolved for at least 2 weeks prior to starting study treatment. 
211 
History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
212 
Uncontrolled endocrine disorder including thyroid disease. 
213 
Subjects with active, known or suspected autoimmune disease.  Exceptions:  
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, euthyroid subjects with history of 
Grave’s disease (subjects with suspected autoimmune thyroid disorders must be 
negative for thyroglobulin and thyroid peroxidase antibodies and 
thyroid-stimulating immunoglobin prior to first dose of study treatment), psoriasis 
not requiring systemic treatment, or conditions expected to recur in the absence of 
an external trigger. 
214 
History or evidence of any other clinically significant disorder, condition or disease 
that, in the opinion of the investigator or Sponsor, if consulted, would pose a risk 
to subject safety or interfere with the study evaluation, procedures or completion. 
Prior/Concomitant Therapy 
215 
Autologous HSCT within 6 weeks prior to start of treatment. 
216 
Allogeneic HSCT within 5 years prior to start of treatment or active GVHD 
requiring systemic treatment. 
217 
Has had an allogenic tissue/solid organ transplant. 
218 
Prior treatment of AML with anti-CD33 chimeric antigen receptor (CAR) T cells. 
219 
Prior therapy with anti-PD-1 agent that was discontinued due to a grade ≥ 3 
immune-related adverse event. 
220 
Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, 
retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever 
is shorter) of day 1.  Exception:  hydroxyurea to control peripheral blood leukemic 
cell counts is allowed until start of investigational product treatment.   
221 
Treatment with systemic immune modulators including, but not limited to, 
non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks 
before enrollment (day 1).  Exceptions:  physiologic replacement steroids or 
hydrocortisone for treatment of transfusion reactions. 
222 
Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not 
allowed. 
223 
Major surgery within 28 days of study day 1 with the exception of biopsy and long 
line insertion.  Note:  If participant received major surgery, they must have 
recovered adequately from the toxicity and/or complications from the intervention 
prior to starting study treatment. 
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Prior/Concurrent Clinical Study Experience 
224 
Is currently participating in or has participated in a study of an investigational 
agent or has used an investigational device within 14 days prior to the first dose of 
study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational 
study may participate as long as it has been 14 days after the last dose of the 
previous investigational agent. 
Other Exclusions 
225 
White blood cells (WBC) > 15 x 109 cells/L at screening. 
226 
Known hypersensitivity to immunoglobulins or to any other component of 
AMG 330 formulation.  
227 
Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its 
excipients. 
228 
Women with a positive pregnancy test. 
229 
Women who are lactating/breastfeeding or who plan to breastfeed while on study 
through 120 days after receiving the last dose of study drug. 
230 
Men and women of reproductive potential who are unwilling to practice a highly 
effective method(s) of birth control while on study and for at least 120 days after 
receiving the last dose of study drug.  Acceptable methods of highly effective 
birth control include sexual abstinence (men, women); vasectomy; bilateral tubal 
ligation/occlusion; or a condom with spermicide (men) in combination with 
hormonal birth control or IUD (women). 
231 
Subjects likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge.  Has a history or current evidence of any 
condition, therapy, or laboratory abnormality that might confound the results of 
the study, interfere with the participant's participation for the full duration of the 
study, or is not in the best interest of the participant to participate, in the opinion 
of the treating investigator. 
232 
Has a known psychiatric or substance abuse disorder that would interfere with 
the participant’s ability to cooperate with the requirements of the study. 
5.3 
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 11.3). 
The subject or the subject’s legally authorized representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
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A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (up to 14 days prior to 
study day 1) receives a unique subject identification number before any study-related 
activities/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 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.   
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study within the 14-day 
screening period (screen failure) may be rescreened up to 3 times at the discretion of 
the investigator.  Refer to Section 8.1.1 for rescreening procedures. 
5.5 
Washout Period/Run-in Period/Invasive Procedure(s) 
Not applicable 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment (shown in Table 6-1). 
 
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6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 330 
Non-Amgen Investigational Product:b 
Pembrolizumab 
Dosage Formulation 
Powder for solution for infusion in a vial containing 
 mg of AMG 330 
AMG 330 is formulated with potassium phosphate, 
captisol, sucrose, polysorbate 80, pH 
. 
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 (
 
, pH 
).  The 
IVSS is intended for pre-treatment of IV bags prior to 
dilution of AMG 330 drug product. 
Solution for infusion 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
Various dosage level(s) (see Table 4-1, Table 4-2, and 
Table 4-3). 
100 mg/4 mL (25 mg/mL) single-dose vials 
Dosage level(s) 200 mg Q3W 
Route of Administration 
Continuous IV infusion 
Intermittent IV infusion 
Accountability 
The amount dispensed, date dispensed, and lot 
number of investigational product is to be recorded on 
each subject's CRF. 
The amount dispensed, date dispensed, and lot number 
of investigational product is to be recorded on each 
subject's CRF. 
Dosing Instructions 
Each vial will be reconstituted with 1.2 mL of sterile 
water for injection for a final concentration of 
0.5 mg/mL AMG 330.  The dose, start date/time, stop 
date/time, lot number of investigational product is to be 
recorded on each subject's CRF. 
The dose, start date/time, stop date/time, lot number of 
investigational product is to be recorded on each 
subject's CRF. 
CRF = case report form; IV = intravenous; Q3W = every 3 weeks (21 days) 
a AMG 330 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 
b Pembrolizumab will be manufactured and packaged by Merck & Co Inc and distributed using Amgen clinical study drug distribution procedures.  
 
 
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6.1.1.1 
AMG 330 Dosage, Administration, and Schedule 
AMG 330 is administered as a cIV infusion.  The infusion bags will be changed by site 
nursing personnel trained on the protocol and on the proper administration of AMG 330. 
The first cycle of AMG 330 treatment is 56-77 days in duration.  Please refer to the study 
schema (Figure 1-1).  The first cycle is followed by a 7-day AMG 330 treatment-free 
interval.  The dosing and schedule will be as outlined in Table 4-1 and Table 4-2. 
The drug administration should not be interrupted, if possible.  In case of infusion 
interruption, due to any technical or logistic reason, the interruption should be as short 
as possible and the infusion continued at the earliest time possible.  Every interruption 
longer than 1 hour should be documented.  Administration of dexamethasone 
premedication will occur as described in Section 6.7.   
The start time of infusion should be chosen carefully so as to avoid any interference or 
inconvenience with time points of safety assessments, PK/pharmacodynamic 
measurements and changes of infusion bags.  The site should record any unscheduled 
interruption of an infusion on the eCRF, and provide the start and stop date/time of the 
infusion and the bag change. 
AMG 330 should be administered through a central venous access at a constant flow 
rate.  The drug should not be administered as a bolus and flushing residual drug at the 
time of bag change is prohibited.  In the event that administration through a central 
venous access is not possible, AMG 330 may be administered temporarily through a 
peripheral venous line if the subject is hospitalized.  The final solution for infusion should 
be administered through a sterile 0.2 μm in-line filter. 
Infusion bags should be changed in accordance with local pharmacy standards for 
infusion of compounded sterile products but at least every 4 days.  In the US, infusion 
bags should be changed at least every other day and in no case should AMG 330 be 
administered for more than 48 hours at ambient temperature. 
The dose, start and stop date/time, and lot number of protocol-specified therapy is to be 
recorded on each subject’s CRF.  The date and time of infusion bag changes, all 
infusion start and stop times, and any dose modifications should also be recorded 
accurately. 
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6.1.1.1.1 
Infusion-Free Interval for AMG 330 
The planned length of an AMG 330 infusion-free interval between cycles is 1 week 
(+3 days if needed for logistical reasons).  The duration can be extended up to 4 weeks 
after consultation with the sponsor for subjects who achieved a response (CR, CRh, 
CRi, or MLFS) with no detectable blasts in bone marrow at the end of infusion.  Weekly 
hematology assessments should be performed to confirm recovery of peripheral blood 
counts.  Once peripheral blood counts have returned to baseline levels, the next 
treatment cycle can be initiated. 
In subjects who achieved a response with no detectable blasts in bone marrow at end of 
infusion, the infusion-free interval may also be extended up to a maximum of 6 weeks in 
case of insufficient recovery of peripheral blood counts (neutrophils < 500/µL, platelets 
< 20 000/µL without transfusion) and after consultation with the sponsor.  In case the 
infusion-free interval is extended to 4-6 weeks, a bone marrow assessment is 
recommended 4 weeks after the end of the infusion cycle.  In case this assessment 
shows detectable leukemic infiltration of the bone marrow, treatment should be resumed 
immediately even if peripheral blood counts have not yet recovered at this time point. 
6.1.1.1.2 
Overdose 
A dose of up to 10% higher than the intended AMG 330 dose (per day) may not require 
specific intervention.  In case of overdose or medication error, the infusion should be 
immediately stopped.  Routine supportive and symptomatic care according to standard 
medical practice is recommended.  Once the subject is stabilized and no clinically 
relevant safety findings due to AMG 330 are observed, resumption of AMG 330 at a 
correct dose can be considered after consultation with the Amgen medical monitor. 
For AMG 330, a dose of greater than 10% higher than the intended dose will be 
considered clinically important and classified as a serious adverse event under the 
criterion of “other medically important serious event” per Section 11.4.  If the overdose 
results in additional adverse event/s, the subject should be followed carefully until all 
signs of toxicity are resolved and the adverse event/s should be recorded/reported per 
Section 11.4 of the protocol. 
6.1.1.2 
AMG 330 Inpatient Dosing 
Subjects are required to be monitored in a hospital for a minimum of 72 hours following 
initiation of therapy and for a minimum of 72 hours after each dose level increase.  Close 
monitoring is indicated because of the potential adverse events associated with T cell 
redistribution and potential cytokine release effects triggered by the administration of 
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AMG 330.  Nurses/physicians familiar with such conditions should be available for 
immediate intervention in case of complications. 
Also, if AMG 330 is interrupted for longer than 4 hours, re-start of the infusion should be 
performed in the hospital, under the supervision of the investigator or designee.  The 
subject should be observed overnight for possible side effects after the re-start, either in 
the hospital or in the outpatient setting as applicable.  Administration of dexamethasone 
premedication will occur as described in Section 6.7. 
6.1.1.3 
AMG 330 Outpatient Dosing 
Apart from the situations where inpatient dosing is required per Section 6.1.1.1.2, and if 
deemed stable by the investigator, a subject may continue AMG 330 cIV infusion as an 
outpatient.  Subjects will receive a patient card indicating that the subject is participating 
in a clinical study.  The patient card will also provide site contact details to be used in 
case of questions on the study or an emergency.  In the outpatient setting, the subject 
will either return to the study site for infusion bag changes or the subject will be visited 
by a well-trained home health care service provider at specific intervals to change the 
infusion bag, measure vital signs, monitor and document adverse events and/or serious 
adverse events, and document any issues with the cIV infusion or infusion pump.  The 
subject and home health care service provider will be trained and will receive written 
instructions for storage of the IV bags, if applicable.  The home health care service 
provider will complete the study delegation log and will be authorized by the investigator 
before any study-related tasks are started. 
Refer to the home health care manual for detailed information on the storage, handling, 
and administration of AMG 330, mandatory procedures, and data collection 
requirements. 
Following each visit or telephone contact by the home health care service provider, the 
information collected will be documented on the Home Health Care Services visit 
worksheet and forwarded to the investigator.  Any unexpected or unusual events as well 
as any deviations will be communicated promptly to the investigator.  If any adverse 
event occurs in the outpatient setting, the home health care service provider should 
directly contact the site for further management.  The home health care service 
professionals provide 24 hour emergency on-call service for any pump related issues.  In 
the event of an interruption of the AMG 330 cIV infusion of > 4 hours, restart of the 
infusion should be performed in the clinic/hospital under the supervision of the 
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investigator or designee and the subject should be hospitalized for a minimum of 
48 hours (see Section 6.2.2.1). 
6.1.1.4 
Pembrolizumab Dosage, Administration, and Schedule 
Trial treatment should begin as close as possible to the date on which the subject is 
allocated/assigned.  The pembrolizumab treatment to be used in this study is outlined 
below in Table 6-2. 
Schedule of pembrolizumab dosing and related assessments are specified in the 
Schedule of Activities (Table 1-1, Table 1-3, Table 1-5).  Pembrolizumab will be 
administered as a dose of 200 mg using a 30-minute IV infusion.  Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window between - 5 minutes 
and + 10 minutes is permitted (ie, infusion time is 30 minutes - 5 minutes/+ 10 minutes).  
Following the completion of the pembrolizumab administration, the subject will be 
observed for 1 hour to monitor tolerability of the infusion. 
For this study, an overdose of pembrolizumab will be defined as ≥ 1000 mg (≥ 5 times 
the indicated dose) of pembrolizumab.  No specific information is available on the 
treatment of overdose of pembrolizumab.  In the event of overdose of pembrolizumab, 
the subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
Table 6-2.  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Maximum 
Length of 
Dosing 
Route of 
Administration 
Regimena 
Use 
Pembrolizumab 
200 mg 
Every 
21 days 
Up to 
35 cycles 
Intravenous 
Day 1 of 
each cycle.  
Starting at 
study day 15 
(cohort 1), 
and study 
day 1 
(cohort 2) 
(21-day 
cycles) 
Experimental 
a Pembrolizumab may be administered up to 3 days before or after each scheduled day 1 from 
pembrolizumab cycle 2 onwards. 
When pembrolizumab administration falls on the same day as an AMG 330 dose level 
increase, pembrolizumab will be given first.  After the pembrolizumab infusion is 
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complete, dexamethasone will be administered.  The patient will then be observed for 
1 hour.  If the dose is well tolerated, the dose of AMG 330 may be increased to the next 
level.  When pembrolizumab is administered as a monotherapy, dexamethasone will not 
be administered at the completion of the pembrolizumab infusion. 
6.1.2 
Non-investigational Products 
There are no non-investigational products in this study. 
6.1.3 
Medical Devices 
AMG 330 must be administered using infusion pumps approved for use by the 
appropriate regulatory authorities for the country in which the subject is undergoing 
treatment in both the inpatient and outpatient setting.  Investigational product infusion for 
solution will be prepared in bags for IV infusion and delivered through infusion lines with 
a 0.2 μm in-line filter that are both compatible with the investigational product as 
described in the IPIM. 
Additional details are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
6.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies including dexamethasone and tocilizumab that are 
commercially available are not provided by Amgen.  The investigator will be responsible 
for obtaining supplies of these protocol-required therapies. 
Dexamethasone: 
Premedication with dexamethasone is required prior to each AMG 330 treatment cycle 
and prior to each dose step for the prevention of CRS.  Dexamethasone should be 
administered as a single IV dose (8 mg) within 1 hour of start of AMG 330 infusion or 
dose step, respectively.  Dexamethasone will not be given as a premedication prior to 
pembrolizumab administration. 
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In the case of re-start of AMG 330 infusion after an infusion interruption of > 24 hours, 
dexamethasone (8 mg IV) should be administered within 1 hour prior to re-start and 
within 1 hour prior to the dose step. 
For administration of dexamethasone after occurrence of CRS or other immune related 
adverse events, follow guidance in Section 6.8 and Table 6-3. 
Tocilizumab: 
For administration of tocilizumab after occurrence of CRS, follow guidance in 
Section 6.8. 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7.  Supportive care may include premedication with anti-emetics to 
limit treatment-related nausea and vomiting.  Subjects should receive medications for 
treatment-induced diarrhea as clinically indicated.  Anti-inflammatory or narcotic 
analgesics may be offered as needed.  Packed red blood cell and platelet transfusions 
should be administered as clinically indicated. 
Concomitant therapies are to be collected from the day of signing the informed consent, 
through the end of study.  For all concomitant therapies collect therapy name, indication, 
dose, unit, frequency, route, start date, and stop date. 
6.1.5 
Other Treatment Procedures 
Not applicable 
6.1.6 
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 investigational/non-investigational product(s), device(s) or combination 
product(s) provisioned and/or repackaged/modified by Amgen including AMG 330 and 
pembrolizumab. 
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported according to the instructions provided in the IPIM. 
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6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Any antitumor 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 HSCT is not allowed during screening and during the 
study treatment period until end of study.  Exception:  Hydroxyurea is allowed to control 
blasts as described in Section 6.7.2. 
Radiotherapy is not permitted during screening and during the study treatment period 
until end of study except for palliation of symptoms and should be approved by Sponsor.  
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. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to 
continue the participant on study treatment requires the mutual agreement of the 
investigator, the Sponsor and the participant. 
Listed below are specific restrictions for concomitant therapy or vaccination during the 
course of the study: 
 
Antineoplastic systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 
 
Chemotherapy not specified in this protocol 
 
Investigational agents other than pembrolizumab 
 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, 
the following:  measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines and are not allowed. 
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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 
and during the study 
 
Major surgery within 28 days of study day 1 (with the exception of biopsy or long line 
insertion)  
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules, 
Dose-Limiting Toxicities (DLTs) 
Step Dose Level Determination 
A decision to proceed with the next step dose of AMG 330 for each subject in cohorts 1 
and 2 will be based on investigator’s assessment of safety and upon approval by 
Sponsor. 
In cohort 1, a sentinel subject will be treated first.  The minimal interval between 
treatment start for the sentinel subject and other subjects in the cohort is 21 days.  If the 
sentinel subject has not experienced a DLT by day 14 at 
 µg/day AMG 330, he/she 
will proceed with 200 mg pembrolizumab on day 15 and remain at an AMG 330 dose 
level of 
 µg/day for 7 days (until day 21).  If the sentinel subject experiences a DLT 
during the first 7 days of treatment with AMG 330 at 
 µg/day, this subject will be 
replaced, but the DLT will still be counted towards the study stopping rules.  If the 
sentinel subject does not experience a DLT before or on day 21, the next subjects in the 
cohort may initiate dosing.  If a sentinel subject experiences a DLT, the sponsor will 
issue a decision based on the evaluation of clinical significance of the adverse event by 
the DLRT and potential decisions by the sponsor may include stopping AMG 330 and/or 
pembrolizumab, dose de-escalation of AMG 330, or continuing therapy at full dose.   
Cohort 2 will be initiated only after all subjects in cohort 1 completed study day 28 (ie, 
AMG 330 
 µg/day dose level in combination with pembrolizumab for 7 days), and if 
the rate of DLT is ≤ 3 out of 10 subjects.  After receiving the DLRT recommendation, 
sponsor will render a final decision and will issue a written notification of the decision to 
investigators.  Further information on dose level review meetings (DLRMs) is provided in 
Section 11.3. 
Individual Stopping Rules 
Dosing for an individual will be stopped for any occurrence of a DLT.  The event will be 
reviewed by the investigator and Sponsor for evidence of relationship to treatment and 
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clinical or medical significance to decide whether dosing may be resumed for the 
individual and any modifications to the dosing, if appropriate. 
Dose Limiting Toxicities 
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 investigational product.  
The DLT window will start on day 1 and last for the duration of cycle 1.  The CTCAE v5 
will be used to assess toxicities/adverse events with the exception of CRS (see 
Table 6-5 for grading of CRS).   
DLT Evaluation 
To be DLT evaluable, subjects must meet 1 of the following criteria during DLT 
evaluation period (cycle 1 day 1 to cycle 1 end of infusion): 
 
The subject experienced a DLT; OR 
 
The subject has received at least 70% of planned cumulative dose of AMG 330 and 
has not missed more than 1 dose of pembrolizumab; OR 
 
The subject did not experience a DLT and completed the DLT evaluation period 
Events listed below are to be considered as DLTs and exceptions when occurring in a 
subject during the DLT window unless clearly attributable to causes other than AMG 330 
and pembrolizumab treatment: 
 
Any treatment-related death. 
 
Grade 4 neutropenia lasting ≥ 4 weeks from last day of cycle in absence of evidence 
of active AML.  Note:  grade 4 neutropenia maybe assessed retrospectively and 
outside of the DLT window 
 
Grade 3−4 non-hematologic toxicity not clearly resulting from the underlying 
leukemia EXCEPT: 
 
Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
 
Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral 
nutrition, or requiring or prolonging hospitalization 
 
Infection, bleeding, or other expected direct complication of cytopenias due to 
active underlying leukemia 
 
Grade 3 infusion reaction, unless attributed to pembrolizumab, if successfully 
managed and which resolves within 72 hours 
 
Grade 3 rash or pruritus 
 
Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically and 
resolves within 7 days without end-organ damage. 
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 
Grade 3 or 4 isolated analyte abnormalities (ie, those occurring without clinical 
consequence) that resolve, with or without intervention, to < grade 2 levels in 
< 72 hours will not be considered DLT. 
 
Grade 3 or 4 asymptomatic enzyme elevations including aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) (without bilirubin 
elevation), gamma glutamyl transferase that resolve, with or without intervention, 
to ≤ grade 2 within 7 days will not be considered a DLT, unless attributed to 
pembrolizumab.  
 
Isolated grade 3 elevation of amylase or lipase not associated with clinical or 
radiological evidence of pancreatitis 
 
Grade 3 endocrinopathy that is well controlled by hormone replacement 
 
CRS meeting any of the criteria listed below: 
 
Grade 2 CRS that does not resolve, with or without intervention to grade 1 within 
7 days will be considered a DLT 
 
Grade 3 CRS that does not resolve, with or without intervention to ≤ grade 2 
within 5 days, will be considered a DLT 
 
Any grade 4 CRS 
 
Any grade 5 toxicity 
 
Receive less than 70% of the planned cumulative dose of AMG 330 or miss more 
than 1 dose of pembrolizumab during the first cycle due to investigational product(s) 
related toxicity that does not meet the DLT criteria listed above 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  AMG 330 
Subjects will be monitored continuously for adverse events while on study therapy.  
Subjects will be instructed to notify their physician immediately for any and all adverse 
events.  The criteria presented in this section for dose modifications and delays for 
AMG 330 are meant as general guidelines. 
Criteria for Dose Delay or Dose Reduction 
Subjects will receive continuous AMG 330 therapy as long as they have not had disease 
progression or an adverse event requiring dose modification, as described below. 
Subjects who experience a grade 4 non-hematologic adverse event will not receive 
additional protocol-related therapy and will be removed from study unless discussed and 
agreed upon by the Sponsor and investigators that it is in the best interest of the subject 
to receive additional therapy with AMG 330 (eg, if the subject has demonstrated a 
response to therapy). 
Dose modifications, interruptions, or delays may occur in the setting of lower grade 
adverse events based on the clinical judgement of the investigator, and in consultation 
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with the sponsor.  Dose reductions should be to the previous lower dose level, or to a 
dose level in between the previous dose level and the current dose level, after 
discussion between the investigator and the sponsor. 
No more than 2 dose level reductions of AMG 330 will be allowed per subject.  If a third 
dose reduction is required, the subject must discontinue AMG 330 (and pembrolizumab, 
if receiving combination therapy based on response to therapy).  Dose re-escalation 
after a dose reduction may occur in limited circumstances (such as a change in 
attribution of adverse event, or if re-escalation is in the best interest of the subject) after 
discussion and agreement between the sponsor and the investigator. 
For an adverse event requiring dose modification, AMG 330 (and pembrolizumab for 
subjects receiving combination therapy) should be interrupted to allow recovery from the 
adverse event.  Re-initiation of study drug cannot occur until adverse event decreases to 
grade ≤ 1.  In case of delayed recovery to grade ≤ 1 from treatment-related adverse 
events that results in a delay of treatment for > 21 days, the subject will not receive 
additional protocol-related therapy and will be removed from study unless discussed and 
agreed upon by the sponsor and investigators that it is in the best interest of the subject 
to receive additional therapy with AMG 330 and pembrolizumab (eg, if subject 
demonstrated response to therapy). 
Assessment of causality (chronology, confounding factors such as disease, concomitant 
medications, diagnostic tests and previous experience with the agent) must be 
determined and documented by the investigator, prior to dose modification. 
In case of grade 2 CRS, administration of AMG 330 can be continued on the currently 
tested dose level for 8 hours, and treatment provided to mitigate CRS symptoms.  If 
symptoms do not improve to grade 1, the dose will be de-escalated by 50% for an 
additional 24 hours.  If CRS grade 2 resolves to grade 1, the dose can be re-escalated 
back to the level being tested.  If symptoms persist, AMG 330 infusion will be interrupted 
and pembrolizumab infusion will be delayed until symptoms improve to grade 1.  If 
treatment is interrupted for < 24 hours, the interrupted AMG 330 dose can be resumed 
and re-escalated back to the tested dose level.  If treatment is interrupted for > 24 hours, 
restart or repeat rules apply (see below). 
In case of grade 3 CRS, AMG 330 treatment must be interrupted and pembrolizumab 
treatment postponed.  Sponsor has to be consulted prior to a planned re-start.  In case 
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of grade 4 CRS, treatment must be permanently discontinued.  See Section 6.8 for 
specific instructions for the management of CRS. 
If the same grade 3 non-hematologic adverse event recurs despite a dose reduction, a 
second dose reduction versus discontinuation of the subject from further protocol 
therapy should be discussed and agreed upon the sponsor and investigators. 
If a DLT occurs in a subject with clinical benefit from treatment, a restart at a lower dose 
can be considered if the toxicity has resolved to grade ≤ 1 and after consultation with the 
sponsor.  If AMG 330 is discontinued, pembrolizumab may be continued as a 
monotherapy until disease progression for a maximum of 35 cycles (approximately 
2 years) after discussion and agreement between the sponsor and the investigator.  If 
pembrolizumab is discontinued, AMG 330 may be continued as a monotherapy. 
Dose delay:  treatment should be interrupted until the adverse event is resolved to grade 
≤ 1, and can then be resumed at the same dose unless the interruption lasted for more 
than 24 hours, please see below.  (Note:  if the event needs > 21 days to resolve, 
treatment has to be permanently discontinued, see also below). 
Infusion Interruption 
Significant events requiring a change in treatment will be managed by immediate 
infusion interruption:  
 
The subject experiences a DLT as defined in Section 6.2.1 
 
The subject experiences a clinically relevant grade 4 adverse event related to 
investigational product (see above) but does not meet the DLT criteria 
 
The subject meets criteria for discontinuation of investigational product as described 
in Section 6.2.2 
 
The subject experiences disease related adverse events and AMG 330 interruption 
is required for medical interventions 
 
Technical problem with the infusion pump 
 
The investigational product is incorrectly prepared or administered (eg, overdose) 
Restarting the Infusion 
Treatment may resume if the interruption is ≤ 21 days and if:  
 
The interruption occurred due to other reasons than toxicity (disease-related events, 
technical or logistic reasons; eg, diagnostic measurements).  The infusion can be 
restarted at the same dose and without additional measures. 
 
The toxicity has resolved to CTCAE v5 grade ≤ 1 (in case of dose reduction, infusion 
may be re-started without prior resolution of the toxicity to CTCAE v5 grade ≤ 1 if the 
adverse event is not clinically relevant and upon discussion and agreement between 
the investigator and the sponsor) 
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Please also refer to specific guidance on restart after CRS in Section 6.8.  Restarting the 
infusion after a treatment interruption requires care.  The re-start should be performed in 
the hospital, under supervision of the investigator or designee, if the reason for the 
interruption was other than a technical issue or the interruption exceeded 4 hours 
independent of reason.  Assessments should be performed after infusion re-start 
depending on the length of the interruption.  The subject should be hospitalized for at 
least 48 hours after re-start of the infusion. 
In case of an AMG 330 infusion interruption of > 24 hours, regardless of the reason for 
interruption, re-start of the infusion (repeat cycle) should be performed using step doses, 
which will be defined upon consultation with the sponsor.  Only 2 repeat cycles may be 
performed in cycle 1.  For cycle 2 and beyond, additional repeat cycles can be permitted 
upon discussion and agreement between the investigator and sponsor. 
Step doses will be performed within 1 – 2 weeks (± 1 day) to return to the interrupted 
AMG 330 dose level, and the number and duration of repeat step doses will depend on 
the level of interrupted AMG 330 dose.  During this 1-2 weeks, Table 1-7 Schedule of 
Activities should be followed (eg, for AMG 330 doses interrupted at 
 µg/day and 
below, 2 step doses can be used:  
 µg/day for 3 days followed by 
 µg/day for 
4 days; for doses interrupted above 
 µg/day, 3 step doses can be used:  
 µg/day 
for 1 day followed by 
 µg/day for 3 days followed by 
 µg/day for 3 days).  In case of 
AMG 330 infusion interruption for < 24 hours, regardless of the reason for interruption, 
restart of infusion should be performed at the same dose level as the last dose level.  
Administration of pembrolizumab will remain on the Q3W schedule. 
After 2 unsuccessful restarts, the subject may remain on the study and continue 
AMG 330 treatment with a previously tested target dose that has been well tolerated.  
The dose of pembrolizumab will remain unchanged. 
Dexamethasone (8 mg IV) should be administered within 1 hour prior to re-start and 
within 1 hour prior to each AMG 330 dose step(s).  Dexamethasone is not required prior 
to the pembrolizumab administration unless it co-occurs with the AMG 330 step dose.  In 
cases when administration of pembrolizumab co-occurs with AMG 330 step, 
pembrolizumab is administered first followed by dexamethasone followed by AMG 330.  
The subject should be hospitalized starting from re-start of infusion until 72 hours after 
the dose step.  After each dose level increase, vital signs will be obtained as per the 
Schedule of Activities (see Table 1-1, Table 1-3, Table 1-5). 
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The number of days of exposure to both investigational products before and after an 
interruption should sum up to at least 70% of planned cumulative dose of AMG 330.  In 
this case, the subject would still be DLT-evaluable.  However, if the cycle was 
interrupted for more than 24 hours but less than 21 days, a new repeat cycle should be 
started and the interrupted cycle would not be evaluable for DLT, unless the event that 
lead to the interruption was a DLT. 
Note:  The end of infusion bone marrow assessment should be performed once it is 
confirmed that the cycle will not be resumed to assess treatment response.  
 
 
. 
Permanent Discontinuation 
A subject will permanently discontinue treatment with investigational product in the event 
of:  
 
Dose-limiting or other unmanageable toxicity.  Exception:  If a DLT occurs in a 
subject with a clear clinical benefit from treatment a restart at a lower dose can be 
considered if the toxicity has resolved and after consultation with the sponsor.  This 
includes: 
 
Grade 4 CRS 
 
Grade 3 CRS occurring at the initial step dose for a cycle (ie, at the 10 µg/day)  
 
Grade 2 or 3 CRS meeting any of the criteria listed below: 
 
Grade 2 or 3 CRS that does not improve to ≤ grade 1 within 7 days  
 
Grade 3 CRS that does not improve to ≤ grade 2 within 5 days  
 
Re-occurrence of the same grade 4 adverse event  
 
3 infusion interruptions > 24 hours in cycle 1 
 
Disease progression as defined by 2017 European LeukemiaNet (ELN) criteria 
(Döhner et al, 2017) 
 
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/MLFS 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. 
 
An infusion interruption of more than 21 days due to an adverse event not clearly 
related to the underlying disease. 
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 
Occurrence of CNS-related adverse event considered related to AMG 330 by the 
investigator and meeting 1 or more of the following criteria: 
 
More than 1 seizure 
 
A CNS-related adverse event CTCAE grade 4 
 
A CNS-related adverse event leading to treatment interruption that needed more 
than 1 week to resolve to CTCAE grade ≤ 1 
 
Non-manageable GVHD 
 
Investigator’s decision that a change of therapy is in the subject’s best interest 
 
Administration of relevant non-permitted concomitant medications 
Women who become pregnant while on study through 1 week after receiving the last 
dose of study drug will not receive subsequent scheduled doses and will be followed for 
safety until the end of study visit. 
Men with pregnant partners or whose partners become pregnant while the subject is on 
study will receive subsequent scheduled doses and must practice sexual abstinence or 
use a condom while on study through 120 days after receiving the last dose of study 
drug. 
All reasons for treatment discontinuation should be clearly and concisely documented in 
the eCRF.  If a subject has not continued to present for study visits, the investigator 
should determine the reason and circumstances as completely and accurately as 
possible. 
In any case of premature treatment discontinuation, the investigator should make every 
effort to perform all examinations scheduled for the end of treatment and safety follow-up 
visits.  These data should be recorded, as they comprise an essential evaluation that 
should be performed prior to discharging any subject from the study and to allow for the 
evaluation of the study endpoints. 
6.2.2.2 
Non-Amgen Investigational Product(s):  Pembrolizumab 
6.2.2.2.1 
Dose Modification of Pembrolizumab if AMG 330 has been 
Interrupted 
If toxicities due to AMG 330 do not resolve to grade ≤ 1 within 7 days of treatment 
interruption and supportive care as outlined, pembrolizumab may be postponed until 
both may be resumed per protocol.  If AMG 330 is discontinued, pembrolizumab 
treatment may be continued following discussion and agreement between the 
investigator and Sponsor. 
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6.2.2.2.2 
Dose Modification for Pembrolizumab 
Adverse events associated with pembrolizumab exposure may represent an immune 
related response.  These immune-related adverse events may occur shortly after the 
first dose or several months after the last dose of pembrolizumab treatment and may 
affect more than 1 body system simultaneously.  Therefore, early recognition and 
initiation of treatment is critical to reduce complications.  Based on existing clinical study 
data, most immune-related adverse events ensure adequate evaluation to confirm 
etiology or exclude other causes.  Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation.  Dose modification 
and toxicity management guidelines for immune-related adverse events associated with 
pembrolizumab are provided in Table 6-3. 
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Table 6-3.  Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated With Pembrolizumab 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids.  
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. 
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤ 10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤ grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to 
≤ grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
 
Recurrent grade 2, 
grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation (ie, 
peritoneal signs 
and ileus) 
Participants with 
≥ grade 2 
diarrhea 
suspecting colitis 
should consider 
GI consultation 
and performing 
endoscopy to 
rule out colitis 
Participants with 
diarrhea/colitis 
should be 
advised to drink 
Recurrent grade 3 
or grade 4 
Permanently 
discontinue 
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liberal quantities 
of clear fluids.  If 
sufficient oral 
fluid intake is not 
feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
Administer 
corticosteroids (initial 
dose of 0.5 - 1 mg/kg 
prednisone or 
equivalent) followed by 
taper 
Monitor with liver 
function tests 
(consider weekly 
or more 
frequently until 
liver enzyme 
value returned to 
baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) 
or hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
Initiate insulin 
replacement therapy 
for participants with 
T1DM 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
 
Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
Treat with non-
selective beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate 
Monitor for signs 
and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs 
and symptoms of 
thyroid disorders 
Nephritis: 
grading 
Grade 2 
Withhold 
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according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 3 or 4 
Permanently 
discontinue 
Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) followed by 
taper 
Monitor changes 
of renal function 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other irAEs 
Persistent grade 2 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent grade 3 
or grade 4  
Permanently 
discontinue 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; 
irAE = immune-related adverse event; IV = intravenous; ULN = upper limit of normal 
a AST/ALT: > 3.0 - 5.0 x ULN if baseline normal; > 3.0 - 5.0 x baseline, if baseline abnormal; 
bilirubin: > 1.5 - 3.0 x ULN if baseline normal; > 1 .5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: > 5.0 to 20.0 x ULN, if baseline normal; > 5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:> 3.0 - 10.0 x ULN if baseline normal; > 3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: > 20.0 x ULN, if baseline normal; > 20.0 x baseline, if baseline abnormal; 
bilirubin: > 10.0 x ULN if baseline normal; > 10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician.  If control achieved or ≤ grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to:  Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion (Pembrolizumab Investigator’s Brochure).  Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction are provided in 
Table 6-4.  
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Table 6-4.  Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
 Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤ 24 hrs. 
 Stop Infusion. 
 Additional appropriate medical therapy may 
include but is not limited to: 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
 If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve 
and the participant should be premedicated 
for the next scheduled dose. 
Participants who develop grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilator 
support indicated 
 Stop Infusion. 
 Additional appropriate medical therapy may 
include but is not limited to: 
 Epinephrine** 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroids 
 Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
 Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.  For further information, please refer to the CTCAE v5.0 at 
http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer 
Institute; NSAID = non-steroidal anti-inflammatory drug 
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6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational products (AMG 330 and pembrolizumab) during the study 
are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with AMG 330 in 
combination with pembrolizumab.  
6.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance 
Not applicable  
6.6 
Treatment of Overdose 
Treatment of Overdose with AMG 330 
The effects of overdose of this product are not known.  The daily AMG 330 dose may be 
up to 10% lower or higher in order to account for possible pump inaccuracies.  A dose of 
up to 10% higher than the intended dose may not require specific intervention. 
In case of overdose or medication error, the infusion should be immediately stopped.  
Consultation with the sponsor is strongly recommended for prompt reporting of clinically 
apparent or laboratory adverse events possibly related to overdosage.  Consultation with 
the sponsor is also strongly recommended even if there are no adverse events, in order 
to discuss the minimal duration of dose interruption.  If the overdose results in clinically 
apparent or symptomatic adverse events, the subject should be followed carefully until 
all signs of toxicity are resolved and the adverse event(s) should be recorded/reported 
per Section 11.4.  Resumption of AMG 330 is possible after consultation with the 
sponsor and should adhere to the guidelines in Section 6.2.2.1. 
A dose of > 10% higher than the intended AMG 330 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 11.4. 
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Refer to the AMG 330 Investigational Brochure for further information. 
Treatment of Overdose With Pembrolizumab: 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
≥ 5 times the indicated dose. 
No specific information is available on the treatment of overdose of pembrolizumab.  In 
the event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken/used from the time of initial diagnosis of AML 
through the signing of informed consent will be collected. 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7.   
Concomitant therapies are to be collected from signing of informed consent through the 
end of the safety follow-up period. 
Oxygen administration as supportive measure is permitted during study treatment. 
Hydroxyurea for 7 days at a dose of 1 – 10 g/day is recommended prior to the first cycle 
of investigational product treatment for subjects with high WBC (> 15 000 cells/mcL).  
Administration of hydroxyurea after start of investigational product may be permitted 
after discussion with sponsor. 
Premedication with dexamethasone is required prior to each AMG 330 treatment cycle 
and prior to each dose step for the prevention of CRS.  Dexamethasone should be 
administered as a single IV dose (8 mg) within 1 hour of start of infusion or dose step, 
respectively. 
In the case of re-start of infusion after an infusion interruption of > 24 hours, 
dexamethasone (8 mg IV) should be administered within 1 hour prior to re-start and 
within 1 hour prior to the dose step. 
For administration of dexamethasone and tocilizumab after occurrence of CRS, follow 
guidance in Section 6.8. 
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6.8 
Specific Recommendations for Cytokine Release Syndrome, Tumor 
Lysis Syndrome, and Infection Prophylaxis 
Cytokine Release Syndrome 
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 be at an increased risk for CRS during the first few days following the 
initial infusion of AMG 330.  Cytokine release syndrome may be life-threatening or fatal.  
Infusion reactions may be clinically indistinguishable from manifestations of CRS.  
Throughout the infusion with AMG 330, monitor subjects for clinical signs (eg, fever, 
tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) 
which may be related to CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in Table 6-5 (based on the adopted grading system referenced in Lee et al, 
2014). 
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Table 6-5.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Minimum Expected Interventionc 
Instructions for 
Interruption of 
AMG 330 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
 
Administer symptomatic treatment 
(eg, paracetamol/ acetaminophen 
for fever, fluids for hypotension). 
 
Consider use of tocilizumab 4 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.  Up to 3 additional doses can be 
given 8 hours apart, if needed. 
Monitor for CRS symptoms including vital 
signs and pulse oximetry at least Q2 
hours for 12 hours or until resolution to 
CRS grade ≤ 1, whichever is earlier. 
For subjects with extensive 
co-morbidities or poor performance 
status, manage per grade 3 CRS 
guidance below. 
Institute medical 
management.  If 
hypotension persists 
8 hours after adequate 
medical management, 
de-escalate AMG 330 to 
50% of the current dose 
for 24 hours.  If 
symptoms persist, 
interrupt AMG 330.  
Refer to Section 6.2.2 
for dose interruption 
guidelines.  If symptoms 
improve to ≤ grade 1, 
re-escalate to the dose 
at which the CRS event 
previously occurred.  If 
symptoms progress to 
grade 3 criteria, see row 
below. 
Discontinue AMG 330 if 
there is no improvement 
to CRS ≤ grade 1 within 
7 days.  Do not 
administer 
pembrolizumab until 
symptoms improve to 
CRS grade ≤ 1 
Page 1 of 2 
Footnotes defined on next page of table 
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Table 6-5.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of AMG 
330 
3  
Symptoms require and 
respond to aggressive 
intervention 
 Oxygen requirement 
≥ 40%, OR 
 Hypotension 
requiring high doseb 
or multiple 
vasopressors, OR 
 Grade 3 organ 
toxicity or grade 4 
transaminitis per 
CTCAE v5 criteria 
Admit to intensive care unit for close 
clinical and vital sign monitoring per 
institutional guidelines. 
Administer tocilizumab 8 mg/kg IV.  Up 
to 3 additional doses of 8 mg/kg of 
tocilizumab can be given 8 hours 
apart, if needed.   
Administer dexamethasone (or 
equivalent) IV at a dose maximum of 
3 doses of 8 mg (24 mg/day).  The 
dose should then be reduced 
step-wise. 
 
Immediately interrupt 
AMG 330 until event 
resolves to CRS 
grade ≤ 1. 
Discontinue AMG 330 if 
there is no improvement 
to CRS ≤ grade 2 within 
5 days or CRS ≤ grade 1 
within 7 days. 
Permanently discontinue 
AMG 330 if CRS grade 3 
occurs at the initial step 
dose (ie, at MTD1). 
Do not administer 
pembrolizumab until 
symptoms improve to 
CRS grade ≤ 1 
If recurrent grade 3 CRS, 
permanently discontinue 
pembrolizumab.   
4 
Life-threatening 
symptoms 
 Requirement for 
ventilator support OR 
 Grade 4 organ 
toxicity (excluding 
transaminitis) per 
CTCAE criteria 
Admit to intensive care unit for close 
clinical and vital sign monitoring per 
institutional guidelines. 
Administer dexamethasone (or 
equivalent) IV at a dose maximum of 
3 doses of 8 mg (24 mg/day).  Further 
corticosteroid use should be discussed 
with the Amgen medical monitor. 
Additionally, tocilizumab should be 
administered at a dose of 8 mg/kg.  Up 
to 3 additional doses can be given 
8 hours apart, if needed.  
Immediately stop the 
infusion and permanently 
discontinue AMG 330 
therapy and 
pembrolizumab 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 cytokine release syndrome (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. 
c Investigators may also consider additional therapy, based on clinical judgment. 
Re-start of Treatment after Infusion Interruption due to Cytokine Release 
Syndrome: 
After interruption of AMG 330 infusion due to grade 3 CRS, the infusion may be 
re-started if all of the following criteria are met: 
 
Sponsor must be consulted prior to re-starting treatment 
 
The event has resolved to grade ≤ 1 prior to re-starting treatment 
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In case of an infusion interruption of > 24 hours, regardless of the reason for interruption, 
re-start of the infusion should be performed at the initial dose and dose steps should be 
performed prior to administering the interrupted dose.  The dose level for each step and 
number of steps should be determined in consultation with the Sponsor prior to 
re-initiation of the infusion. 
Tumor Lysis Syndrome 
Subjects with AML and WBC < 10 000/µL are considered to be at low risk for tumor lysis 
syndrome.  WBC > 10 000/µL and < 50 000/µL are considered to be at intermediate risk, 
and subjects with WBC > 50 000/µL are considered at high risk.  This protocol requires 
that subjects have a maximum WBC count of 15 000/µL. 
Additional high risk features include baseline uric acid > 450 µg/L (7.5 mg/dL), serum 
creatinine > 1.4 mg/dL, and lactate dehydrogenase (LDH) greater than the upper limit of 
normal (ULN). 
Patients with intermediate risk WBC count and elevated baseline uric acid (> 450 µg/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 IV fluid as clinically indicated. 
For grade 3 and 4 tumor lysis syndrome, please see Section 6.2.1 for DLT 
considerations. 
Infection Prophylaxis 
Subjects who may experience neutropenia for 7 days or longer are at a high risk for 
infectious complications.  As appropriate, these subjects should be administered 
prophylactic antibacterial (eg, fluoroquinolones), antifungal and antiviral medications.  
These subjects should be monitored for early signs of breakthrough infections after the 
initiation of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
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The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 7.1 and Section 7.2.1. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally authorized representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 1-1, 
Table 1-3, Table 1-5) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other treating 
physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events, and device-related events and must document this decision 
in the subject’s medical records.  Subjects who have discontinued investigational 
product and/or other 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. 
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 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Decision by investigator 
 
Ineligibility determined 
 
Protocol deviation 
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 
Non-compliance 
 
Disease progression  
 
Requirement for alternative therapy 
 
Protocol-specified criteria  
 
Pregnancy 
 
Recurrent grade 2 pneumonitis 
 
Completion of 35 treatments (approximately 2 years) with pembrolizumab 
Note:  The number of treatments is calculated starting with the first dose of 
pembrolizumab. 
7.2 
Discontinuation From the Study 
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 and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-1, 
Table 1-3, Table 1-5) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.2.1 
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 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
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 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
For subjects who are lost to follow-up, 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. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1, Table 1-3, Table 1-5). 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  The screening window is 
up to 14 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
rescreening up to 3 times at the discretion of the investigator. 
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Once the subject is registered as rescreened, a new 14 day/week screening window will 
begin.  Subjects will retain the same subject identification number assigned at the 
original screening.  If the rescreening period begins more than 14 days after the original 
signing of the ICF, screening procedures, including informed consent, must be repeated.  
Hepatitis serology does not need to be repeated in case of rescreening if it was 
performed within 6 weeks prior to start of treatment with AMG 330.  Bone marrow 
assessment does not need to be repeated in case it was performed within 3 weeks prior 
to start of treatment with AMG 330. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1, Table 1-3, Table 1-5).  The 
date of the first dose of protocol-required therapies (AMG 330 and/or pembrolizumab) is 
defined as day 1.  All subsequent doses and study visits will be scheduled based on the 
day 1 date.  Cycle 1 on-study visits have a ± 1-day window from designated time point.  
All subsequent visits beginning in cycle 2 will have a ± 3-day window. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, 2 safety 
follow-up visits should be performed:  30 days (+ 7 days) after the last dose of AMG 330 
and 30 days (+ 7 days) after the last dose of pembrolizumab.  If the 2 safety follow-up 
periods overlap, the 2 safety follow-up visits can be combined into one. 
If a subject starts a new anti-leukemia treatment within 30 (± 3) days of their last dose of 
protocol-assigned therapy, a safety follow-up visit must be conducted immediately prior 
to starting any new treatment. 
8.1.4 
Long-term Follow-up 
Not applicable 
8.1.5 
End of Study 
The end of study visit is defined as the date of the final study visit when assessments 
and/or procedures are performed. 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
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8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.1.2 
Demographics 
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 on 
 
and pharmacokinetics of the protocol-required therapies. 
8.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that is 
not related to AML and started within 5 years prior to screening through the time of 
signing of the informed consent.  Record all findings on the medical history CRF. 
Relevant medical history, including previous chemotherapy or radiotherapy, antecedent 
hematologic or oncologic disease, other diseases/symptoms such as fatigue, bleeding, 
and infection (resolved and ongoing) will be collected.  AML history must date back to 
the initial diagnosis and any response duration must be recorded.  The current toxicity 
grade will be collected for each condition that has not resolved.  Exception:  no toxicity 
grade should be recorded for ongoing AML history. 
8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Height (in centimeters) should be measured without shoes.  Weight (in kilograms) should 
be measured without shoes. 
8.2.1.6 
Performance Status  
The Eastern Cooperating Oncology Group (ECOG) Performance status will be recorded 
at the time points noted in the Schedule of Activities (Table 1-1, Table 1-3, Table 1-5). 
8.2.2 
Efficacy Assessments 
8.2.2.1 
Disease Response 
Disease response assessments will be based upon review of cytogenetics, bone marrow 
aspirates/biopsies, and peripheral blood count.  Refer to the 2017 ELN criteria in 
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Section 11.11 for additional detail.  In addition, a presence of AML blasts in 
extramedullary compartment can be assessed using other approaches (eg, tissue 
biopsies, peripheral blood, etc.).  Response must be established from a bone marrow 
sample supplemented with neutrophil and platelet counts. 
8.2.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 1-1, Table 1-3, Table 1-5). 
8.2.4.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  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 sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
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8.2.4.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before electrocardiogram (ECG) assessment is conducted.  If the subject is unable to be 
in the supine position, the subject should be in most recumbent position as possible.  
ECGs should be performed in a standardized method, in triplicate, and run consecutively 
(all 3 ECGs should be completed within a total of 5 minutes from the start of the first to 
the completion of the third), prior to blood draws or other invasive procedures.  Each 
ECG must include the following measurements:  QRS, QT, QTc, RR, and PR intervals. 
 
3 baseline ECGs collected ≥ 30 minutes apart, with each baseline ECG in triplicate 
run consecutively (all 3 ECGs should be completed within a total of 5 minutes from 
the start of the first to the completion of the third) (total 9 ECGs) 
 
Triplicate ECGs at time points after dosing 
Baseline is defined as pre-dose on cycle 1 day 1.  The investigator or designated site 
physician will review all ECGs.  ECGs 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 or designee.  Standard ECG 
machines should be used for all study-related ECG requirements. 
8.2.4.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.4.4 
Other Safety 
Not applicable 
8.2.5 
Adverse Events and Serious Adverse Events  
8.2.5.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.5.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE v5 and is 
described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product(s)/study treatment/protocol-required therapies through the safety follow-up visit 
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or 30 days following cessation of study treatment, whichever is later, are reported using 
the Event CRF. 
8.2.5.1.2 
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 safety follow-up visit or 90 days following cessation of study treatment, 
(30 days following cessation of study treatment if the subject initiates new anticancer 
therapy), whichever is later, are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE v5 grading scale differs from the regulatory criteria 
for serious adverse events.  It is left to the investigator’s judgment to report these grade 
4 abnormalities as serious adverse events. 
8.2.5.1.3 
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.  Per local requirements in some countries, 
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 and handled accordingly based 
on relationship to investigational product. 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4. 
8.2.5.1.4 
Pembrolizumab Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported to the Sponsor.  Refer to Section 8.2.5.1.2 and 
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8.2.5.1.3 for the required reporting period and the reporting requirements for non-serious 
and serious ECIs. 
 
an overdose of pembrolizumab, as defined in Section 6.1.1.4 
 
an elevated AST or ALT lab value that is greater than or equal to 3 x ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 x ULN and, at the 
same time, an alkaline phosphatase lab value that is less than 2 x ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note:  These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be made available.  It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting 
of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above.  In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor.  However, abnormalities of liver blood tests that 
do not meet the criteria noted above are not ECIs for this study. 
8.2.5.1.5 
Reporting a Safety Endpoint as a Study Endpoint 
Safety endpoints (subject incidence of DLTs, TEAEs, treatment-related adverse events 
[TRAEs], and changes in vital signs, ECGs, and clinical laboratory tests) that are study 
endpoints are reported on the Event CRF.  All endpoints that also meet the criteria of 
serious adverse event must also be transmitted to safety within 24 hours of the 
investigator’s knowledge of the event (refer to Section 11.4). 
8.2.5.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.5.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported 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 
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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. 
8.2.5.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
8.2.5.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.5.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
120 days following cessation of study treatment or 30 days following cessation of study 
treatment if the subject initiates a new anti-cancer therapy. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.6 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1, Table 1-3, Table 1-5) for the timing and frequency. 
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine 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. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1, Table 1-3, Table 1-5). 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within 24 hours of initiation of investigational product for females of childbearing potential 
(eg, after admission and prior to a first dose of investigational product). 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, Figure 11-2).  Refer to Section 11.5 for contraceptive requirements. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.7 
Pharmacokinetic Assessments 
All subjects enrolled in the study will have pharmacokinetic samples assessed. 
Blood samples of approximately 5 mL will be collected for measurement of serum 
concentrations of AMG 330 and pembrolizumab as specified in the Schedule of Activities 
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(Section 1.3).  Instructions for the collection and handling of biological samples will be 
provided by the sponsor.  The actual date and time (24-hour clock time) of each sample 
will be recorded. 
Blood must not be drawn from the port catheter.  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.  If 
the PK sample must be drawn through the central line, AMG 330 administration should 
be interrupted during sample withdrawal.  PK samples for pembrolizumab will be 
collected and held for PK assessments. 
8.2.8 
Pharmacodynamic Assessments 
Venous blood samples of approximately 3 mL will be collected for measurement of 
 at timepoints listed in the Schedule of 
Activities. 
8.2.10 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Table 1-1, Table 1-3, Table 1-5) for the 
measurement of anti-AMG 330 binding antibodies and anti-pembrolizumab antibody (as 
necessary).  Subjects testing positive for binding antibodies may be further 
characterized.  Subjects who test positive for anti-AMG 330 antibodies at the final 
scheduled antibody time point and have clinical sequelae that are considered potentially 
related to an anti-AMG 330 antibody response will also be asked to return for additional 
follow-up testing.  This testing is to occur approximately every 3 months from the last 
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antibody time point and continue until: (1) antibodies are no longer detectable; or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks) post administration 
of AMG 330.  All follow-up results, both positive and negative will be communicated to 
the sites.  More frequent testing or testing for a longer period of time may be requested 
in the event of safety-related concerns.  Refer to the Schedule of Activities (Table 1-1, 
Table 1-3, Table 1-5), as applicable, for specific time points, and the laboratory manual 
for detailed collection and handling instructions. 
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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
This is a phase 1 study and no formal statistical hypothesis will be tested. 
9.2 
Sample Size Determination 
Approximately 20 subjects will be enrolled in this study with at least 6 DLT evaluable 
subjects in each cohort.  With 6 evaluable subjects in 1 cohort, there is an 82% chance 
of observing at least 1 DLT if the true DLT rate is 25%.  For cohort 1, at least 10 subjects 
will be dosed through study day 28. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 330 or pembrolizumab. 
The analysis of DLT will be restricted to DLT-evaluable subjects (see definition of 
DLT-evaluable in Section 6.2.1). 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
AMG 330 or pembrolizumab and have at least 1 PK sample collected.  These subjects 
will be evaluated for PK analysis unless the number of data points required for analysis 
is not enough, or significant protocol deviations have affected the data, or if key dosing 
or sampling information is missing. 
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9.3.2 
Covariates 
This phase 1 study has no prespecified covariates. 
9.3.3 
Subgroups 
This phase 1 study has no prespecified subgroups. 
9.3.4 
Handling of Missing and Incomplete Data 
Details on handling of missing and incomplete data are described in the statistical 
analysis plan. 
9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  
Details of the statistical analysis will be described in the statistical analysis plan.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1.  
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  A DLRM will occur when at least 
10 treated subjects in cohort 1 have been dosed through study day 28 to determine if the 
safety profile of initial steps in cohort 1 is acceptable to begin enrollment of cohort 2 or if 
the study should be stopped.  If 3 or more of the 10 treated subjects in cohort 1 
experience a DLT by day 28, the guidance to the DLRT is to recommend not to initiate 
cohort 2.  The stopping rule is based on having at least a posterior probability of > 70% 
that the DLT rate is > 20% assuming a prior distribution of Beta (0.40, 1.60).  If the true 
DLT rate is 10%, 20%, 30%, 40%, or 50%, then the probability of stopping the study at 
the interim analysis is 7%, 32%, 62%, 83%, 95%, respectively. 
9.4.1.2 
Primary Analysis 
The primary analysis will occur when all subjects complete end of study. 
9.4.1.3 
Final Analysis 
The primary analysis will also be the final analysis. 
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9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
 and 
 data overall and by cohort 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. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper and Pearson (1934). 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
The proportion of subjects with a response to treatment (CRMRD-, CR, 
CRi, MLFS, or CRh*) and exact 80% CI will be tabulated overall by 
cohort.  Duration of response will be presented per subject and 
Kaplan-Meier estimates may also be further presented if data allows. 
Exploratory 
Details will be provided in the statistical analysis plan  
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses of safety endpoints will 
be done using subjects from the safety analysis set. 
Subject incidence of DLT will be tabulated overall and by planned 
cohort. 
The statistical analysis methods for other safety endpoints are 
described in Sections 9.4.2.3.2 through 9.4.2.3.6. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all TEAEs will be tabulated by system organ class and preferred 
term.  Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required therapies will be 
provided. 
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9.4.2.3.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject.  
Depending on the size and scope of changes in laboratory data, the analyses of safety 
laboratory endpoints including summary statistics over time and/or changes from 
baseline over time may be provided.  Shifts in grades of safety laboratory values from 
baseline for selected laboratory values may also be provided. 
9.4.2.3.4 
Vital Signs 
Vital signs data will be reviewed for each subject.  The analyses of vital signs including 
summary statistics over time and/or changes from baseline over time may be provided. 
9.4.2.3.5 
Physical Measurements 
Physical measurements will be reviewed for each subject. 
9.4.2.3.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects' maximum change from baseline in QTc 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 plotted. 
9.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 330 antibodies at any 
time will be tabulated overall and by cohort. 
9.4.2.3.8 
Exposure to Investigational Product 
Details of AMG 330 and pembrolizumab administration will be listed for every subject. 
9.4.2.3.9 
Exposure to Other Protocol-required Therapy 
Details of dexamethasone and tocilizumab administration will be listed for every subject. 
9.4.2.3.10 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each cohort as coded by the World Health Organization 
Drug dictionary. 
9.4.2.4 
Other Analyses 
Based on the review of the data, analyses to describe the relationship between 
AMG 330/pembrolizumab exposure and either 
 and/or clinical 
outcome may also be performed. 
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10. 
References 
AMG 330 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Alfayez M, Borthakur G.  Checkpoint inhibitors and acute myelogenous leukemia:  
promises and challenges.  Expert Rev Hematol.  2018;11(5):373-389. 
Andrews RG, Singer JW, Bernstein ID.  Precursors of colony-forming cells in humans 
can be distinguished from colony-forming cells by expression of the CD33 and CD34 
antigens and light scatter properties.  J Exp Med.  1989;169:1721-1731. 
Andrews RG, Takahashi M, Segal GM, et al.  The L4F3 antigen is expressed by 
unipotent and multipotent colony-forming cells but not by their precursors.  Blood.  
1986;68:1030-1035. 
Arber DA, Orazi A, Hasserjian R, et al.  The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia.  Blood.  
2016;127(20):2391-2405. 
Blank C, Brown I, Peterson AC, et al.  PD-L1/B7H-1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells.  Cancer Res.  
2004;64(3):1140-1145. 
Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N.  The emerging 
role of immune checkpoint based approaches in AML and MDS.  Leuk Lymphoma.  
2018;59(4):790-802. 
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.  2011;29:369-377. 
Chemnitz JM, Parry RV, Nichols KE, et al.  SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary 
Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation.  J 
Immunol.  2004;173:945-954. 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-13. 
Curran MA, Montalvo W, Yagita H, Allison JP.  PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors.  Proc Natl Acad Sci U S A.  2010;107(9):4275-4280. 
De la Fuente H, Cibrián D, Sánchez-Madrid F.  Immunoregulatory molecules are master 
regulators of inflammation during the immune response.  FEBS Lett.  
2012;586(18):2897-2905. 
Disis ML.  Immune regulation of cancer.  J Clin Oncol.  2010;28(29):4531-4538. 
Döhner H, Estey E, Grimwade D, et al.  Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel.  Blood.  
2017;129(4):424-447. 
Dudley ME, Wunderlich JE, Yang, JC, et al.  Adoptive Cell Transfer Therapy Following 
Non-myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients 
With Refractory Metastatic Melanoma.  J Clin Oncol.  2005;2346-2357. 
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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 
Francisco LM, Sage PT, Sharpe AH.  The PD-1 pathway in tolerance and autommunity.  
Immunol Rev.  2010;236:219-242. 
Greenwald, RJ, Freeman GJ, Sharpe AH.  The B7 Family Revisited.  Annu Rev 
Immunol.  2005;23:515-548. 
Hirano F, Kaneko K, Tamura H, et al.  Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity.  Cancer Res.  
2005;65(3):1089-1096. 
Hobo W, Hutten TJA, Schaap NPM, Dolstra H.  Immune checkpoint molecules in acute 
myeloid leukaemia:  managing the double-edged sword.  Br J Haematol.  
2018;181(1):38-53. 
Hunder NN, Wallen H, Cae J, et al.  Treatment of metastatic melanoma with autologous 
CD4+ T cells against NY-ESO-1.  N Engl J Med.  2008;358(25):2698-2703. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Krupka C, Kufer P, Kischel R, et al.  Blockade of the PD-1/PD-L1 axis augments lysis of 
AML cells by the CD33/CD3 BiTE antibody construct AMG 330:  reversing a 
T-cell-induced immune escape mechanism.  Leukemia.  2016;30(2):484-491. 
Krupka C, Kufer C, Kischel R, et al.  PD-1/PD-L1 Blocking Enhances CD33/CD3-
Bispecific BiTE® Antibody (AMG 330) Mediated Lysis of Primary AML Cells.  Blood.  
2014;124:3738. 
La Russa VF, Griffin JD, Kessler SW, et al.  Effects of anti-CD33 blocked ricin 
immunotoxin on the capacity of CD34+ human marrow cells to establish in vitro 
hematopoiesis in long-term marrow cultures.  Exp Hematol.  1992;20:442-448. 
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. 
Nomi T, Sho M, Akahori T, et al.  Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.  
Clin Cancer Res.  2007;13(7):2151-2157. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T.  PD-1 immunoreceptor inhibits 
B cell receptor mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine.  Proc Natl Acad Sci USA.  
2001;98(24):13866-13871. 
Parry RV, Chemnitz JM, Frauwirth KA, et al.  CTLA-4 and PD01 Receptors Inhibit T-Cell 
Activation by Distinct Mechanisms.  Mol Cell Biol.  2005;25(21):9543-9553. 
Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ.  Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma.  
J Immunol.  2010;184(7):3442-3449. 
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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. 
Ravandi F.  Relapsed acute myeloid leukemia:  why is there no standard of care? Best 
practice & research.  2013;26:253-9. 
Ravandi F, et al.  A Phase 1 first-in-human study of AMG 330, an anti-CD33 bispecific 
T-Cell engager (BiTE®) antibody construct, in relapsed/refractory acute myeloid leukemia 
(R/R AML).  2018 Dec 1; Oral Abstract #25:  60 ASH Annual Meeting and Exposition, 
San Diego, CA. 
Riley JL.  PD-1 signaling in primary T cells.  Immunol Rev.  2009:0105-2896. 
Scheinberg DA, Tanimoto M, McKenzie S, Strife A, Old LJ, Clarkson BD.  Monoclonal 
antibody M195:  a diagnostic marker for acute myelogenous leukemia.  Leukemia.  
1989;3:440-445. 
Sheppard KA, Fitz LJ, Lee JM, et al.  PD-1 inhibits T-cell receptor induced 
phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to 
PKCtheta.  FEBS Lett.  2004;574(1-3):37-41. 
Society AC.  Cancer Facts and Figures, 2014.  Atlanta, George, USA:  American Cancer 
Society; 2014. 
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF.  Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment.  J Immunother Cancer.  2014;2:3. 
Strome SE, Dong H, Tamura H, et al.  B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma.  Cancer Res.  2003;63(19):6501-6505. 
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;3:339-348. 
Weber J.  Immune checkpoint proteins:  a new therapeutic paradigm for cancer - 
preclinical background:  CTLA-4 and PD-1 blockade.  Semin Oncol.  
2010;37(5):430-439. 
Westervelt, P, Roboz, GJ, Cortes, JE, et al.  Phase 1 first-in-human trial of AMV564, a 
bivalent bispecific (2x2) CD33/CD3 T-cell engager, in patients with relapsed/refractory 
acute myeloid leukemia (AML).  Blood.  2018;132:1455. 
Zhang L, Gajewski TF, Kline J.  PD-1/PD-L1 interactions inhibit antitumor immune 
responses in a murine acute myeloid leukemia model.  Blood.  
2009;114(8):1545-1552. 
 
 
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11. 
Appendices 
 
 
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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APML 
promyelocytic leukemia 
AST 
aspartate aminotransferase 
BCG 
Bacillus Calmette–Guérin 
BiTE 
bispecific T-cell engager 
CAR 
chimeric antigen receptor 
CD 
cluster of differentiation 
CI 
confidence interval 
cIV 
continuous intravenous 
CL 
clearance 
CNS 
central nervous system 
CR 
complete remission 
CRF 
case report form 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete count recovery 
CRMRD- 
complete remission without mininum residual disease 
CRS 
cytokine release syndrome 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
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 
ECG 
electrocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELN 
European LeukemiaNet 
EOI 
end of infusion 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
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GLP 
Good Laboratory Practice 
GSO 
Global Safety Officer 
GVHD 
Graft versus Host Disease 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HRT 
hormonal replacement therapy 
HSCT 
hematopoietic stem cell transplantation 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
Ig 
immunoglobulin 
IL 
interleukin 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
IUD 
intrauterine device 
IV 
intravenous 
IVSS 
intravenous solution stabilizer 
LDH 
lactate dehydrogenase 
 
 
MLFS 
morphologic leukemia-free state 
 
 
MTD 
maximum tolerated dose 
NCT 
National Clinical Trials 
NOD 
non-obese diabetic 
PCR 
polymerase chain reaction 
PD-1 
programmed cell death receptor 
PD-L1/PD-L2 
programmed cell death ligand 1/2 
PK 
pharmacokinetic 
PR 
partial remission 
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R/R AML 
relapsed or refractory AML 
RBC 
red blood cell 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SCID 
severe combined immunodeficiency 
SFU 
safety follow-up 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse events 
TLS 
tumor lysis syndrome 
TRAE 
treatment-related adverse event 
ULN 
upper limit of normal 
WBC 
white blood cells 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
ZAP 
zeta-chain-associated protein kinase 
 
 
 
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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local laboratory.  Protocol-specific requirements for inclusion or exclusion of subjects are 
detailed in Sections 5.1 to 5.2 of the protocol.  Additional tests may be performed at any 
time during the study as determined necessary by the investigator or required by local 
regulations. 
Table 11-1.  Analyte Listing 
Local Laboratory 
Chemistry 
Urinalysis 
Hematology 
Coagulation 
sodium 
potassium 
chloride 
bicarbonate  
total protein 
albumin 
calcium 
magnesium 
phosphorus 
glucose 
creatinine 
uric acid 
total bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
CRP 
ferritin 
specific gravity 
pH 
blood 
protein  
glucose 
bilirubin 
ketones 
Microscopic exam 
(performed at the 
discretion of the 
investigator): 
WBC 
RBC 
epithelial cells 
bacteria 
casts 
crystals 
RBC 
nucleated RBC 
hemoglobin 
hematocrit 
MCV 
reticulocytes 
platelets 
WBC 
WBC differential: 
• total neutrophils 
• seg. neutrophils 
• bands/stabs 
• eosinophils 
• basophils 
• lymphocytes 
• monocytes  
• myeloblasts 
• monoblasts 
• megakaryoblasts 
• promyelocytes 
• myelocytes 
• metamyelocytes 
• atypical  
• lymphocytes 
• blasts 
• immature 
granulocytes 
PTT/APTT 
PT/INR 
fibrinogen 
AT III 
Thyroid Function Tests 
T3 or FT3 
FT4 
TSH 
Other Labs 
HLA typing 
hep B surface antigen 
hep C antibody 
HBV DNA 
HCV RNA 
HIVa 
serum or urine 
pregnancy 
 
Central Laboratory 
anti-AMG 330 antibodies 
anti-pembrolizumab antibodiesb 
AMG 330 PK samples 
pembrolizumab PK samplesb 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
APTT = activated partial thromboplastin time; AT III = antithrombin III; CRP = c-reactive protein; FT3 = free 
triiodothyronine; FT4 = free thyroxine; HBV = hepatitis B virus; HCV = hepatitis C virus; Hep = hepatitis; 
HIV = human immunodeficiency virus; HLA = human leukocyte antigen; INR = international normalized 
ratio; LDH = lactate dehydrogenase; 
; MCV = mean corpuscular volume; 
; PK = pharmacokinetic; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell count; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic-pyruvic transaminase; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; 
WBC = white blood cell count 
a HIV assessment is recommended. 
b Collect and hold; analysis to be triggered at the discretion of the sponsor. 
 
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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings 
In this study, a dose level review meeting (DLRM) will be conducted 1 time to review and 
interpret safety data for the purposes of making recommendations about opening cohort 
2 and evaluating safety signals for purposes of applying dose cohort/individual stopping 
rules.  The Dose Level Review Team (DLRT) will meet to confirm the decision rules 
when the following criterion is met: 
 
at least 10 treated subjects in cohort 1 have been dosed through the end of 
 
µg/day Step Dose (study day 28). 
The required DLRT members are the Early Development Lead, Medical Monitor, Global 
Safety Officer (GSO), and Site Investigators.  The DLRT will also include the Early 
Development Medical Director (Merck) in an advisory role.  The DLRT will include Site 
Investigators from activated sites.  The Early Development Lead, Medical Monitor, GSO, 
and Site Investigators are the only voting DLRT members.  The following non-voting 
Amgen representatives may also be part of the DLRT:  clinical study manager, 
biostatistician, pharmacokinetics (PK) scientist. 
The Early Development Lead and Medical Monitor must be in attendance and cannot be 
represented by a voting designee or delegate.  Voting designees can be identified as 
appropriate by the GSO or Site Investigator(s).  A Site Investigator may identify a 
delegate (eg, sub-Investigator) who is listed in the Delegation of Authority.  If a Site 
Investigator does this, the Site Investigator must provide written agreement with the 
designee or delegate’s vote.   
For a DLRM to occur, the Early Development Lead and Medical Monitor must attend, 
and the GSO or delegate must attend.  In addition, a quorum of Site Investigators must 
be present.  A quorum is defined as more than 50% of the participating investigators or 
their qualified designee.  The DLRM will be rescheduled if these requirements are not 
met. 
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.  Data to be reviewed will be 
unqueried. 
DLRM voting will occur as follows:  there will be a total of 4 votes, 1 for Early 
Development Lead, 1 for the Medical Monitor, 1 for the GSO or delegate, and 1 for all of 
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the Site Investigators or delegates combined.  Regardless of how many Site 
Investigators there are, all of the Site Investigators combined will have a total of 1 vote 
decided by a majority of the investigators (defined as greater than or equal to 50%). 
DLRM recommendations to escalate to the next planned cohort (cohort 2) must be by 
unanimous vote.  If the voting members of the DLRT are not able to reach a unanimous 
recommendation on whether to escalate to the next planned cohort, then this should be 
reflected in the DLRM Memo. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and ICF must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  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 must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
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 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
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 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S.  Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the sample ICF are to be 
communicated formally in writing from the Amgen Trial Manager to the investigator.  The 
written ICF is to be prepared in the language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study. 
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  Subject withdrawal of consent 
or discontinuation from study treatment and/or procedures must also be documented in 
the subject’s medical records; refer to Section 6.8. 
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Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the subject. 
Subjects who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future research.  The investigator or authorized designee will 
explain to each subject the objectives of the future research.  Subjects will be told that 
they are free to refuse to participate and may withdraw their specimens at any time and 
for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for future 
research.  Subjects who decline to participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at 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 age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental regulations/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.   
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The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to 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 need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
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 must qualify for authorship, and all those who qualify are 
to be listed.  Each author must 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 review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
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Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
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 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
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. 
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. 
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In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit 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. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the country-
specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
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 provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
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.  Source documents may also include data captured in the 
Interactive Response Techonology (IRT) system (if used, such as subject ID and 
randomization number) and CRF entries if the CRF is the site of the original recording 
(ie, there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
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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. 
 
Subject files containing completed CRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s) 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
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(s) 
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 the product(s) is/are available commercially. 
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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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. 
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events (TEAEs) will be defined in the 
Statistical Analysis Plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], radiological scans, 
vital signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as 
an adverse event/serious adverse event unless it is an intentional overdose taken 
with possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
For situations when an adverse event or serious adverse event is due to acute 
myeloid leukemia (AML), report all known signs and symptoms.  Death due to 
disease progression in the absence of signs and symptoms should be reported as 
the primary tumor type (eg, metastatic pancreatic cancer).  Note:  The term 
“disease progression” should not be used to describe the adverse event. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event 
or serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
 
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Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
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Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (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 (or toxicity defined below); 
 
Assessment of relatedness to investigational product, other protocol-required 
therapies and 
 
Action taken. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor in lieu of completion of the Event CRF page. 
 
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.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
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Evaluating Adverse Events and Serious Adverse Events 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product or protocol-required therapies and each occurrence of each adverse 
event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
Assesment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 
which is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
with the exception of cytokine release syndrome (CRS), which must be graded using 
the criteria referenced in the publication by Lee et al (2014), and tumor lysis syndrome 
(TLS), which must be graded using the Cairo-Bishop criteria. 
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of a serious adverse event, NOT when it is rated as severe. 
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 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form. 
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Event Contingency 
Report Form (see Figure 11-1) within 24 hours of the investigator’s knowledge of 
the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on the 
Serious Adverse Event Contingency Report Form (see Figure 11-1). 
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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 
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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female subjects of childbearing 
potential are outlined in Sections 5.1 and 5.2. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 120 days after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception.  The investigator must discuss 
these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) 
review of subject’s medical records; 2) subject’s medical examination; or 3) subject’s 
medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single follicle 
stimulating hormone measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 
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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 120 days after the last dose of 
protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, IUD, intrauterine hormonal-releasing system, female 
barrier method (diaphragm, cap, sponge [a female condom is not an option because 
there is a risk of tearing when both partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 120 days after the last 
dose of study drug. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 120 days after 
the last dose of the study drug.  This information will be forwarded to Amgen Global 
Patient Safety.  Generally, infant follow-up will be conducted up to 12 months after 
the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
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. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting. 
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
120 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  (Note:  Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
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 
The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 120 days after the last dose of study 
drug. 
 
Information will be recorded on the Lactation Notification Form (Figure 11-2) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 229. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
comlete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 120 days after discontinuing protocol-
required therapies. 
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Figure 11-2.  Pregnancy and Lactation Notification Forms 
 
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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood, bone marrow, or saliva sample collected according to the Schedule of 
Activities (Section 1.3) 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 the 
leukemia disease state, the dose response and/or prediction of response to AMG 330 in 
combination with pembrolizumab, and characterize aspects of the molecule (eg, 
mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of 
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 
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 
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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. 
 
 
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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [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 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver 
(TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix. 
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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product and/or 
other protocol-required therapies is to be permanently discontinued.  Subjects who 
clearly meet the criteria for permanent discontinuation (as described in Table 11-2) are 
never to be rechallenged. 
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Drug-induced Liver Injury Reporting and 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 the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to 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 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated 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 (BIL) (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. 
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 with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
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 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-
type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase 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 a 
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 the corresponding CRFs. 
 
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11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as an FDA IND safety report by the sponsor.  
Identification and reporting of anticipated serious adverse events is the responsibility of 
the sponsor; the investigator is responsible for reporting adverse events and serious 
adverse events as described in Section 11.4. 
Anticipated Serious Adverse Events for Study 20170646 
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 
1Represents preferred terms under Infections and infestations SOC 
2 Represents haemorrhage HLGT preferred terms contained within multiple SOCs 
Coded:  MedDRA v17.0  
 
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11.9 
Appendix 9.  Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
Grade 
Description 
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 house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed 
or chair 
5 
Dead 
Source:  Oken et al, 1982 
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11.10 
Appendix 10.  World Health Organization Classification for Acute 
Myeloid Leukemias 
Definition acute myeloid leukemia (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 promyelocytic leukemia (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 (Arber et al, 2016). 
Table 11-3.  2016 WHO Classification for AML 
Type of AML diagnosis 
 
Acute myeloid leukemia with recurrent genetic abnormalities 
 
Acute myeloid leukemia with myelodysplasia-related changes 
 
Therapy-related myeloid neoplasms 
 
Acute myeloid leukemia not otherwise specified 
 
Myeloid sarcoma (syn.:  extramedullary myeloid tumor; granulocytic sarcoma; chloroma) 
 
Myeloid proliferations related to Down syndrome 
 
Blastic plasmacytoid dendritic cell neoplasm 
 
Acute leukemias of ambiguous lineage 
 
Other 
Subtype of AML at diagnosis for acute myeloid leukemia with recurrent genetic abnormalities 
 
AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
 
AML with PML-RARA 
 
AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A 
 
AML with t(6;9)(p23;q34.1); DEK-NUP214 
 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;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 mutations of CEBPA 
 
Provisional entity:  AML with mutated RUNX1 
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Table 11-3.  2016 WHO Classification for AML 
Subtype of AML at diagnosis for 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 
Subtype of AML at diagnosis for myeloid proliferations related to down syndrome 
 
Transient abnormal myelopoiesis  
 
Myeloid leukemia associated with Down syndrome 
Subtype of AML at diagnosis for acute leukemias of ambiguous lineage 
 
Acute undifferentiated leukemia 
 
Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1ǁ 
 
Mixed phenotype acute leukemia with t(v;11q23.3); KMT2A rearranged 
 
Mixed phenotype acute leukemia, B/myeloid, NOS 
 
Mixed phenotype acute leukemia, T/myeloid, NOS 
Page 2 of 2 
 
 
Approved 
 
 


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11.11 
Appendix 11.  European LeukemiaNet (ELN) Response Criteria in 
Acute Myeloid Leukemia (2017) 
Category 
Definition 
Comment 
Response 
CR without 
minimal residual 
disease (CRMRD–) 
If studied pretreatment, CR with negativity for a genetic 
marker by RT–qPCR, or CR with negativity by MFC 
Sensitivities vary by marker 
tested, and by method used; 
therefore, test used and 
sensitivity of the assay should 
be reported; analyses should 
be done in experienced 
laboratories (centralized 
diagnostics) 
Complete 
remission (CR) 
Bone marrow blasts < 5%; absence of circulating blasts 
and blasts with Auer rods; absence of extramedullary 
disease; ANC ≥ 1.0 x 109/L (1000/µL); platelet count 
≥ 100 x 109/L (100 000/µL) 
MRD+ or unknown 
CR with 
incomplete 
hematologic 
recovery (CRi) 
All CR criteria except for residual neutropenia 
(< 1.0 x 109/L [1000/µL]) or thrombocytopenia 
(< 100 x 109/L [100 000/µL]) 
  
Morphologic 
leukemia-free 
state (MLFS) 
Bone marrow blasts < 5%; absence of blasts with Auer 
rods; absence of extramedullary disease; no 
hematologic recovery required 
Marrow should not merely be 
"aplastic"; at least 200 cells 
should be enumerated or 
cellularity should be at least 
10% 
Partial remission 
(PR) 
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% 
Especially important in the 
context of phase 1/2 clinical 
trials 
Treatment failure 
Primary refractory 
disease 
No CR or CRi after 2 courses of intensive induction 
treatment; excluding patients with death in aplasia or 
death due to indeterminate cause 
Regimens containing higher 
doses of cytarabine are 
generally considered as the 
best option for patients not 
responding to a first cycle of 
7+3; the likelihood of 
responding to such regimens is 
lower after failure of a first 
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 
  
Page 1 of 2 
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Category 
Definition 
Comment 
Response criteria for clinical trials only 
Stable disease 
Absence of CRMRD–, CR, CRi, PR, MLFS; and criteria 
for PD not met 
Period of stable disease should 
last at least 3 months 
Progressive 
disease (PD)*¶ 
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast counts in 
the blood:  
 
> 50% increase in marrow blasts over baseline (a 
minimum 15% point increase is required in cases 
with < 30% blasts at baseline; or persistent marrow 
blast percentage of > 70% over at least 3 months; 
without at least a 100% improvement in ANC to an 
absolute level (> 0.5 x 109/L [500/µL], and/or 
platelet count to > 50 x 109/L [50 000/µL] 
nontransfused); or  
 
> 50% increase in peripheral blasts 
(WBC x % blasts) to > 25 x 109/L (> 25 000/µL) (in 
the absence of differentiation syndrome)¶; or  
 
New extramedullary disease  
Category mainly applies for 
older patient given low-intensity 
or single-agent "targeted 
therapies" in clinical trials 
In general, at least 2 cycles of a 
novel agent should be 
administered 
Some protocols may require 
blast increase in 2 consecutive 
marrow assessments at least 
4 weeks apart; the date of 
progression should then be 
defined as of the first 
observation date 
Some protocols may allow 
transient addition of 
hydroxyurea to lower blast 
counts 
"Progressive disease" is 
usually accompanied by a 
decline in ANC and platelets 
and increased transfusion 
requirement and decline in 
performance status or increase 
in symptoms  
Relapse 
Hematologic 
relapse (after 
CRMRD–, CR, CRi) 
Bone marrow blasts ≥ 5%; or reappearance of blasts in 
the blood; or development of extramedullary disease 
  
Molecular relapse 
(after CRMRD–) 
If studied pretreatment, reoccurrence of MRD as 
assessed by RT–qPCR or by MFC 
Test applied, sensitivity of the 
assay, and cutoff values used 
must be reported; analyses 
should be done in experienced 
laboratories (centralized 
diagnostics) 
Page 2 of 2 
ANC = absolute neutrophil count; CR = complete response; CRMRD- = CR without minimal residual disease; 
IDH = isocitrate dehydrogenase; MFC = multiparameter flow cytometry; MLFS = morphologic 
leukemia-free state; MRD = measurable residual disease (also known as minimal residual disease); 
PD = progressive disease; PR = partial remission; RT-qPCR = real-time quantitative polymerase chain 
reaction; WBC = white blood cell. 
* The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at 
harmonizing the various definitions used in different clinical trials. 
¶ Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation 
syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase 
in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily 
indicate PD. 
Reproduced with permission of the American Society of Hematology.  From:  Döhner H, Estey E, Grimwade 
D, et al.  Diagnosis and management of AML in adults:  2017 ELN recommendations from an international 
expert panel.  Blood.  2017;129:424; permission conveyed through Copyright Clearance Center.  
Copyright © 2017. 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 330 + Pembrolizumab 
Protocol Number:  20170646 
Date:  25 August 2020 
Page 1 of 35 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b Study Assessing Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and 
Efficacy of AMG 330 cIV in Combination With 
Pembrolizumab in Adult Subjects With Relapsed or 
Refractory Acute Myeloid Leukemia 
Short Protocol Title: 
A Phase 1b Study of AMG 330 in Combination With 
Pembrolizumab in Adult Subjects with Relapsed or 
Refractory Acute Myeloid Leukemia 
Protocol Number: 
20170646 
NCT Number: 
N/A 
Authors: 
, Global Biostatistical 
Science 
, Global Biostatistical Science 
, Clinical Pharmacology 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Date 
Original (v[1.0]) 
25 August 2020 
 
NCT Number: NCT04478695
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 330 + Pembrolizumab 
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CONFIDENTIAL 
Table of Contents 
1.
Introduction ............................................................................................................. 7
2.
Objectives, Endpoints and Hypotheses ................................................................... 7
2.1
Objectives and Endpoints ............................................................................ 7
2.2
Hypotheses and/or Estimations ................................................................... 8
3.
Study Overview ...................................................................................................... 8
3.1
Study Design ............................................................................................... 8
3.1.1 
Cohort 1 Design ........................................................................ 10
3.1.2 
Cohort 2 Design ........................................................................ 12
3.2
Sample Size .............................................................................................. 13
3.3
Adaptive Design ........................................................................................ 13
4.
Covariates and Subgroups ................................................................................... 13
4.1
Planned Covariates ................................................................................... 13
4.2
Subgroups ................................................................................................. 13
5.
Definitions ............................................................................................................. 13
5.1
General Definitions .................................................................................... 13
5.2
Study Points of Reference ......................................................................... 14
5.3
Study Dates .............................................................................................. 15
5.4
Endpoints .................................................................................................. 16
5.5
Treatment Response ................................................................................. 17
6.
Analysis Sets ........................................................................................................ 17
6.1
Safety Analysis Set ................................................................................... 17
6.2
Dose Limiting Toxicity (DLT) Evaluable Analysis Set ................................ 17
6.3
Pharmacokinetic Analyses Set(s) .............................................................. 17
7.
Planned Analyses ................................................................................................. 17
7.1
Interim Analysis and Early Stopping Guidelines ........................................ 17
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 ....................................................................................... 18
8.5
Outliers ..................................................................................................... 18
8.6
Distributional Characteristics ..................................................................... 19
8.7
Validation of Statistical Analyses ............................................................... 19
9.
Statistical Methods of Analysis.............................................................................. 19
9.1
General Considerations ............................................................................. 19


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9.2 
Subject Accountability ............................................................................... 19 
9.3 
Important Protocol Deviations ................................................................... 19 
9.4 
Demographic and Baseline Characteristics ............................................... 20 
9.5 
Efficacy Analyses ...................................................................................... 20 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 20 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 20 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 21 
9.6 
Safety Analyses ........................................................................................ 21 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 21 
9.6.2 
Adverse Events ......................................................................... 21 
9.6.3 
Laboratory Test Results ............................................................ 22 
9.6.4 
Vital Signs ................................................................................. 22 
9.6.5 
Physical Measurements ............................................................ 22 
9.6.6 
Electrocardiogram ..................................................................... 22 
9.6.7 
Antibody Formation ................................................................... 23 
9.6.8 
Exposure to Investigational Product .......................................... 23 
9.6.9 
Exposure to Other Protocol-required Therapy ........................... 23 
9.6.10 
Exposure to Concomitant Medication ........................................ 24 
9.7 
Other Analyses ......................................................................................... 24 
9.7.1 
Analyses of Pharmacokinetic Endpoints .................................... 24 
9.7.1.1 
Pharmacokinetic Analysis of AMG 330 .................... 24 
9.7.1.2 
Pharmacokinetic Analysis of 
Pembrolizumab ....................................................... 24 
10. 
Changes From Protocol-specified Analyses.......................................................... 24 
11. 
Literature Citations / References ........................................................................... 25 
12. 
Prioritization of Analyses....................................................................................... 28 
13. 
Data Not Covered by This Plan............................................................................. 28 
14. 
Appendices ........................................................................................................... 29 
 
List of Table 
Table 3-1.  Dosing for Cohort 1 (Cycle 1) ...................................................................... 11 
Table 3-2.  Dosing for Cohort 1 (Cycle 2 and Beyond) ................................................... 11 
Table 3-3.  Dosing for Cohort 2 (All Cycles) ................................................................... 12 
Table 14-1.  Notable Abnormalities of Vital Signs and Physical Measurement ............... 32 


Product:  AMG 330 + Pembrolizumab 
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List of Appendices 
Appendix A.  Technical Details and Supplemental Information Regarding 
Statistical Procedures ............................................................................. 30 
Appendix B.  Reference Values/Toxicity Grades ........................................................... 32 
Appendix C.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ..................................................................................................... 33 
Appendix D.  European LeukemiaNet (ELN) Response Criteria in Acute 
Myeloid Leukemia (2017) ....................................................................... 34 


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List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
ADA 
AE 
Anti-drug antibodies 
Adverse event 
AML 
Acute myeloid leukemia 
CI 
Confidence interval 
cIV 
CPMS 
Continuous intravenous 
Clinical Pharmacology, Modeling and Simulation 
CR 
Complete remission 
CRF 
Case report form 
CRi 
Complete remission with incomplete count recovery 
CRMRD- 
Complete remission without minimal residual disease 
CRS 
CSR 
Cytokine release syndrome 
Clinical study report   
CTCAE 
Common Terminology Criteria for Adverse Events 
DLRM 
Dose level review meeting 
DLRT 
Dose level review team 
DLT 
DM 
DOR 
Dose-limiting toxicity 
Data Management 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Easter Cooperative Oncology Group 
ELN 
European Leukemia Net 
EOI 
End of infusion 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GSO 
Global Safety Officer 
HSCT 
Hematopoietic stem cell transplantation 
IP 
IPD 
Investigational Product  
Important Protocol Deviation 
IV 
Intravenous 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLFS 
mg 
Morphologic leukemia-free state 
Milligram 


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Abbreviation or Term 
Definition/Explanation 
PK 
Pharmacokinetic 
PR 
Q3W 
QTcB 
QTcF 
Partial remission 
Every  3 weeks 
Bazett-corrected QT Interval (QTcB) 
Fridericia-corrected QT Interval (QTcF) 
R/R AML 
Relapsed or refractory AML 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SFU 
Safety follow-up 
Study Day 1 
Defined as the first day that investigational product(s) is 
administered to the subject 
TEAE 
TLS 
Treatment-emergent adverse events 
Tumor Lysis Syndrome 
TRAE 
Treatment-related adverse event 
WHO 
World Health Organization 
μg 
Microgram 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20170646, AMG 330 + 
Pembrolizumab dated 04 May 2020.  The scope of this plan includes the final analysis 
that is planned and will be executed by the Amgen Global Biostatistical Science 
department unless otherwise specified. Pembrolizumab PK/ADA will be analyzed by 
Merck if required. 
 
 
 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 330 administered in combination 
with pembrolizumab in subjects with 
relapsed or refractory acute myeloid 
leukemia (R/R AML) 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent adverse events (TEAEs), 
treatment-related adverse events (TRAEs), 
and changes in vital signs, electrocardiograms 
(ECGs), and clinical laboratory tests 
Secondary 
 
Evaluate the anti-leukemia activity of 
AMG 330 administered in combination 
with pembrolizumab in R/R AML 
patients 
 
Responses to treatment with AMG 330 
administered in combination with 
pembrolizumab.  Response is defined as any 
of the following:  complete remission without 
minimal residual disease (CRMRD-), 
complete remission (CR), CR with incomplete 
recovery (CRi), or morphological leukemia-
free state (MLFS), or partial remission (PR) 
(all according to the 2017 European Leukemia 
Net (ELN) criteria (Döhner et al, 2017) 
 
Duration of response 
 
Evaluate the pharmacokinetics (PK) 
of AMG 330 when AMG 330 and 
pembrolizumab are administered in 
combination 
 
AMG 330 concentrations and PK parameters 
(eg: half-life, steady state concentration, 
volume of distribution, and clearance) 
 
Evaluate the immunogenicity of 
AMG 330 when administered in 
combination with pembrolizumab 
 
Anti-AMG 330 antibody formation 
 
 


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Objectives 
Endpoints 
Exploratory 
 
Evaluate the pharmacokinetics (PK) 
of pembrolizumab when AMG 330 
and pembrolizumab are administered 
in combination 
 
Pembrolizumab (serum samples) 
concentrations. 
 
Evaluate the immunogenicity of 
pembrolizumab when AMG 330 and 
pembrolizumab are administered in 
combination 
 
Anti-pembrolizumab antibody formation  
 
Evaluate the relationship between 
AMG 330 and pembrolizumab 
exposure and response to treatment 
 
Serum levels AMG 330 and pembrolizumab, 
changes in tumor burden (exposure/efficacy) 
and adverse events  (exposure/safety) 
 
2.2 
Hypotheses and/or Estimations 
This is a phase 1 study and no formal statistical hypothesis will be tested. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b study assessing safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and efficacy of AMG 330 administered as continuous 
intravenous (cIV) infusion in combination with pembrolizumab in adult subjects with R/R 
AML.   
The study is a non-randomized study and will consist of 2 sequential dosing cohorts.  
Both cohorts will include AMG 330 and pembrolizumab with the difference being the 
initiation date for pembrolizumab treatment. 


Product:  AMG 330 + Pembrolizumab 
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This study will use a staggered enrollment approach. Subject enrollment will start with 
cohort 1 (Section 3.1.1).  The first subject dosed in cohort 1 will serve as the sentinel 
subject.  Subsequent subjects dosed in cohort 1 will start AMG 330 (
 µg/day) 
administration once sentinel subject has cleared the study day 21 dose (AMG 330 
monotherapy at 
 µg/day).  Per sponsor determination, if the sentinel subject does not 
experience a dose-limiting toxicity (DLT) on days 15 to 21 after pembrolizumab is 
administered, the other subjects in cohort 1 will be allowed to continue the planned 
treatment schedule.  If the sentinel subject experiences a DLT during days 15 to 21, the 
dose level review team (DLRT) will discuss the case and the decision will be made by 
the sponsor based on clinical assessments of the adverse event and potential decisions 
by the sponsor may include stopping AMG 330 and/or pembrolizumab, dose 
de-escalation of AMG 330, or continuing therapy at full dose.  Investigators and sponsor 
will meet after all subjects in cohort 1 have completed study day 28 (ie, AMG 330 
 µg/day dose level in combination with pembrolizumab) to assess the safety profile.  
If pre-specified safety criteria are met (≤ 3 out of 10 treated subjects in cohort 1 
experienced DLT by day 28), subjects enrolled in cohort 2 (Section 3.1.2) may proceed 
with the treatment schedule.  Similar to cohort 1, the first subject dosed in cohort 2 will 
serve as the sentinel subject.  Per sponsor determination, if the sentinel subject does not 
experience a DLT during the first 7 days, the other subjects in cohort 2 will be allowed to 
continue the planned treatment schedule. 
Safety data will be continuously monitored throughout the whole treatment period.  
Sponsor in consultation with investigators may reconvene to make appropriate safety 
measures and adjustments as needed. 
Subjects in both cohort 1 and cohort 2 may continue with cycle 2 and beyond of 
AMG 330 and pembrolizumab up to 6 months if the combination regimen remains 
tolerable and is deriving clinical benefit in the opinion of the investigator.  In both 
cohorts 1 and 2, subjects continuing with cycle 2 and beyond may be permitted to 
shorten the duration of AMG 330 step dose levels to 2 to 5 days based on individual 
clinical experience from cycle 1 and based on the clinical judgement of the investigator 
and in consultation and agreement with the sponsor.  The duration of the combination 
treatment period for individual subjects may be extended up to 1 year if the subject is 
deriving clinical benefit in the opinion of the investigator and in consultation with the 
sponsor. If AMG 330 is discontinued, pembrolizumab may be continued as a 
monotherapy until disease progression for a maximum of 35 cycles (approximately 


Product:  AMG 330 + Pembrolizumab 
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2 years).  If pembrolizumab is discontinued, AMG 330 may be continued as a 
monotherapy. 
3.1.1 
Cohort 1 Design 
Cycle 1 is 77 days in duration and subsequent cycles are 57 days.  Treatment will start 
with AMG 330 on day 1.  Dexamethasone 8 mg will be given to subjects 1 hour prior to 
each step dose of AMG 330.  AMG 330 will be administered at a starting dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 7 days.  
If the subject experiences DLT during these first 7 days of treatment with AMG 330 at 
 µg/day, this subject will be replaced.  If the subject has not experienced a DLT by 
day 14, they will receive pembrolizumab on day 15.  Pembrolizumab will be administered 
at a dose of 200 mg (Q3W) by a 30-minute IV infusion.  The subject will remain at an 
AMG 330 dose level of 
 µg/day for additional 7 days. 
Thereafter, AMG 330 dosing will continue as per Table 3-1, increasing dose levels to 
 µg/day for 7 days followed by 
 µg/day for 7 days.  If the subject has not 
experienced a DLT at the 
 µg/day dose level of AMG 330 between days 29 to 35, 
they will receive pembrolizumab on day 36 and remain on the AMG 330 
 µg/day 
dose for an additional 7 days.  AMG 330 dosing will further increase to 
 µg/day for 
7 days followed by 
 µg/day for 7 days.  If the subject has not experienced a DLT at 
the 
 µg/day dose level of AMG 330 between days 50 to 56, they will receive 
pembrolizumab on day 57 and remain on the 
 µg/day dose for additional 7 days.  To 
complete cycle 1, a final dose level increase to 
 µg/day AMG 330 for an additional 
14 days will be administered. 
Cycle 1 will be followed by a 1-week interval without AMG 330 administration and 
administration of pembrolizumab will continue non-interrupted on the Q3W schedule.  
The AMG 330-infusion free interval may be extended up to 4 weeks (depending on 
safety, treatment response, and in case of prolonged marrow aplasia and cytopenia in 
aleukemic subjects) after consultation with the sponsor. 
Cycle 2 will start with the initiation of AMG 330 administration and include the same step 
dose levels and duration as in cycle 1 with the exception of the 
 and 
 µg/day 
dose levels, which will be shortened from 14 days to 7 days (Table 3-2).  The duration of 
AMG 330 step dose levels in cycle 2 and beyond can be shortened to 2 to 5 days if a 
subject tolerated the investigational product in cycle 1 and based on the discussion and 
agreement between the investigator and the sponsor. All subsequent cycles will be 
conducted similarly to cycle 2. 


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On days when pembrolizumab administration and an AMG 330 dose level increase will 
occur, the subject will receive dexamethasone 8 mg at the conclusion of the 
pembrolizumab infusion.  Dexamethasone will be given 1 hour prior to increasing the 
AMG 330 dose.  If the subject does not develop a ≥ grade 2 infusion reaction, or if the 
infusion reaction is reversible after the 1-hour observation period, AMG 330 may be 
increased to the next dose level, as shown in Table 3-2. 
Table 3-1.  Dosing for Cohort 1 (Cycle 1) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
 
D4-7 
 
D8-14, D15-21 
D15 
D22-28 
 
D29-35; D36-42 
D36 
D43-49 
 
D50-56; D57-63 
D57 
D64-77 
 
(infusion-free period) 
D78-85 
D78 
cIV = continuous intravenous; D = day; IV = intravenous 
Table 3-2.  Dosing for Cohort 1 (Cycle 2 and Beyond) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
 
D4-7 
 
D8-14 
 
D15-21 
D15 
D22-28 
 
D29-35 
 
D36-42 
D36 
D43-56 
 
(infusion-free period) 
D57-64 
D57 
cIV = continuous intravenous; D = day; IV = intravenous 


Product:  AMG 330 + Pembrolizumab 
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3.1.2 
Cohort 2 Design 
Subjects in cohort 2 will receive both AMG 330 and pembrolizumab on day 1.  All cycles 
are 57 days in duration.  Pembrolizumab will be administered at a dose of 200 mg 
(Q3W) by a 30-minute IV infusion. The subject will then receive dexamethasone 8 mg.  
Dexamethasone will be given 1 hour prior to each step dose of AMG 330.  If the subject 
does not develop a ≥ grade 2 infusion reaction, or if the infusion reaction is reversible 
after the 1-hour observation period, the subject will start AMG 330 at a starting dose of 
 µg/day for 3 days, followed by 
 µg/day for 4 days, followed by 
 µg/day for 7 days, 
and continue dosing as per Table 3-3, increasing dose levels every 7 days up to 
 µg/day as tolerated by subjects.  Pembrolizumab will be administered at 200 mg IV 
once every 3 weeks.  Subjects will continue 
 µg/day of AMG 330 and pembrolizumab 
for 14 days.  Cycle 1 will be followed by a 1-week interval without AMG 330 
administration, and administration of pembrolizumab will continue non-interrupted on 
Q3W schedule. The AMG 330-infusion free interval may be extended up to 4 weeks 
(depending on safety, treatment response, and in case of prolonged marrow aplasia and 
cytopenia in aleukemic subjects) after consultation with the sponsor.  Cycle 2 and all 
subsequent cycles will start with the initiation of AMG 330 administration and include the 
same step dose levels and duration as in cycle 1.  The duration of AMG 330 step dose 
levels in cycle 2 and beyond can be shortened to 2 to 5 days if a subject tolerated the 
investigational product in cycle 1 and based on the discussion and agreement between 
the investigator and the sponsor. 
Table 3-3.  Dosing for Cohort 2 (All Cycles) 
AMG 330 Dose Level 
(µg/day, cIV) 
AMG 330 Days 
Administered 
Pembrolizumab Days 
Administered (IV infusion) 
D1-3 
D1 
D4-7 
 
D8-14 
 
D15-21 
 
D22-28 
D22  
D29-35 
 
D36-42 
 
D43-56 
D43 
(infusion-free period) 
D57-64 
 
cIV = continuous intravenous; D = day; IV = intravenous 


Product:  AMG 330 + Pembrolizumab 
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The overall study design is described by a study schema in Section 1.2 of the protocol.  
The endpoints are defined in Section 2.1. 
3.2 
Sample Size 
Approximately 20 subjects will be enrolled in this study with at least 6 DLT evaluable 
subjects in each cohort.  With 6 evaluable subjects in 1 cohort, there is an 82% chance 
of observing at least 1 DLT if the true DLT rate is 25%.  For cohort 1, at least 10 subjects 
will be dosed through study day 28. 
3.3 
Adaptive Design 
Early stopping for safety rule is specified in Section 7.1.  
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
This phase 1 study has no prespecified covariates. 
4.2 
Subgroups 
This phase 1 study has no prespecified subgroups. 
5. 
Definitions 
5.1 
General Definitions 
Age at Enrollment 
Subject age at enrollment will be collected in years in the clinical database. 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to AMG 330 in combination with 
pembrolizumab. 
Amgen IP: refers to AMG 330 and Non-Amgen IP: refers to Pembrolizumab. 
Cumulative Dose of AMG 330, Pembrolizumab 
AMG 330: The cumulative dose in microgram (μg) is defined as the following with 
summation over infusions: 
(duration of infusion (days) for each dose received × dose received [µg/day]) 


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Pembrolizumab: The cumulative dose in milligram (mg) is defined as the following with 
summation over infusions:                                                                                                    
(number of infusion for each dose received × dose received [mg])                      
Cumulative dose will be calculated within a cycle and across all cycles. 
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcB=QT/ (RR/1000)1/2. 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: QTcF=QT/ (RR/1000)1/3 
5.2 
Study Points of Reference 
Baseline 
For any variable, unless otherwise specified the baseline is the last assessment taken 
prior to the first administration of any IP.  For parameters/assessments not scheduled to 
be performed (or scheduled but not performed) on the same day as the first 
administration of any IP, the baseline value is the value from the screening period 
measured closest to the day of first administration of any IP. 
Baseline and Post-baseline ECG Values in Triplicate 
The baseline ECG is defined as the mean of all pre-dose on cycle 1 day 1 assessments; 
the mean of values in a triplicate should be calculated before taking the mean of the 
triplicate averages.  
For all post-baseline ECG, the mean value for measurements taken at the same 
assessment will be calculated and used in the analysis.  
For post dose ECG measurements, unscheduled ECG measurements taken up to 
5 minutes after the last assessments of a triplicate will be included in the average for a 
time point.  When an ECG is missing within a triplicate, all available data will be 
averaged for that time point. 
Change from Baseline 
Change from baseline is the arithmetic difference between post-dose assessment and 
baseline. 


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Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Percent Change from Baseline 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline  
Value] x 100 
5.3 
Study Dates 
Informed Consent Date 
The date on which the subject signs the informed consent form. 
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 final collection of data for the primary endpoint(s). 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 across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, additional antibody testing), as 
applicable. 
End of Investigational Product (IP) Administration Date 
End of IP Administration for each subject is defined as the date of decision was made to 
end IP reported on the End of IP Administration CRF page. 
Enrollment Date 
A subject’s enrollment date is defined as the date the investigator has determined he or 
she has met all eligibility criteria, as defined by the “Date of Enrollment” field on the 
Subject Enrollment form on the CRF. 
Last Dose Date of AMG 330 / Pembrolizumab  
This is the stop date of the last infusion of AMG 330/pembrolizumab administration 
reported on the Investigational Product Administration CRF. 


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Death Date  
For subjects who die during the study, the death date will be recorded on the end of 
study, event and survival status CRF. The earliest date will be used if the dates are 
inconsistent among these CRF pages.   
Study Day 1 
Study Day 1 is defined as the first day that investigational product is administered to the 
subject. 
Study Day: 
Study Day is defined as: 
Pre study day 1: study day = (date – date of study day 1) 
Post study day 1: study day = (date - date of study day 1) + 1  
5.4 
Endpoints 
Treatment-emergent Adverse Event (TEAE) 
Treatment emergent adverse event refers to an adverse event that starts on or after first 
dose of any IP (as indicated by the flag whether an event starts before first dose of any 
IP is “No” or missing on the Events CRF page) and up to and including end of study 
date. This reporting window also applies to treatment-emergent serious adverse events 
(SAEs). 
Treatment-related Adverse Event (TRAE) 
A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by the investigational product  (either AMG 330 or 
pembrolizumab or in combination of AMG 330 and pembrolizumab). 
Dose Limiting toxicity (DLT) 
Investigators will determine whether an adverse event qualifies as a DLT per protocol 
Section 6.2.1. 
Duration of Response (DOR) 
Duration of response is calculated for subjects who have achieved overall response 
(CRMRD-, CR, CRi, PR or MLFS). It is defined as time from the first observation indicating 
an objective response to the subsequent date of disease progression or death, 
whichever is earlier. 


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DOR time in days: (date of disease progression or death - date of the first observation of 
objective response +1) 
DOR time in months: (date of disease progression or death - date of the first observation 
of objective response +1)/30.4 
Subjects without disease progression or death until the analysis data cut-off date will be 
censored at the last adequate disease assessment date. 
5.5 
Treatment Response 
Treatment response is defined in Appendix D. The data will be recorded on Disease 
Response CRF page. 
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined in Section 6.1 
6.1 
Safety Analysis Set 
Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 330 or pembrolizumab. 
6.2 
Dose Limiting Toxicity (DLT) Evaluable Analysis Set 
Dose limiting toxicity evaluable Analysis Set is defined as DLT-evaluable subjects in the 
Safety Analysis Set (see definition of DLT-evaluable in Section 6.2.1. of the protocol).  
The analysis of DLT will be conducted on the DLT evaluable Analysis Set. 
6.3 
Pharmacokinetic Analyses Set(s) 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
AMG 330 or pembrolizumab and have at least 1 PK sample collected.   
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  The dose level review meeting  
(DLRM) will occur when at least 10 treated subjects in cohort 1 have been dosed 
through study day 28 to determine if the safety profile of initial steps in cohort 1 is 
acceptable to begin enrollment of cohort 2 or if the study should be stopped.  If 3 or 
more of the 10 treated subjects in cohort 1 experience a DLT by day 28, the guidance to 
the DLRT is to recommend not to initiate cohort 2.  The stopping rule is based on having 
at least a posterior probability of > 70% that the DLT rate is > 20% assuming a prior 
distribution of Beta (0.40, 1.60).  If the true DLT rate is 10%, 20%, 30%, 40%, or 50%, 


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then the probability of stopping the study at the interim analysis is 7%, 32%, 62%, 83%, 
95%, respectively. 
7.2 
Primary Analysis 
The primary analysis will occur when all subjects have ended study. 
7.3 
Final Analysis 
The primary analysis will also be the final 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 
database. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required:  
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations following 
Amgen SOP. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified.  
PK concentration data will be evaluated for outliers by visual inspection and decisions to 
re-assay individual samples will be made in accordance with standard CPMS practices. 
All excluded observations will be detailed by CPMS along with reasons for exclusion, in 
accordance with standard CPMS practices. 


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8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later.  
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
 and 
data overall and by cohort 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. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper and Pearson (1934). 
9.2 
Subject Accountability 
The number (and percent) of subjects who were enrolled, received AMG 330 and 
pembrolizumab and ended the study will be summarized. The number (and percent) of 
subjects who discontinue each treatment and the study along with the reasons for 
discontinuation will be summarized. Also, the date that the first subject and last subject 
was enrolled will be presented based on the enrolled subjects. 
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 


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descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized using 
descriptive statistics. If multiple races have been reported for a subject, the subject will 
be categorized as multiple race as well as by the combination of race.  
The baseline characteristics to be summarized include:  
 
Sex: Male, Female 
 
Age: < 65, ≥ 65 to < 75, ≥ 75 
 
Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other  
 
Eastern Cooperative Oncology Group (ECOG) performance status (Appendix C) 
 
Prior HSCT: Yes, No 
 
Response to prior therapies : Yes, No 
 
ELN Classification of AML (at initial diagnosis and at study entry)  
 
Type of AML (at initial diagnosis and at study entry) 
 
White blood cell count  
 
Absolute Neutrophil count 
 
Height 
 
Weight 
 
Platelet count 
 
Percentage of bone marrow blast 
9.5 
Efficacy Analyses 
Analysis of efficacy endpoints will be based on the Safety Analysis Set unless otherwise 
specified. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
No efficacy parameter is considered in primary endpoints. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The percentage of subjects with a response (CRMRD-, CR, CRi, MLFS, or PR) to 
treatment using the European Leukemia Net (ELN) Response Criteria in Acute Myeloid 
Leukemia (AML) (2017) will be summarized with an exact 80% confidence interval (CI) 
overall and by cohort. It will be presented using an exact method proposed by Clopper 
and Pearson (1934). Subjects missing post baseline disease assessments will be 
considered not to have achieved response.  


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Duration of response will be presented per subject and Kaplan-Meier (KM) estimates 
may be presented. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Subject incidence of DLT will be summarized overall and by planned cohort. The DLT 
summary will be based on the DLT evaluable analysis set. 
The statistical analysis methods for other safety endpoints are described in Section 9.6.2 
to Section 9.6.6. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, treatment-related adverse event, serious adverse events, grade 3 and 
above adverse events, adverse events leading to withdrawal of investigational product, 
and fatal adverse events.  Also subject incidence of adverse event may be summarized 
by dose step.  
Subject incidence of all treatment-emergent adverse events, treatment-related 
(AMG 330 related, pembrolizumab related and in combination of AMG 330 with 
pembrolizumab related) adverse events, serious adverse events (SAEs), grade 3 and 
above adverse events, adverse events leading to withdrawal of investigational product, 
and fatal adverse events will be tabulated by system organ class and preferred term in 
decreasing order of frequency. In addition, treatment-emergent adverse events and 
treatment-related adverse events will be summarized by system organ class, preferred 
term, and worst grade. Also SAEs and grade 3 and above will be summarized by 
preferred term only in descending order of frequency. The severity of each adverse 
event will be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 criteria with the exception of cytokine release syndrome (CRS), which must 


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be graded using the criteria referenced in the publication by Lee et al (2014), and tumor 
lysis syndrome (TLS), which must be graded using the Cairo-Bishop criteria. 
Treatment-emergent events of interest (EOIs) will be summarized by EOI category and 
preferred term. Subject incidence by PT and the worst grade will be summarized for 
selected EOIs. CSR symptoms will also be summarized. 
9.6.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject.  
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters may be provided. 
9.6.4 
Vital Signs 
Vital signs will be listed and reviewed for each subject in dose level review meeting 
(DLRM). The analyses of vital signs including summary statistics over time and/or 
changes from baseline over time may be provided. The number and percentage of 
subjects with abnormal changes (defined in Appendix B, Table 14-1) in systolic blood 
pressure, diastolic blood pressure, temperature and heart rate may be summarized. 
9.6.5 
Physical Measurements 
Physical measurements will be reviewed for each subject in DLRM. Summary statistics 
over time may be provided.  
9.6.6 
Electrocardiogram 
All on-study electrocardiogram (ECG) data parameter (QRS, QT, QTc, RR, and PR 
intervals) will be listed and during the analysis one or all of these parameters will be 
plotted.  
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. Subjects' maximum change from baseline in QTc 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. 
Summaries over time and/or changes from baseline over time will be provided for all 
12-lead ECG parameters. The analysis of Fridericia’s (QTcF) QT correction and Bazett’s 
(QTcB) QT correction will be performed using the derived results as specified in 
Section 5.2 . 


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Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcF and QTcB. Unscheduled assessments will be included in the 
determination of the maximum change.  
 
≤ 30 msec  
 
> 30 – 60 msec  
 
> 60 msec  
The number and percentage of subjects in each group will be summarized. A listing of 
the subjects with > 60 msec change from baseline in QTcF and QTcB will be provided.  
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF and QTcB. Unscheduled assessments will be included in the 
determination of the maximum post baseline value.  
 
≤ 450 msec  
 
> 450 – 480 msec  
 
> 480 – 500 msec  
 
> 500 msec  
The number of subjects in each group will be summarized for each dosing group. A 
listing of the subjects with > 500 msec post baseline in QTcF and QTcB will be provided.  
9.6.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 330 antibodies 
(binding and if positive, neutralizing) and anti-pembrolizumab antibodies at any time will 
be tabulated overall and by cohort. 
9.6.8 
Exposure to Investigational Product 
Details of AMG 330 and pembrolizumab administration will be listed for every subject. 
Descriptive statistics will be produced to describe the exposure to AMG 330 and 
pembrolizumab. The number of cycles initiated, completed, discontinued, and re-started 
will be summarized. In addition, the duration of therapy and the cumulative dose may be 
summarized by cycle and overall. The number and percentage of subjects with dose 
modifications (eg, dose changes, dose interruptions) and reasons for modification will be 
summarized. 
9.6.9 
Exposure to Other Protocol-required Therapy 
Details of dexamethasone and tocilizumab administration may be listed for every 
subject. 


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9.6.10 
Exposure to Concomitant Medication 
The number and percent of subjects receiving concomitant medications from study day 1 
through AMG 330 or pembrolizumab safety follow-up (SFU), whichever is later, will be 
summarized by preferred term or category or indication for each cohort as coded by the 
World Health Organization Drug (WHODRUG) dictionary.  
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic Endpoints 
9.7.1.1 
Pharmacokinetic Analysis of AMG 330 
AMG 330 PK parameters (eg,: half-life, steady state concentration, volume of 
distribution, and clearance) will be determined as appropriate from the time-
concentration profile using standard non-compartmental methods and will be listed for 
individual subjects. 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. Analyses will be performed 
based on Pharmacokinetic Analysis Set. 
9.7.1.2 
Pharmacokinetic Analysis of Pembrolizumab  
Pembrolizumab serum samples will be taken as listed in Schedule of Assessment of 
protocol. Summary statistics, including mean, standard deviation, CV%, median, range 
(Minimal, Maximal), geometric mean and CV% of geometric mean will be computed. 
Individual concentration-time data will be tabulated and presented in PK appendix. 
Analyses will be based on Pharmacokinetic Analysis Set.   
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


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11. 
Literature Citations / References 
AMG 330 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Alfayez M, Borthakur G.  Checkpoint inhibitors and acute myelogenous leukemia:  
promises and challenges.  Expert Rev Hematol.  2018;11(5):373-389. 
Andrews RG, Singer JW, Bernstein ID.  Precursors of colony-forming cells in humans 
can be distinguished from colony-forming cells by expression of the CD33 and CD34 
antigens and light scatter properties.  J Exp Med.  1989;169:1721-1731. 
Andrews RG, Takahashi M, Segal GM, et al.  The L4F3 antigen is expressed by 
unipotent and multipotent colony-forming cells but not by their precursors.  Blood.  
1986;68:1030-1035. 
Arber DA, Orazi A, Hasserjian R, et al.  The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia.  Blood.  
2016;127(20):2391-2405. 
Blank C, Brown I, Peterson AC, et al.  PD-L1/B7H-1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells.  Cancer Res.  
2004;64(3):1140-1145. 
Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N.  The emerging 
role of immune checkpoint based approaches in AML and MDS.  Leuk Lymphoma.  
2018;59(4):790-802. 
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.  2011;29:369-377. 
Chemnitz JM, Parry RV, Nichols KE, et al.  SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary 
Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation.  J 
Immunol.  2004;173:945-954. 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-13. 
Curran MA, Montalvo W, Yagita H, Allison JP.  PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors.  Proc Natl Acad Sci U S A.  2010;107(9):4275-4280. 
De la Fuente H, Cibrián D, Sánchez-Madrid F.  Immunoregulatory molecules are master 
regulators of inflammation during the immune response.  FEBS Lett.  
2012;586(18):2897-2905. 
Disis ML.  Immune regulation of cancer.  J Clin Oncol.  2010;28(29):4531-4538. 
Döhner H, Estey E, Grimwade D, et al.  Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel.  Blood.  
2017;129(4):424-447. 
Dudley ME, Wunderlich JE, Yang, JC, et al.  Adoptive Cell Transfer Therapy Following 
Non-myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients 
With Refractory Metastatic Melanoma.  J Clin Oncol.  2005;2346-2357. 


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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 
Francisco LM, Sage PT, Sharpe AH.  The PD-1 pathway in tolerance and autommunity.  
Immunol Rev.  2010;236:219-242. 
Greenwald, RJ, Freeman GJ, Sharpe AH.  The B7 Family Revisited.  Annu Rev 
Immunol.  2005;23:515-548. 
Hirano F, Kaneko K, Tamura H, et al.  Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity.  Cancer Res.  
2005;65(3):1089-1096. 
Hobo W, Hutten TJA, Schaap NPM, Dolstra H.  Immune checkpoint molecules in acute 
myeloid leukaemia:  managing the double-edged sword.  Br J Haematol.  
2018;181(1):38-53. 
Hunder NN, Wallen H, Cae J, et al.  Treatment of metastatic melanoma with autologous 
CD4+ T cells against NY-ESO-1.  N Engl J Med.  2008;358(25):2698-2703. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Krupka C, Kufer P, Kischel R, et al.  Blockade of the PD-1/PD-L1 axis augments lysis of 
AML cells by the CD33/CD3 BiTE antibody construct AMG 330:  reversing a 
T-cell-induced immune escape mechanism.  Leukemia.  2016;30(2):484-491. 
Krupka C, Kufer C, Kischel R, et al.  PD-1/PD-L1 Blocking Enhances CD33/CD3-
Bispecific BiTE® Antibody (AMG 330) Mediated Lysis of Primary AML Cells.  Blood.  
2014;124:3738. 
La Russa VF, Griffin JD, Kessler SW, et al.  Effects of anti-CD33 blocked ricin 
immunotoxin on the capacity of CD34+ human marrow cells to establish in vitro 
hematopoiesis in long-term marrow cultures.  Exp Hematol.  1992;20:442-448. 
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. 
Nomi T, Sho M, Akahori T, et al.  Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.  
Clin Cancer Res.  2007;13(7):2151-2157. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T.  PD-1 immunoreceptor inhibits 
B cell receptor mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine.  Proc Natl Acad Sci USA.  
2001;98(24):13866-13871. 
Parry RV, Chemnitz JM, Frauwirth KA, et al.  CTLA-4 and PD01 Receptors Inhibit T-Cell 
Activation by Distinct Mechanisms.  Mol Cell Biol.  2005;25(21):9543-9553. 
Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ.  Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma.  
J Immunol.  2010;184(7):3442-3449. 


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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. 
Ravandi F.  Relapsed acute myeloid leukemia:  why is there no standard of care? Best 
practice & research.  2013;26:253-9. 
Ravandi F, et al.  A Phase 1 first-in-human study of AMG 330, an anti-CD33 bispecific 
T-Cell engager (BiTE®) antibody construct, in relapsed/refractory acute myeloid leukemia 
(R/R AML).  2018 Dec 1; Oral Abstract #25:  60 ASH Annual Meeting and Exposition, 
San Diego, CA. 
Riley JL.  PD-1 signaling in primary T cells.  Immunol Rev.  2009:0105-2896. 
Scheinberg DA, Tanimoto M, McKenzie S, Strife A, Old LJ, Clarkson BD.  Monoclonal 
antibody M195:  a diagnostic marker for acute myelogenous leukemia.  Leukemia.  
1989;3:440-445. 
Sheppard KA, Fitz LJ, Lee JM, et al.  PD-1 inhibits T-cell receptor induced 
phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to 
PKCtheta.  FEBS Lett.  2004;574(1-3):37-41. 
Society AC.  Cancer Facts and Figures, 2014.  Atlanta, George, USA:  American Cancer 
Society; 2014. 
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF.  Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment.  J Immunother Cancer.  2014;2:3. 
Strome SE, Dong H, Tamura H, et al.  B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma.  Cancer Res.  2003;63(19):6501-6505. 
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;3:339-348. 
Weber J.  Immune checkpoint proteins:  a new therapeutic paradigm for cancer - 
preclinical background:  CTLA-4 and PD-1 blockade.  Semin Oncol.  
2010;37(5):430-439. 
Westervelt, P, Roboz, GJ, Cortes, JE, et al.  Phase 1 first-in-human trial of AMV564, a 
bivalent bispecific (2x2) CD33/CD3 T-cell engager, in patients with relapsed/refractory 
acute myeloid leukemia (AML).  Blood.  2018;132:1455. 
Zhang L, Gajewski TF, Kline J.  PD-1/PD-L1 interactions inhibit antitumor immune 
responses in a murine acute myeloid leukemia model.  Blood.  
2009;114(8):1545-1552. 


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12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
None 


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14. 
Appendices 


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Appendix B.  Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
used. 
Refer to protocol Sections Table 6-3, Table 6-4 and Table 6-5. 
Notable values for vital signs and physical measurements are defined in the following 
table. 
Table 14-1.  Notable Abnormalities of Vital Signs and Physical Measurement 
Vital Signs or Physical Measurements 
Notable Abnormalities 
Heart rate (bpm) 
 
> 120 
 
 
< 50 
Blood pressure (mmHg)  
Systolic 
≥ 160 
 
 
≤ 90 
 
Diastolic 
≥105 
 
 
≤ 50 
Body temperature (°C) 
 
> 39 
Weight (kg) 
 
Change from baseline ≥ 10% (in both 
directions) 
 


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Appendix C.  Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Grade 
Description 
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 house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair 
5 
Dead 
Source:  Oken et al, 1982 


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Appendix D.  European LeukemiaNet (ELN) Response Criteria in Acute Myeloid 
Leukemia (2017) 
 
Category 
Definition 
Comment 
Response 
CR without 
minimal residual 
disease (CRMRD–) 
If studied pretreatment, CR with negativity for a 
genetic marker by RT–qPCR, or CR with negativity by 
MFC 
Sensitivities vary by marker 
tested, and by method used; 
therefore, test used and 
sensitivity of the assay should be 
reported; analyses should be 
done in experienced laboratories 
(centralized diagnostics) 
Complete 
remission (CR) 
Bone marrow blasts < 5%; absence of circulating 
blasts and blasts with Auer rods; absence of 
extramedullary disease; ANC ≥ 1.0 x 109/L (1000/µL); 
platelet count ≥ 100 x 109/L (100 000/µL) 
MRD+ or unknown 
CR with 
incomplete 
hematologic 
recovery (CRi) 
All CR criteria except for residual neutropenia 
(< 1.0 x 109/L [1000/µL]) or thrombocytopenia 
(< 100 x 109/L [100 000/µL]) 
  
Morphologic 
leukemia-free 
state (MLFS) 
Bone marrow blasts < 5%; absence of blasts with 
Auer rods; absence of extramedullary disease; no 
hematologic recovery required 
Marrow should not merely be 
"aplastic"; at least 200 cells 
should be enumerated or 
cellularity should be at least 10% 
Partial remission 
(PR) 
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% 
Especially important in the 
context of phase 1/2 clinical 
trials 
Treatment failure 
Primary refractory 
disease 
No CR or CRi after 2 courses of intensive induction 
treatment; excluding patients with death in aplasia or 
death due to indeterminate cause 
Regimens containing higher 
doses of cytarabine are 
generally considered as the best 
option for patients not 
responding to a first cycle of 
7+3; the likelihood of responding 
to such regimens is lower after 
failure of a first 
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 
  
Page 1 of 2 
Footnotes defined on next page of table 


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Category 
Definition 
Comment 
Response criteria for clinical trials only 
Stable disease 
Absence of CRMRD–, CR, CRi, PR, MLFS; and 
criteria for PD not met 
Period of stable disease should last 
at least 3 months 
Progressive 
disease (PD)* 
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast 
counts in the blood:  
 50% increase in marrow blasts over baseline 
(a minimum 15% point increase is required in 
cases with < 30% blasts at baseline; or 
persistent marrow blast percentage of > 70% 
over at least 3 months; without at least a 
100% improvement in ANC to an absolute 
level (> 0.5 x 109/L [500/µL], and/or platelet 
count to > 50 x 109/L [50 000/µL] 
nontransfused); or  
 50% increase in peripheral blasts 
(WBC x % blasts) to > 25 x 109/L  
(> 25 000/µL) (in the absence of differentiation 
syndrome)¶; or  
 New extramedullary disease  
Category mainly applies for older 
patient given low-intensity or single-
agent "targeted therapies" in clinical 
trials 
In general, at least 2 cycles of a 
novel agent should be administered 
Some protocols may require blast 
increase in 2 consecutive marrow 
assessments at least 4 weeks apart; 
the date of progression should then 
be defined as of the first observation 
date 
Some protocols may allow transient 
addition of hydroxyurea to lower 
blast counts 
"Progressive disease" is usually 
accompanied by a decline in ANC 
and platelets and increased 
transfusion requirement and decline 
in performance status or increase in 
symptoms  
Relapse 
Hematologic 
relapse (after 
CRMRD–, CR, CRi) 
Bone marrow blasts ≥ 5%; or reappearance of 
blasts in the blood; or development of 
extramedullary disease 
  
Molecular relapse 
(after CRMRD–) 
If studied pretreatment, reoccurrence of MRD as 
assessed by RT–qPCR or by MFC 
Test applied, sensitivity of the assay, 
and cutoff values used must be 
reported; analyses should be done in 
experienced laboratories (centralized 
diagnostics) 
Page 2 of 2 
ANC = absolute neutrophil count; CR = complete response; CRMRD- = CR without minimal residual disease; 
IDH = isocitrate dehydrogenase; MFC = multiparameter flow cytometry; MLFS = morphologic 
leukemia-free state; MRD = measurable residual disease (also known as minimal residual disease); 
PD = progressive disease; PR = partial remission; RT-qPCR = real-time quantitative polymerase chain 
reaction; WBC = white blood cell. 
* The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at 
harmonizing the various definitions used in different clinical trials. 
¶ Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation 
syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase 
in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily 
indicate PD. 
Reproduced with permission of the American Society of Hematology.  From:  Döhner H, Estey E, Grimwade 
D, et al.  Diagnosis and management of AML in adults:  2017 ELN recommendations from an international 
expert panel.  Blood.  2017;129:424; permission conveyed through Copyright Clearance Center.  
Copyright © 2017.