Conditions: Higher Risk Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia
Keywords: Higher Risk Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Myelomonocytic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The main objective is to assess the safety, tolerability, and efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of azacitidine for the treatment of Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia (HR-MDS/CMML).

Detailed description:
This study is a Phase 1 clinical trial designed to assess the safety, tolerability, and efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of azacitidine for the treatment of HR-MDS/CMML. Participants will be treated with intravenous (IV) AMG 176 and IV or subcutaneous (SC) azacitidine.

Arms:
arm 1: Two dose levels of AMG 176 will be tested in Part 1A to find the optimal biological dose/minimum safe biologically effective dose (OBD/MSBED). arm 2: After the OBD is found in Part 1A, two dose levels of AMG 176 in combination with azacitidine will be tested in Part 1B to find the OBD/MSBED. arm 3: After the completion of Part 1, the Part 2 dose expansion phase will begin at the OBD/MSBED identified in Part 1.

Venetoclax-naïve and venetoclax-exposed R/R HR-MDS participants after HMA failure will be enrolled along with participants with newly diagnosed HR-MDS/CMML.

Interventions: intervention 1: AMG 176 intervention 2: Azacitidine
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion. intervention 2: Administered as an IV infusion or subcutaneous (SC) injection.

Protocol document:
Prot_000.pdf: 
Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 1 of 149 
CONFIDENTIAL 
Title Page 
Protocol Title: 
A Phase 1 Study of AMG 176 as Monotherapy 
and in Combination with Azacitidine in 
Higher-Risk Myelodysplastic Syndrome and 
Chronic Myelomonocytic Leukemia 
Short Protocol Title: 
Phase 1 Study of AMG 176 with Azacitidine in 
Subjects with MDS/CMML 
Protocol Number: 
20200392 
Investigational Product: 
AMG 176 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
+1-805-447-1000
Protocol 
Approver 
Name: 
, MD PhD 
Function: 
Vice President, Early Development, TA Head 
Oncology 
Lead 
Principal 
Investigator 
Name 
, MD 
Address 
Department of Leukemia 
The University of Texas MD Anderson Cancer 
Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
Telephone Number 
Lead Co-
investigator 
Name 
, MD 
Address 
Department of Leukemia 
The University of Texas MD Anderson Cancer 
Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
Telephone Number 
Key 
Sponsor 
Contacts 
Name: 
, DO, PhD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
Email Address: 
Name 
MD 
Address 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number 
Email Address 
EudraCT Number: 
Not available at the time of amendment 
NCT Number: NCT05209152
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 2 of 149 
CONFIDENTIAL 
NCT Number: 
Not available at the time of amendment 
Protocol Version Date: 
Document Version 
Date 
Original 
12 August 2021 
Amendment 1  
25 October 2021 
Amendment 2 
14 February 2022 
Amendment 3 
11 April 2022 
Superseding 
Amendment 3 
28 April 2022 
Data Elements Standards 
Version: 
8.0 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 
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.


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 3 of 149 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1 Study of AMG 176 as Monotherapy 
and in Combination with Azacitidine in Higher-Risk Myelodysplastic Syndrome and 
Chronic Myelomonocytic Leukemia, dated 28 April 2022, 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 
sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) at the start of the study and for up to 1 year after the study is 
completed, if there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 
 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 4 of 149 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 11 
1.1 
Synopsis ................................................................................................... 11 
1.2 
Study Schema ........................................................................................... 17 
1.3 
Schedule of Activities (SoA) ...................................................................... 18 
2. 
Introduction ........................................................................................................... 28 
2.1 
Study Rationale ......................................................................................... 28 
2.2 
Background ............................................................................................... 28 
2.2.1 
Disease ..................................................................................... 28 
2.2.2 
Amgen Investigational Product Background:  AMG 
176 ............................................................................................ 30 
2.2.2.1 
AMG 176 Preclinical Pharmacodynamic 
and Antitumor Studies ............................................. 31 
2.2.2.2 
AMG 176 Pharmacokinetics .................................... 32 
2.2.2.3 
AMG 176 Preclinical Toxicology .............................. 33 
2.2.2.4 
AMG 176 Clinical Experience .................................. 33 
2.2.3 
Non-Amgen Non-Investigational Product Background:  
Azacitidine ................................................................................. 35 
2.2.3.1 
Azacitidine Pharmacokinetics .................................. 35 
2.2.3.2 
Azacitidine Clinical Experience ................................ 35 
2.3 
Benefit/Risk Assessment ........................................................................... 36 
2.3.1 
Key Benefits .............................................................................. 37 
2.3.2 
Key Risks .................................................................................. 37 
3. 
Objectives and Endpoints/Estimands .................................................................... 38 
4. 
Study Design ........................................................................................................ 40 
4.1 
Overall Design .......................................................................................... 40 
4.1.1 
Part 1 – Dose Escalation/Determination of Optimal 
Biological Dose (OBD) and Minimal Safe and 
Biologically Effective Dose (MSBED) ........................................ 40 
4.1.2 
Part 2 – Dose Expansion ........................................................... 41 
4.2 
Patient Input into the Study Design ........................................................... 43 
4.3 
Justification for Dose ................................................................................. 43 
4.3.1 
Justification for Investigational Product Dose............................. 43 
4.3.2 
Justification for Non-investigational Product Dose ..................... 44 
4.4 
End of Study ............................................................................................. 44 
5. 
Study Population .................................................................................................. 44 
5.1 
Inclusion Criteria ....................................................................................... 44 
5.2 
Exclusion Criteria ...................................................................................... 45 
5.3 
Subject Enrollment .................................................................................... 48 
5.4 
Screen Failures ......................................................................................... 49 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 5 of 149 
CONFIDENTIAL  
 
 
6. 
Study Intervention ................................................................................................. 49 
6.1 
Study Interventions Administered .............................................................. 50 
6.1.1 
Investigational Products ............................................................ 50 
6.1.2 
Non-investigational Products ..................................................... 53 
6.1.3 
Medical Devices ........................................................................ 53 
6.1.4 
Other Protocol-required Therapies ............................................ 54 
6.1.4.1 
Tumor Lysis Prophylaxis (All Subjects).................... 54 
6.1.5 
Other Intervention Procedures ................................................... 56 
6.1.6 
Product Complaints ................................................................... 56 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 56 
6.2 
Dose Modification ...................................................................................... 57 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 57 
6.2.1.1 
Dose-limiting Toxicity Evaluation Period .................. 58 
6.2.1.2 
Definition of Dose Limiting Toxicities ....................... 58 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 62 
6.2.2.1 
Amgen Investigational Product:  AMG 176 .............. 64 
6.2.2.2 
AMG 176 Management of Toxicities ........................ 67 
6.2.2.3 
Amgen/Non-Amgen Non-Investigational 
Product:  Azacitidine................................................ 69 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 70 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 70 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 70 
6.4.1 
Method of Treatment Assignment .............................................. 70 
6.4.2 
Blinding ..................................................................................... 71 
6.5 
Treatment Compliance .............................................................................. 71 
6.6 
Treatment of Overdose ............................................................................. 71 
6.7 
Prior and Concomitant Treatment ............................................................. 71 
6.7.1 
Prior Treatment ......................................................................... 71 
6.7.2 
Concomitant Treatment ............................................................. 71 
6.7.2.1 
Antifungal Prophylaxis ............................................. 72 
6.7.2.2 
Concomitant Cautions to Consider .......................... 72 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 72 
7.1 
Discontinuation of Study Treatment........................................................... 73 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 73 
7.2.1 
Reasons for Removal From Study ............................................. 74 
7.3 
Lost to Follow-up ....................................................................................... 74 
8. 
Study Assessments and Procedures .................................................................... 74 
8.1 
General Study Periods .............................................................................. 75 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 6 of 149 
CONFIDENTIAL  
 
 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 75 
8.1.2 
Treatment Period ....................................................................... 75 
8.1.3 
End of Treatment ....................................................................... 76 
8.1.4 
Safety Follow-up ........................................................................ 76 
8.1.5 
Long-term Follow-up .................................................................. 76 
8.1.6 
End of Study .............................................................................. 76 
8.2 
General Assessments ............................................................................... 76 
8.2.1 
Informed Consent ...................................................................... 76 
8.2.2 
Demographics ........................................................................... 76 
8.2.3 
Medical History .......................................................................... 77 
8.2.4 
Physical Examination ................................................................ 77 
8.2.5 
Physical Measurements ............................................................ 77 
8.2.6 
Eastern Cooperative Oncology Group Performance 
Status ........................................................................................ 77 
8.3 
Efficacy Assessments ............................................................................... 77 
8.3.1 
Bone Marrow ............................................................................. 77 
8.3.2 
Peripheral Blood ........................................................................ 78 
8.3.3 
Disease Response .................................................................... 78 
8.4 
Safety Assessments .................................................................................. 78 
8.4.1 
Vital Signs ................................................................................. 78 
8.4.2 
Electrocardiograms (ECGs) ....................................................... 79 
8.4.3 
Clinical Laboratory Assessments ............................................... 79 
8.4.3.1 
Hepatitis Serology ................................................... 80 
8.4.3.2 
Tumor Lysis Syndrome Laboratory 
Monitoring ............................................................... 80 
8.4.3.3 
Cardiac Monitoring Tests ........................................ 80 
8.4.4 
Vital Status ................................................................................ 80 
8.4.5 
Other Safety .............................................................................. 81 
8.4.5.1 
Echocardiogram (ECHO)/Multigated 
Acquisition (MUGA) Scan/Cardiac MRI ................... 81 
8.4.6 
Adverse Events and Serious Adverse Events ............................ 81 
8.4.6.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 81 
8.4.6.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 82 
8.4.6.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 82 
8.4.6.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 83 
8.4.6.5 
Safety Monitoring Plan ............................................ 83 
8.4.6.6 
Pregnancy and Lactation ......................................... 83 
8.5 
Pharmacokinetic Assessments .................................................................. 84 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 7 of 149 
CONFIDENTIAL  
 
 
9. 
Statistical Considerations ...................................................................................... 86 
9.1 
Statistical Hypotheses ............................................................................... 86 
9.2 
Sample Size Determination ....................................................................... 86 
9.3 
Populations for Analysis ............................................................................ 86 
9.3.1 
Covariates ................................................................................. 86 
9.3.2 
Subgroups ................................................................................. 86 
9.4 
Statistical Analyses ................................................................................... 87 
9.4.1 
Planned Analyses ...................................................................... 87 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 87 
9.4.1.2 
Primary Analysis ..................................................... 87 
9.4.1.3 
Final Analysis .......................................................... 87 
9.4.2 
Methods of Analyses ................................................................. 87 
9.4.2.1 
General Considerations ........................................... 87 
9.4.2.2 
Efficacy Analyses .................................................... 87 
9.4.2.3 
Safety Analyses ...................................................... 88 
9.4.2.4 
Other Analyses ........................................................ 89 
10. 
References ........................................................................................................... 90 
11. 
Appendices ........................................................................................................... 93 
11.1 
Appendix 1.  List of Abbreviations ............................................................. 94 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 99 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 102 
Regulatory and Ethical Considerations .................................................... 103 
Informed Consent Process ...................................................................... 104 
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 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 8 of 149 
CONFIDENTIAL  
 
 
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 ........................................................ 120 
Collection of Lactation Information .......................................................... 122 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 125 
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.  Tumor Lysis Syndrome ....................................................... 132 
11.9.1 
Cairo-Bishop Tumor Lysis Syndrome Definition and 
Grading ................................................................................... 132 
11.9.2 
Tumor Lysis Syndrome Laboratory Monitoring ........................ 133 
11.9.3 
Prophylaxis and Management of Tumor Lysis 
Prophylaxis ............................................................................. 134 
11.10 Appendix 10:  Cardiac Monitoring ........................................................... 140 
11.10.1 
Management of Troponin and Other Cardiac Enzymes 
Elevation ................................................................................. 140 
11.10.2 
Management of Cardiac Arrhythmia ........................................ 140 
11.11 Appendix 11:  ECOG Performance Status and NYHA 
Classification ........................................................................................... 141 
11.11.1 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status................................................................. 141 
11.11.2 
New York Heart Association Functional Classification ............. 141 
11.12 Appendix 12.  Uniform Response Criteria for Myelodysplastic/ 
Myeloproliferative Neoplasms (MDS/MPN) ............................................. 142 
11.13 Appendix 13.  Medications That may Cause QTc Prolongation ............... 146 
11.14 Appendix 14.  Modified Toxicity Probability Interval Design ..................... 149 
 
 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 9 of 149 
CONFIDENTIAL  
 
 
List of Tables 
Table 1-1.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycle 1, All Doses ............. 18 
Table 1-2.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycles 2 and 
Beyond, All Doses .................................................................................. 20 
Table 1-3.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy 
Cycle 1, All Doses .................................................................................. 22 
Table 1-4.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy 
Cycles 2 and Beyond, All Doses ............................................................. 24 
Table 4-1.  Guidelines for Dose Level Decisions in Part 1 ............................................. 41 
Table 4-2.  Stopping Boundary for Each Cohort in Part 2 .............................................. 42 
Table 4-3.  Operating Characteristics in Part 2 .............................................................. 42 
Table 6-1.  Investigational Products ............................................................................... 51 
Table 6-2.  DLT Criteria ................................................................................................. 60 
Table 6-3.  Dose Adjustments for Non-hematologic AEs That Are at Least 
Possibly Related ..................................................................................... 64 
Table 6-4.  Azacitidine Hematology Dose Reduction Guidance ..................................... 69 
Table 6-5.  Azacitidine Dose Reduction Based on Bone Marrow Cellularity ................... 70 
Table 11-1.  Analyte Listing ......................................................................................... 100 
Table 11-2.  DILI Potential Analyte Listing ................................................................... 101 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 128 
Table 11-4.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome ................. 132 
Table 11-5.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 133 
Table 11-6.  Tumor Lysis Syndrome Management Recommendations ........................ 137 
 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 10 of 149 
CONFIDENTIAL  
 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 17 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ...................................................................... 116 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 123 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 11 of 149 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1 Study of AMG 176 as Monotherapy and in Combination with 
Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic 
Leukemia 
Short Protocol Title:  Phase 1 Study of AMG 176 with Azacitidine in Subjects with 
MDS/CMML 
Study Phase:  1 
Indication:  Higher Risk Myelodysplastic Syndrome/Chronic Myelomonocytic Leukemia 
(HR-MDS/CMML) 
Rationale 
Myeloid Leukemia Cell 1 (MCL1) is a member of the B-Cell Lymphoma 2 (BCL2) family 
of proteins integral to the control of apoptosis (programmed cell death) with 
anti-apoptotic activity that promotes cell survival.  In contrast, pro-apoptotic family 
members, such as pro-apoptotic effector proteins BCL2 homologous antagonist/killer 
(BAK) and pro-apoptotic effector proteins BCL2-associated X (BAX) are critical effectors 
for the induction of apoptosis.  Upon apoptotic stimuli, pro-apoptotic BH3 only proteins 
(eg, Bid) bind MCL1, and disrupt the interaction between MCL1 and BAK or BAX.  This 
leads to the oligomerization of BAK/BAX, mitochondrial outer membrane 
permeabilization (MOMP), and the release of cytochrome C, caspase activation and cell 
death (Youle and Strasser, 2008). 
The acquired resistance and evasion of apoptosis, which is central to therapeutic 
resistance, is an established hallmark of cancer (Hanahan and Weinberg, 2000).  MCL1 
is integral to the resistance of apoptosis in a substantial number of solid and 
hematopoietic cancers, as supported by a wealth of genetic and functional data.  Internal 
efforts have demonstrated that knockdown of MCL1 expression by small interfering 
ribonucleic acid (siRNA) induces cell death in multiple cancer cell lines.  
MCL1 provides a useful target for the treatment of subjects with acute myeloid leukemia 
(AML) as it is essential for the development and sustained growth of AML.  MCL1 
dependency was detected in AML mouse models (Xiang et al, 2010) and in human 
AML-derived cell lines.  It was shown that deletion of MCL1 but not loss or 
pharmacological blockade of BCL-XL, BCL-2, or BCL-W induced the death of 
transformed AML cells and cured the disease in AML afflicted mice (Glaser et al, 2012).  
The upregulation of MCL1 has been described at the time of AML relapse 
(Kaufmann et al, 1998).  In FLT3-ITD AML, upregulation of MCL1 is dependent on FLT3 
signaling and an essential effector of FLT3-ITD mediated drug resistance (Bose and 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 12 of 149 
CONFIDENTIAL  
 
 
Grant, 2013).  Targeting MCL-1 sensitizes FLT3 ITD positive leukemia to cytotoxic 
therapies (Kasper et al, 2012). 
The combination of AMG 176 and azacitidine in subjects with relapsed or refractory 
(R/R) AML is being tested in the AMG 176 phase I first in human (FIH) Study 20150161.  
However, this combination has yet to be investigated in patients with myelodysplastic 
syndrome (MDS).  Given the need for improved therapies in patients with higher-risk 
(HR) MDS and the potential use of AMG 176 in patients who have failed chemotherapy 
and BCL2 inhibitors, such as venetoclax, the exploration of AMG 176 with and without 
azacitidine in this population, especially those with R/R disease who have progressed on 
hypermethylating agent (HMA) with and without venetoclax, is warranted. 
Objective(s) and Endpoint(s)/Estimands 
 
Part 1A – QW Monotherapy (Dose Exploration) 
 
Evaluate the safety and tolerability of 
AMG 176 once weekly (QW) 
monotherapy in subjects with R/R 
higher risk myelodysplastic 
syndrome (HR-MDS) 
 
Incidence of dose limiting toxicities 
(DLTs), treatment-related, 
treatment-emergent adverse events 
and clinically significant changes in 
vital signs, electrocardiogram (ECGs), 
and clinical laboratory tests 
Part 1B – QW Combination Therapy (Dose Exploration) 
 
Evaluate the safety and tolerability of 
AMG 176 in combination with 
azacitidine in subjects with R/R 
HR-MDS and determine the Optimal 
Biological Dose (OBD) and Minimum 
Safe and Biologically Effective Dose 
(MSBED) of AMG 176 in combination 
with azacitidine 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events 
and clinically significant changes in 
vital signs, ECGs, and clinical 
laboratory tests 
Part 2 – QW Combination Therapy (Dose Expansion) 
 
Evaluate the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with R/R 
HR-MDS/CMML in: 
- HMA Failure, Venetoclax-Naïve 
- HMA Failure, Venetoclax-Exposed 
 
To assess the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with Newly 
Diagnosed MDS/CMML 
 
Overall response rate (ORR), 
according to the Uniform Response 
Criteria for Myelodysplastic/ 
Myeloproliferative Neoplasms 
(MDS/MPN), including: 
 
Complete Remission (CR) 
 
Partial Remission (PR) 
 
Marrow CR 
 
Cytogenic response 
Objectives 
Endpoints 
Primary 


Product:  AMG 176  
Protocol Number:  20200392  
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CONFIDENTIAL  
 
 
Secondary 
Part 1A – QW Monotherapy (Dose Exploration) 
 
Evaluate preliminary efficacy of 
AMG 176 QW when given as 
monotherapy in R/R MDS/CMML 
 
Overall response according to the 
Uniform Response Criteria for 
MDS/MPN, Event-Free Survival 
(EFS), time to response, and Duration 
of Response (DOR) 
 
Evaluate the pharmacokinetics (PK) 
of AMG 176 when administered as 
monotherapy 
 
PK parameters for AMG 176 
including, but not limited to, maximum 
observed concentration (Cmax), area 
under the concentration-time curve 
(AUC), clearance (CL), and half-life 
(t1/2) 
Part 1B – QW Combination Therapy (Dose Exploration) 
 
Evaluate preliminary efficacy of 
AMG 176 QW in combination with 
azacitidine in R/R MDS/CMML 
 
Overall response according to the 
Uniform Response Criteria for 
MDS/MPN, EFS, time to response, 
and DOR 
 
Evaluate the PK of AMG 176 and 
azacitidine when administered in 
combination 
 
PK parameters for AMG 176 and 
azacitidine including, but not limited 
to, Cmax, AUC, CL, and t1/2 
Part 2 – QW Combination Therapy (Dose Expansion) 
 
Evaluate the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with 
R/R HR-MDS/CMML in: 
- HMA Failure, Venetoclax-Naïve 
- HMA Failure, Venetoclax-Exposed 
- To assess the preliminary efficacy 
of AMG 176 in combination with 
azacitidine in subjects with Newly 
Diagnosed MDS/CMML 
 
Time to transformation to Acute 
Myeloid Leukemia (AML)  
 
Duration of Response (DOR)  
 
Overall Survival (OS)  
 
Time to Next MDS Treatment 
(TTNT)  
 
EFS 
 
Evaluate the PK of AMG 176 and 
azacitidine when administered in 
combination 
 
PK parameters for AMG 176 and 
azacitidine including, but not limited 
to, Cmax, AUC, CL, and t1/2 
 
Overall Design 
This study is a phase 1 clinical trial designed to assess the safety, tolerability, and 
efficacy of AMG 176 as monotherapy and in combination with the 7-day regimen of 
azacitidine for the treatment of HR-MDS/CMML.  Subjects will be treated with 
Intravenous (IV) AMG 176 and IV or Subcutaneous (SC) azacitidine.  The study consists 
of two parts.  


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 14 of 149 
CONFIDENTIAL  
 
 
Part 1 – Dose Escalation/Determination of Optimal Biological Dose (OBD) and Minimum 
Safe and Biologically Effective Dose (MSBED) 
In Part 1, the modified Toxicity Probability Interval (mTPI) design will be applied for dose 
escalation. 
Three dose levels of AMG 176 monotherapy will first be tested in Part 1A, and after the 
OBD or MSBED is found, three dose levels of AMG 176 in combination with azacitidine 
will be tested in Part 1B. 
Each dose cohort will initially enroll 3 to 4 subjects and up to 10 subjects per cohort may 
be enrolled.  After reviewing all available safety data, dose level recommendations (eg, 
escalation, de-escalation) will be made by the Dose Level Review Team (DLRT) using 
an mTPI model (Ji et al, 2010) based on all subjects that have been enrolled at the 
current dose.  The DLRT may change the dose/dosing scheduled based on emerging 
data.  The OBD/MSBED is defined as the minimum safe and biologically effective 
combination dose with a probability of DLT lower than or close to a targeted toxicity 
probability of 0.2. 
Part 2 – Dose Expansion 
Upon completion of Part 1 of the study, the dose expansion phase will begin at the 
OBD/MSBED and drug administration schedule with the intention of confirming the 
safety and tolerability and determining the efficacy of AMG 176 in combination with 
azacitidine in not only R/R HR - MDS/CMML, but also newly diagnosed 
HR- MDS/CMML.  An additional 60 subjects will be enrolled in Part 2 of the study as 
follows: 
 
HMA Failure Cohort:  stratified by venetoclax exposure history 
- 
HMA Failure, venetoclax-Naïve (n  20) 
- 
HMA Failure, venetoclax-Exposed (n  20) 
 
Newly diagnosed (n  20) – subjects will not be enrolled into this cohort until all 
previous cohorts have been completed and the data reviewed by the Food and Drug 
Administration (FDA). 
Toxicity will be monitored for each cohort using a Bayesian approach proposed by Thall, 
Simon, and Estey (1995). 
The incidence of grade 3 or higher treatment-related non-hematological adverse events 
will be evaluated once every 5 subjects have had the chance to receive at least 1 cycle 
of treatment at the determined dose level for Part 2. 
Number of Subjects 
A total of approximately 120 subjects will be enrolled in the study: 
 
Part 1a:  up to 30 subjects (up to 10 per cohort, 3 dose levels). 
 
Part 1b:  up to 30 subjects (up to 10 per cohort, 3 dose levels). 
Part 2:  60 subjects 
Summary of Subject Eligibility Criteria 
Key Inclusion Criteria: 
 
Age  18 years of age. 
 
For Part 1, patients have R/R MDS post-HMA failure, defined as prior receipt of 4 
cycles of HMA therapy (including but not limited to decitabine, azacitidine, 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 15 of 149 
CONFIDENTIAL  
 
 
investigational HMAs such as SGI-110, and oral HMAs such as oral decitabine 
and cedazuridine [ASTX727] and oral azacitidine [CC-486]) with failure to attain a 
response or progression of disease or relapse at any time after prior response to 
HMA therapy. 
Note:  Patients with HR-CMML (CMML-1 or 2 by World Health Organization 
[WHO]) are eligible.  Hydroxyurea administration will be allowed on the study 
to lower the white cell count to  10 000/µL prior to the initiation of therapy.   
 
For Part 2, patients will be divided into 2 cohorts: 
1. HMA Failure Cohort:  patients with R/R MDS post-HMA failure (defined as prior 
receipt of 4 cycles of HMA therapy with failure to attain a response or 
progression of disease or relapse at any time after prior response to HMA 
therapy) are eligible.  Patients who have previously received venetoclax are 
eligible and will be stratified accordingly in the HMA failure cohort. 
2. Newly Diagnosed Cohort:  patients with treatment-naïve newly diagnosed 
HR-MDS (revised International Prognostic Scoring System [IPSS-R] score  3.5) 
are eligible for enrollment only after all prior cohorts have been completed and 
the data reviewed by the FDA.  Hydroxyurea administration will be allowed on the 
study to lower the white cell count to  10 000/µL prior to the initiation of therapy.  
Patients with HR-CMML (CMML-1 or 2 by WHO) are eligible.  Hydroxyurea 
administration will be allowed on the study to lower the white cell count to 
 10000/µL prior to the initiation of therapy.  Patients who have previously 
received venetoclax are eligible and will be stratified accordingly in the HMA 
Failure Cohort. 
Key Exclusion Criteria: 
 
Patients with newly diagnosed MDS with IPSS-R lower-risk category (IPSS-R 
score  3.5) 
 
Patients with CMML-0 by WHO 
 
History of other malignancy within the past 2 years prior to enrollment (with some 
exceptions as listed in full list of criteria) 
 
Excluded prior and/or concomitant therapies as listed in the full list of criteria 
 
Patients who are fit and deemed eligible by the investigator for intensive salvage 
therapy 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
This study is a phase 1 clinical trial designed to assess the safety, tolerability, and 
efficacy of AMG 176 in combination with the 7-day regimen of azacitidine for the 
treatment of HR-MDS.  Subjects will be treated with IV AMG 176 and IV or SC 
azacitidine.  The study consists of two parts. 
Part 1 
Three dose levels of AMG 176 monotherapy will first be tested, and after the OBD is 
found, three dose levels of AMG 176 in combination with azacitidine will be tested.  Each 
dose cohort will initially enroll 3 to 4 subjects and up to 10 subjects per cohort may be 
enrolled.  After reviewing all available safety data, dose level recommendations (eg, 
escalation, de-escalation) will be made by the DLRT. 


Product:  AMG 176  
Protocol Number:  20200392  
Date:  28 April 2022 
Page 16 of 149 
CONFIDENTIAL  
 
 
Part 2 
 
Upon completion of Part 1 of the study, the dose expansion phase will begin at the 
OBD/MSBED and drug administration schedule with the intention of confirming the 
safety and tolerability and determining the efficacy of AMG 176 in combination with 
azacitidine in not only R/R HR- MDS/CMML, but also in frontline HR-MDS/CMML.  
An additional 60 subjects will be enrolled in Part 2 of the study as follows: 
 
HMA Failure Cohort:  stratified by venetoclax exposure history 
o HMA Failure, venetoclax-naïve (n  20) 
o HMA Failure, venetoclax-exposed (n  20) 
 
Newly Diagnosed (n  20) – subjects will not be enrolled into this cohort until all 
previous cohorts have been completed and the data reviewed by the FDA 
Toxicity will be monitored for each cohort using a Bayesian approach proposed by Thall, 
Simon, and Estey (1995). 
Statistical Considerations 
Sample Size Considerations:   
It is anticipated that up to 120 subjects will be enrolled in the study, with up to 
60 subjects in Part 1 and 60 subjects in Part 2.  For each part, the sample size is based 
on practical considerations and it is consistent with conventional oncology studies with 
the objective to identify the OBD/MSBED. 
Planned Analyses: 
Interim Analysis and Early Stopping Guidelines 
No formal interim efficacy analysis is planned.  Safety data will be reviewed on an 
ongoing basis. 
Primary Analysis 
A primary analysis will occur when the last subject has had opportunity to complete 
6 cycles of the treatment of AMG 176. 
Final Analysis 
A final analysis is planned after all subjects have had the opportunity to complete the last 
study visit. 
Methods of Analysis: 
Descriptive statistics will be provided for selected demographics, safety, 
Pharmacokinetics (PK), and biomarker data by dose, dose schedule, and time as 
appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations and ranges, while categorical data will be summarized using 
frequency counts and percentages.  Graphical summaries of the data may also be 
presented.  Unless otherwise specified, statistical analyses will be done using the Full 
Analysis Set (FAS), which includes subjects that are enrolled and received at least 
1 dose of AMG 176.  Data will be analyzed by dose level for each part. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
The clinical hypothesis is that at least 1 dose level of AMG 176 administered in 
combination with azacitidine will achieve acceptable safety and tolerability in subjects 
with HR-MDS.  No formal statistical hypothesis will be tested. 
Sponsor Name: 
 Amgen, Inc. 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 17 of 149 
CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
PART 1A
Monotherapy (QW)
N = up to 10 subjects per cohort
HMA Failure, HR-MDS/CMML
AMG 176 180 mg/m2
HMA Failure, HR-MDS/CMML
AMG 176 120 mg/m2
PART 1B
Combination Therapy (QW)
N = up to 10 subjects per cohort
HMA Failure, HR-MDS/CMML
AMG 176 180 mg/m2
Azacitidine 75 mg/m2
HMA Failure, HR-MDS/CMML
AMG 176 120 mg/m2
Azacitidine 75 mg/m2
PART 2 Dose Expansion
Combination Therapy (QW)
N = 20 subjects per cohort
Newly Diagnosed, HR-MDS/CMML
AMG 176 MSBED
Azacitidine 75 mg/m2
CMML = chronic myelomonocytic leukemia; HMA = hypomethylating agent; HR-MDS = higher-risk myelodysplastic syndrome; 
MSBED = minimum safe and biologically effective dose; QW = once weekly; Ven = venetoclax
HMA Failure, Ven-naïve, HR-MDS/CMML
AMG 176 MSBED
Azacitidine 75 mg/m2
HMA Failure, Ven-exposed, HR-MDS/CMML
AMG 176 MSBED
Azacitidine 75 mg/m2
HMA Failure, HR-MDS/CMML
AMG 176 240 mg/m2
HMA Failure, HR-MDS/CMML
AMG 176 240 mg/m2
Azacitidine 75 mg/m2
 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 18 of 149 
CONFIDENTIAL  
 
 
1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycle 1, All Doses 
 
Screen 
Treatment 
Cycle 
 
1 
Days 
-14  
to  
0 
1 
2 
8 
9 
15 
16 
22 
23 
Hours (relative to start of 
dosing) 
 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D1 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D8 
Pre-dose 
0 
EOI 
8 
24h after D15 
Pre-dose 
0 
EOI 
8 
24h after D22 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluationa 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
12-lead ECGb 
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 
ECHO/MUGAc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationd 
 
Hospitalization 
Hospitalization (if target dose is 
180 mg/m2 or higher only) 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxise 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies review 
 
X 
Adverse events 
 
X 
Serious adverse events 
X 
STUDY TREATMENT 
AMG 176f 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
LABORATORY ASSESSMENTS 
Local labs 
Safety lab testsh 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
TLS monitoringi 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Cardiac monitoring testsj 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
  


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 19 of 149 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycle 1, All Doses 
 
Screen 
Treatment 
Cycle 
 
1 
Days 
-14  
to  
0 
1 
2 
8 
9 
15 
16 
22 
23 
Hours (relative to start of 
dosing) 
 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D1 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D8 
Pre-dose 
0 
EOI 
8 
24h after D15 
Pre-dose 
0 
EOI 
8 
24h after D22 
Local labs (continued) 
HIV testingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central labs 
AMG 176 PKm,n 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
DISEASE AND IMAGING ASSESSMENTS 
Bone marrow aspirate/biopsyp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 20 of 149 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycles 2 and Beyond, All Doses 
 
Treatment 
EOTq 
SFUq 
LTFU/EOSr,s 
Cycle 
2 through 4 
 5 
Days 
1 
2 
8 & 15 
9 
16 
22 
23 
1 
2 
8 
15 
9 
16 
22 
23 
Hours (relative to start of dosing) 
Pre-dose 
0 
EOI 
24h after D1 
Pre-dose 
0 
24h after D8 
24h after D15 
Pre-dose 
0 
24h after D22 
Pre-dose 
0 
24h after D1 
Pre-dose 
0 
Pre-dose 
0 
24h after D8 
24h after D1 
Pre-dose 
0 
24h after D15 
GENERAL ASSESSMENTS 
Clinical evaluationa 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
Vital signs 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
12-lead ECGb 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X X 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECHO/MUGAc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Concomitant therapies review 
X 
Adverse events 
X 
Serious adverse eventss 
X 
Subsequent anti-cancer therapy and 
survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
STUDY TREATMENT 
AMG 176f 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
LABORATORY ASSESSMENTS 
Local labs 
Safety lab testsh 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
Cardiac monitoring testsj 
X 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Pregnancy testk 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Page 1 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 21 of 149 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Part 1A, AMG 176 QW, Cycles 2 and Beyond, All Doses 
 
Treatment 
EOTq 
SFUq 
LTFU/EOSr,s 
Cycle 
2 through 4 
 5 
Days 
1 
2 
8 & 15 
9 
16 
22 
23 
1 
2 
8 
15 
9 
16 
22 
23 
Hours (relative to start of dosing) 
Pre-dose 
0 
EOI 
24h after D1 
Pre-dose 
0 
24h after D8 
24h after D15 
Pre-dose 
0 
24h after D22 
Pre-dose 
0 
24h after D1 
Pre-dose 
0 
Pre-dose 
0 
24h after D8 
24h after D1 
Pre-dose 
0 
24h after D15 
Central labs 
AMG 176 PKm,n 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE AND IMAGING ASSESSMENTS 
Bone marrow aspirate/biopsyp 
C2D1, C3D1, and thereafter prior to every other cycle or when clinically indicated until disease progression and to 
confirm CR and MRD status 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Assessed and documented at every cycle and at time of disease progression 
 
 
Page 2 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 22 of 149 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy Cycle 1, All Doses 
 
Screen 
Treatment 
Cycle 
 
1 
Days 
-14  
to  
0 
1 
2 
3 to 7 
8 
9 
15 
16 
22 
23 
Hours (relative to start 
of dosing) 
 
Pre-dose 
0 
5 minutes 
EOI 
1 
2 
3 
4 
5 
7 
8 
12 
24h after D1 
 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D8 
Pre-dose 
0 
EOI 
8 
24h after D15 
Pre-dose 
0 
EOI 
8 
24h after D22 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluationa 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
12-lead ECGb 
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 
ECHO/MUGAc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationd 
 
Hospitalization 
 
Hospitalization (if target dose is 
180 mg/m2 or higher only) 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxise 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies 
review 
 
X 
Adverse events 
 
X 
Serious adverse events 
   X 
STUDY TREATMENT 
AMG 176f 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Azacitidineg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Local labs 
Safety lab testsh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
TLS monitoringi 
 
X 
 
 
X 
 
 
 
X 
 
 
X X X 
 
X 
 
X 
 
X 
 
 
X X X X 
 
 
 
X X 
 
 
 
X 
Cardiac monitoring testsj 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
X X 
 
 
X X X 
 
 
X X 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 23 of 149 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy Cycle 1, All Doses 
 
Screen 
Treatment 
Cycle 
 
1 
Days 
-14  
to  
0 
1 
2 
3 to 7 
8 
9 
15 
16 
22 
23 
Hours (relative to start of 
dosing) 
 
Pre-dose 
0 
5 minutes 
EOI 
1 
2 
3 
4 
5 
7 
8 
12 
24h after D1 
 
Pre-dose 
0 
EOI 
3 
4 
5 
7 
8 
12 
24h after D8 
Pre-dose 
0 
EOI 
8 
24h after D15 
Pre-dose 
0 
EOI 
8 
24h after D22 
Local labs (continued) 
HIV testingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central labs 
AMG 176 PKm,n 
 
X 
 
 
X 
 
 
X 
 
X X X 
 
X 
 
X  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Azacitidine PKm,o 
 
X 
 
X X X X 
 
X 
 
 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE AND IMAGING ASSESSMENTS 
Bone marrow 
aspirate/biopsyp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood count 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 24 of 149 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy Cycles 2 and Beyond, All Doses  
Cycle 
Treatment 
EOTq 
SFUq 
LTFU/EOSr,s 
2 
3 and 4 
 5 
Days 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
 
Hours (relative to 
start of dosing) 
Pre-dose 
0 
EOI 
24h after 
dose 
 
Pre-dose 
0 
EOI 
Pre-dose 
0 
EOI 
24h after 
dose 
 
Pre-dose 
0 
EOI 
Pre-dose 
0 
24h after 
dose 
 
Pre-dose 
0 
EOI 
Clinical evaluationa 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Vital signs 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
12-lead ECGb 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
ECHO/MUGAc 
 
X 
 
X 
Concomitant 
therapies review 
X 
Adverse events 
X 
Serious adverse 
eventss 
X 
Subsequent anti-
cancer therapy and 
survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
STUDY TREATMENT 
AMG 176f 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Azacitidineg 
 
X 
 
D2 
X 
 
 
 
 
X 
 
D2 
X 
 
 
 
 
X 
D2 
X 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Local labs 
Safety lab testsh 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Cardiac monitoring 
testsj 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Pregnancy testk 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Central Labs 
AMG 176 PKm,n 
X 
 
X 
D2 
 
 
 
 
X 
 
X 
D2 
 
 
 
  
 
 
 
 
 
 
 
 
 
Page 1 of 2 
See end of Table 1-4 for assessment notes and abbreviation definitions 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 25 of 149 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Part 1B and Part 2, Combination Therapy Cycles 2 and Beyond, All Doses 
Cycle 
Treatment 
EOTq 
SFUq 
LTFU/EOSr,s 
2 
3 and 4 
 5 
Days 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
1 
2, 9,  
16, & 23 
3 to 7 
8, 15,  
& 22 
 
Hours (relative to 
start of dosing) 
Pre-dose 
0 
EOI 
24h after 
dose 
 
Pre-dose 
0 
EOI 
Pre-dose 
0 
EOI 
24h after 
dose 
 
Pre-dose 
0 
EOI 
Pre-dose 
0 
24h after 
dose 
 
Pre-dose 
0 
EOI 
DISEASE AND IMAGING ASSESSMENTS 
Bone marrow 
aspirate/biopsyp 
C2D1, C3D1, and thereafter prior to every other cycle or when clinically indicated until disease progression and to confirm CR and 
MRD status 
 
 
Peripheral blood 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
  
X 
 
 
 
 
 
 
 
 
Overall disease 
response 
Assessed and documented at every cycle and at the time of disease progression 
 
 
Page 2 of 2 
AE  adverse event; ALT  alanine aminotransferase; BNP  B-type natriuretic protein; BSA  body surface area; C  cycle; CBC  complete blood count; 
CR  complete remission; CXDX  cycle X day X; D  day; ECG  electrocardiogram; ECHO  echocardiogram; ECOG PS  Eastern Cooperative Oncology Group 
Performance Status; EOI  end of infusion; EOS  end of study; EOT  end of treatment; FDG  fluorodeoxyglucose; h hour; HIV  human immunodeficiency virus; 
IV  intravenous; LTFU  long-term follow-up; min  minute; MRD  minimal residual disease; MUGA  multigated acquisition scan; NT-pro-BNP  N-terminal 
prohormone of brain natriuretic peptide PBMC  peripheral blood mononuclear cell; PK  pharmacokinetics;  QW  weekly; SAE  serious adverse event; 
SC  subcutaneous; SCR  screening; SFU  safety follow-up; SOA  schedule of activities; SOC  standard of care; TLS  tumor lysis syndrome; W  week; 
WBC  white blood cell. 
a Clinical evaluations:  (ie, physical exam, ECOG PS, and weight) When collected on dosing days, will be collected pre-dose.  Medical and surgical history, neurological 
assessment and height need only be collected at the screening visit.  Prior to dosing on day 1 of every cycle, weight must be collected and BSA must be calculated.  
Physical examination (including ECOG PS and concomitant medications) every 28 days ( 7 days) for the first 3 cycles, then every 3 cycles until 12 cycles from the 
start of therapy; then every 6 cycles (2 months). 


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b ECG:  ECGs will be performed at the timepoints in the SOA as follows. 
Screening ECGs:  single ECG 
Baseline (pre-dose cycle 1 day 1):  Three baseline ECGs will be collected  5 minutes apart, with each baseline ECG performed in triplicate, and with at least 
5 minutes between the end of each triplicate and the start of the next (total 9 ECGs). 
Cycles 1 through 4:  Triplicate ECGs run consecutively (ie, all 3 ECGs should be completed within a total of 5 minutes from the start of the first to the completion of 
the third) 
Cycle 5 and all subsequent cycles:  single ECG 
c ECHO or MUGA:  Additional ECHO/MUGA, cardiac imaging and cardiac assessments are to be conducted if any clinical signs or symptoms of cardiomyopathy or 
other cardiac compromise are noted.  If an ECHO or MUGA was performed within 30 days of C1D1 as part of SOC, then it does not have to be repeated during 
screening as long as the same modality is used throughout the study.   
d Hospitalization for TLS monitoring and prophylaxis:  All subjects will be hospitalized to monitor for TLS.  Hospitalization will begin within 24 hours before the first dose 
of AMG 176 and continue until 24 hours post first AMG 176 dose.  If the target dose is 180 mg/m2 or higher, hospitalization will also be required within 24 hours 
before administration of the target dose on day 8 and will continue until 24 hours post administration.  Hospitalization period can be increased per institutional 
standards or investigators discretion.  Hospitalization for the purpose of TLS prophylaxis will not be captured as an SAE. 
e TLS Prophylaxis:  See Protocol for prophylaxis requirements (see Section 11.9) including additional serum chemistry and hematology laboratory samples that must 
be collected within 24 hours prior to the first dose (see Section 8.4.3.2).  Electrolyte values must be within normal range prior to AMG 176 dosing.   
f AMG 176 dosing:  AMG 176 will be administered QW IV on days 1, 8, 15, and 22 on a 28-day cycle.  A lead in dose of 120 mg/m2 will be required if the target dose is 
180 mg/m2 or higher.  AMG 176 will be infused over 2 hours ( 5 minutes).  Clinical visits on dosing days can be scheduled  1 day; however, safety and PK 
evaluations must occur at indicated time points, including a return to clinic 24 hours after dosing for safety and PK evaluations. 
g Azacitidine dosing:  refer to the prescribing information for full details.  The standard dose and schedule for azacitidine is as follows:  Azacitidine will be administered 
at a dose of 75 mg/m2 IV or SC daily on days 1 to 7 of each 4-week cycle.   
h Safety Labs:  Safety labs include chemistry, hematology, urinalysis, and coagulation analytes.  See Protocol for the list of analytes (Table 11-1).  Pre-dose safety labs 
are to be collected per the SOA and can be collected up to approximately 24 hours before treatment begins unless otherwise indicated (eg, TLS monitoring test). 
- 
CBC with differential (differential not required if WBC  0.5 k/L), at least once weekly for the 1st cycle, then every 2 to 4 weeks during cycles 2 to 6, and then 
every 4 weeks ( 14 days) thereafter as long as they are on study. 
- 
Serum chemistry profile at least once weekly for the 1st cycle, then every 2 to 4 weeks during cycles 2 to 6, and then at least every 4 weeks ( 14 days) 
during active treatment. 
i TLS monitoring test:  TLS monitoring tests consists of the chemistry analytes serum potassium, phosphorous, calcium, uric acid, and creatinine and will be performed 
at the timepoints in the SOA.  The pre-dose samples must be collected within 4 hours before AMG 176 administration to ensure electrolytes are within normal range.  
Note:  The pre-dose safety chemistry and TLS monitoring tests can be drawn at the same time provided they are collected within 4 hours before AMG 176 
administration.  
j Cardiac monitoring tests:  Cardiac monitoring tests include the following analytes:  troponin (I or T), creatine kinase-muscle/brain (CK-MB), and N-terminal 
prohormone of brain natriuretic peptide (NT-pro-BNP).  These cardiac monitoring tests will be collected at the time points specified in the SOA and analyzed locally.  
In addition, samples will need to be submitted to the central lab.  Refer to the central lab manual. 
k Pregnancy test (serum or urine).  Applies to females of childbearing potential and will be performed locally at screening, prior to each treatment cycle (pre-dose), end 
of treatment, and at the safety follow-up visit.  Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a 
female subject is pregnant or per local laws and regulations. 
l HIV:  to be performed only if required by local regulatory authorities. 
m PK:  PK samples should be collected at the exact nominal time point as noted.  For pre-dose PK sample, the sample should be collected within 1 hour before the 
dose.  For all other timepoints, PK samples should be collected within  15 min of the designated time points.  If unable to collect a PK sample at the specified 
nominal time point, then collect the sample as close as possible and record the actual collection time.  Note:  It is important to document the exact date and time of 
investigational product administration and PK sample collection. 
n AMG 176 PK:  samples collected and analyzed for AMG 176 at the timepoints indicated. All AMG 176 timepoints are relative to start of infusion. 
o Azacitidine PK:  samples collected and analyzed for azacitidine at the timepoints indicated. All azacitidine timepoints are relative to azacitidine administration. 


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p Cytomorphology:  bone marrow smears (slides) at screening, pre-dose on day 1 of cycle 2 and cycle 3 and thereafter prior to every other cycle or when clinically 
indicated until disease progression.  Bone marrow biopsies/aspirates may be performed with a  3 day window. 
q EOT and SFU:  In any case of premature treatment discontinuation, the investigator should make every effort to perform all examinations scheduled for the EOT and 
SFU visits.  These data should be recorded, as they comprise an essential evaluation that should be performed prior to removing any subject from treatment and to 
allow for the evaluation of the study endpoints.  The EOT visit will occur upon the decision to end the treatment (eg, due to intolerable AE, disease progression).  The 
SFU visit will occur 30 days ( 3 days) after last dose of protocol required therapies.   
Note:  If a subject withdraws consent, it is important to distinguish between withdrawal of consent from treatment (partial withdrawal of consent) which will allow for 
continued follow-up in LTFU (eg, for survival) or withdrawal of consent from study (full consent withdrawal).  These discussions should be thoroughly documented in 
the subject’s medical records.   
r LTFU/EOS:  Long-term follow-up (LTFU) visits will occur every 3 months for up to 1 year after EOT.  The EOS for a subject will occur when the subject completes the 
LTFU or dies, whichever occurs first.   
Note:  If a subject withdraws consent, it is important to distinguish between withdrawal of consent from treatment which will allow for continued follow-up in LTFU (eg, 
for survival) or withdrawal of consent from study.  These discussions should be thoroughly documented in the subject’s medical records.   
s During the Long-term follow-up phase, serious adverse event(s) suspected to be related to Investigational Product will be reported to Amgen.  After end of 
study serious adverse event(s) suspected to be related to Investigational Product will be reported to Amgen.  Please refer to Section 8.4.6.1.3 for 
additional details. 
 


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2. 
Introduction 
2.1 
Study Rationale 
Programmed cell death or apoptosis is a survival mechanism utilized by different types 
of cancer, with evasion of apoptosis leading to malignant transformation (Fouad and 
Aanei, 2017; Hanahan and Weinberg, 2000).  The process of apoptosis is regulated by 
complex protein-protein interactions between subgroups of the B-cell 
lymphoma/leukemia 2 (BCL2) protein family (Strasser et al, 2011; Czabotar et al, 2014).  
Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic member of this protein family that 
promotes cell survival (Kozopas et al, 1993).  With apoptotic stimuli, pro-apoptotic BCL2 
homology 3 (BH3)-only proteins, such as BCL2-Interacting Mediator of cell death (BIM) 
and p53-Upregulated Modulator of Apoptosis (PUMA), bind MCL1 and other pro-survival 
BCL2 family members, thus disrupting interactions between MCL1 and BAK and BAX.  
This disruption leads to the activation and oligomerization of BAK and BAX, 
Mitochondrial Outer Membrane Permeabilization (MOMP), release of cytochrome C, 
caspase activation, and ultimately cell death (Youle and Strasser, 2008).  MCL1 is 
expressed in a range of human and mouse tissues (Strasser et al, 2011; Thomas 
et al, 2013; Wang et al, 2013), and overexpression of MCL1 has been implicated in the 
development of numerous solid and hematopoietic malignancies (Glaser et al, 2012; 
Kotschy et al, 2016; Ashkenazi et al, 2017; Merino et al, 2017), as well as in resistance 
to chemotherapy and to BCL2/BCL-XL inhibitors (van Delft et al, 2006; Wertz et al, 
2011).  These findings suggest that the inhibition of MCL1 is a novel and compelling 
therapeutic strategy for the treatment of malignancies. 
2.2 
Background 
2.2.1 
Disease 
Myelodysplastic Syndromes (MDS) are malignant clonal disorders characterized by 
ineffective hematopoiesis; bone marrow dysplasia; peripheral cytopenias, including 
neutropenia, anemia, and/or thrombocytopenia; and a propensity to transform into acute 
myeloid leukemia (AML) (Albitar et al, 2002; Doll and List, 1989).  The incidence of MDS 
in the United States is increasing, with approximately 20 000 to 30 000 new cases 
diagnosed annually and a median age of diagnosis approximately 70 years (Kadia et al, 
2011; List 2005; Ma et al, 2007).  By the International Prognostic Scoring System (IPSS) 
and Revised IPSS (IPSS-R), MDS patients are divided into two major risk groups:  
lower-risk and HR-MDS (Greenberg et al, 1997; Greenberg et al, 2012).  Patients who 


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present to HR-MDS have a median OS of less than one year with best supportive care 
(Fenaux et al, 2009). 
The selection of therapy for MDS is based on the patient IPSS risk category, age, and 
performance status.  Treatment goals range from managing cytopenias and improving 
quality of life in lower-risk MDS to prolonging survival in HR- MDS (Cheson et al, 2006).  
Current treatment options for patients with MDS range from growth factor support or 
lenalidomide in low risk patients, to intensive chemotherapy and allogeneic 
hematopoietic stem cell transplantation (HSCT) for patients with high-risk disease.  The 
use of lenalidomide has demonstrated significant clinical activity in patients with anemia 
and a chromosome 5q deletion (del [5q]), with response rates as high at 35 to 60 
(Cheson et al, 2006).  However, the only potentially curative therapy for MDS remains 
allogeneic HSCT.  Yet, due to the high risk of HSCT-associated morbidity and mortality, 
less than 1000 patients with MDS currently undergo an HSCT in the US each year 
(Bejar and Steensma, 2014). 
Therapeutic options for MDS remain limited despite some advances.  A small 
percentage of patients with minimal comorbidities and good performance statuses are 
candidates for curative therapies, such as allogeneic stem cell transplantation.  For the 
vast majority of patients, the lack of acceptable donors, advanced age, and/or serious 
comorbid medical conditions and organ dysfunction prevent access to curative options.  
For similar reasons, AML therapy-based intensive chemotherapy regimens present an 
unacceptable risk-benefit ratio for many patients.  The Standard of Care (SOC) in MDS 
has generally been accepted as supportive in nature. 
Over the past 15 years, clinical use of HMA, including azacitidine (Vidaza), have been 
shown to improve patient quality of life, decrease transfusion requirements, and improve 
outcome parameters in MDS patients and has become the SOC for patients with MDS 
requiring treatment (Fenaux et al, 2009; Kantarjian et al, 2006).  Only azacitidine has 
demonstrated a survival advantage compared to conventional care regimens with best 
supportive care, low-dose cytarabine, or intensive chemotherapy with a median OS of 
24.5 months versus 15.0 months respectively (Fenaux et al, 2009).  However, not all 
patients respond to HMA therapy and, unfortunately, patients will ultimately progress on 
HMAs.  Current research demonstrates overall response rate (ORR) of 28 to 48, 
Complete Response rates of 6 to 34, and median DOR of 8 to 10 months in all 
patients treated with HMAs (Kadia et al, 2011; Prebet et al, 2011).  Patients who have 
failed HMA therapy have extremely poor prognoses with a median OS of 4 to 6 months 


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(Prebet et al, 2011; Jabbour et al, 2010).  There are currently no Food and Drug 
Administration (FDA)-approved agents in the setting of HMA failure MDS patients, and 
there are limited therapeutic options, especially given the increased age and frequent 
comorbidities of this patient population.  Because azacitidine is the only drug that has 
been shown to have a survival advantage for MDS patients, combination strategies with 
azacitidine-based therapy have become a major focus of clinical research 
(Steensma 2012). 
2.2.2 
Amgen Investigational Product Background:  AMG 176 
AMG 176 is a potent and selective inhibitor of protein-protein interactions between MCL1 
(Myeloid Cell Leukemia Sequence 1) and pro-apoptotic members of the BCL2 family.  
Programmed cell death or apoptosis is regulated via a complex network of 
protein-protein interactions between the pro- and anti-apoptotic sub-groups that make-up 
the BCL2 protein family (Czabotar et al, 2014; Strasser et al, 2011; Kozopas et al, 1993).  
Myeloid cell leukemia sequence 1 is an anti-apoptotic member of this family and 
promotes cell survival.  In contrast, pro-apoptotic family members such as BAK, BAX, or 
the BH3-only protein family members, such as BIM and PUMA, are critical effectors for 
the induction of apoptosis.  Upon the induction of apoptotic stimuli, pro-apoptotic BH3 
only proteins bind MCL1 and other pro-survival BCL2 family members, disrupting 
interactions between MCL1 and the pro-apoptotic effector proteins, BAK and BAX.  This 
leads to activation and oligomerization of BAK and BAX, MOMP, and the release of 
cytochrome C, caspase activation and cell death (Czabotar et al, 2014; 
Strasser et al, 2011). 
Malignant transformation results in cellular stress from a variety of pro-apoptotic insults, 
including hypoxia and gain-of-function mutations in oncogenes, suggesting there is a 
strong selective advantage for tumors to evolve mechanisms that culminate in the 
evasion of apoptosis.  The over-expression of anti-apoptotic BCL2 family members, such 
as MCL1 and BCL2, has emerged as a central mechanism by which cancers buffer 
pro-apoptotic stress.  There is now considerable data suggesting that MCL1 is integral to 
the resistance of apoptosis in a substantial number of solid and hematopoietic cancers.  
Genetic ablation of MCL1 has been shown to protect mice from the development of AML 
(Glaser et al, 2012).  Additional mouse knockout studies have implicated MCL1 in the 
maintenance of plasma cells, an observation that suggests MCL1 may be a critical 
pro-survival factor in multiple myeloma (Peperzak et al, 2013).  Myeloid cell leukemia 
sequence 1 is highly expressed in a variety of human tumors, and over-expression of 


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MCL1 has been implicated in resistance to chemotherapy and to BCL2/BCL-XL 
inhibitors (Wertz et al, 2011; van Delft et al, 2006).  Finally, focal amplification of the 
MCL1 gene has been observed in up to 10 of cancers derived from multiple tissue 
types, including lung and breast (Beroukhim et al, 2010).  These data suggest that the 
inhibition of MCL1 represents a novel and compelling therapeutic strategy for the 
treatment of cancer.  A promising strategy for targeting MCL1 takes advantage of 
specific small molecules that selectively bind to MCL1 and disrupt its interactions with 
the BH3 domain of pro-apoptotic partner proteins such as BAK, and BIM, leading to the 
activation of the intrinsic apoptotic cascade and death in cells dependent on MCL1 for 
survival. 
The MCL1 inhibitor AMG 176 is a first in class, small molecule therapeutic candidate 
with novel Mechanism of Action (MOA) (disruption of protein-protein interactions) with 
the potential to directly induce apoptosis in cells dependent on MCL1 for survival.  
Furthermore, the activity of AMG 176 in pre-clinical models suggests that AMG 176 may 
have utility in hematological malignancies, particularly MM and AML. 
2.2.2.1 
AMG 176 Preclinical Pharmacodynamic and Antitumor Studies 
AMG 176 selectively disrupts the human MCL1:BIM interaction in a cell-free time 
resolved fluorescence resonance energy transfer-based assay with a mean inhibitory 
constant (Ki) of 0.00006 mol/L (Caenepeel et al, 2018).  Furthermore, AMG 176 is 
highly selective for MCL1, demonstrating  4000-fold selectivity over the pro-survival 
BCL2 family members, BCL2 and BCL-XL in a BIM binding assay (Caenepeel et al, 
2018).  The profiling of a large and diverse panel of tumor cell lines revealed that AML 
cell lines were sensitive to MCL1 inhibition in vitro.  This observation led us to test the 
hypothesis that the combinations of MCL1 inhibition with SOC agents may further 
sensitize AML tumors to treatment with an MCL1 inhibitor.  We characterized the effects 
of MCL1 inhibition when combined with the BCL2 inhibitor venetoclax, cytarabine, 
decitabine, and doxorubicin in AML cell lines.  A synergistic interaction was observed 
with all 4 combinations highlighting the potential for combining MCL1 inhibitors with SOC 
agents in AML (Caenepeel et al, 2018).  
In vivo, treatment with AMG 176 significantly inhibited the growth of established 
orthotopic MOLM13-Luc AML tumors, at doses of 60 and 30 mg/kg on a 2 day on/5-day 
off (Every 2 Weeks [Q2W]) schedule (Caenepeel et al, 2018).  The combination of 
AMG 176 and the HMA decitabine was also tested in the MOLM13 orthotopic 
AML xenograft model.  Mice were treated with the combination of AMG 176 at 30 mg/kg 


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(Q2W) and decitabine administered 3 times a week at a dose of 1 mg/kg and activity 
compared against the single agent treatment.  A significant reduction in tumor burden 
was observed with the combination of AMG 176 plus decitabine (98 tumor growth 
inhibition) compared to single agent AMG 176 (81 tumor growth inhibition) and single 
agent decitabine (64 tumor growth inhibition) (Caenepeel et al, 2018).  We also tested 
the combination of AMG 176 and venetoclax in the MOLM13 orthotopic AML xenograft 
model.  Mice harboring MOLM13 tumors were treated twice weekly with AMG 176 
(30 mg/kg) and daily with venetoclax (50 mg/kg).  Whereas both single agents achieved 
significant reductions in tumor burden (55 and 23, respectively), the combination 
exhibited complete inhibition of tumor burden and achieved regression relative to the first 
day of dosing (Caenepeel et al, 2018).  In summary, these data highlight the promise of 
AMG 176 as a novel therapeutic for the treatment of AML, and also illustrate the 
potential of AMG 176 to be combined with AML SOC to improve clinical outcomes. 
2.2.2.2 
AMG 176 Pharmacokinetics 
AMG 176 was characterized in vitro and in vivo preclinical studies.  In animal species 
AMG 176 had low drug Clearance (CL) relative to hepatic blood flow.  In vitro, the 
metabolism of AMG 176 was catalyzed primarily by cytochrome P450 (CYP) 3A4 and 
CYP2C8.   
In vitro, AMG 176 was highly bound to plasma proteins in all species including human 
(mean fraction unbound of 0.024) and did not partition into Red Blood Cells (RBCs), 
which makes plasma concentrations suitable for Pharmacokinetics (PK). 
In vitro, AMG 176 was a non-selective CYP inhibitor in human liver microsomes 
(Ki ranged from 2.6 to 9.4 M, with the most potent effect against CYP2C9), a 
time-dependent inhibitor of CYP3A4 (Ki of 80 to 178 M and rate of enzyme inactivation 
[kinact] of 0.044 to 0.75 min-1), an inducer of CYP2B6 and CYP3A4 in primary human 
hepatocytes, and an inhibitor of organic anion polypeptide transporters (OATP) 1B1, 
Breast Cancer Resistance Protein (BCRP), and OATP1B3 (concentration of drug 
producing 50 inhibition [IC50] of 1.2, 1.5, and 3.9 M, respectively).  Subject to its 
administered dose and regimen, AMG 176 has the potential to cause CYP mediated 
Drug-Drug Interactions (DDIs) by inhibition (eg, inhibition of CYP3A4 substrates), 
CYP3A4 induction and transporter mediated DDIs. 


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2.2.2.3 
AMG 176 Preclinical Toxicology 
AMG 176 has been evaluated in a comprehensive series of toxicology studies in 
laboratory animals and in vitro test systems.  The design of the nonclinical safety 
assessment program was in accordance with International Council for Harmonisation 
(ICH) Harmonised Tripartite Guideline S9, “Nonclinical Evaluation for Anticancer 
Pharmaceuticals” (ICH S9, 2010).  The goal of this program was to adequately 
characterize the toxicity of AMG 176 for clinical use. 
Potency of AMG 176 vs MCL1 interaction in the dog is nearly identical to that seen in the 
human.  The potency of AMG 176 vs the rodent MCL1 protein is 177-fold lower than in 
the dog (AMG 176 Investigator’s Brochure [IB]).  AMG 176 nonclinical safety studies 
consisted of an exploratory 14-day dog Intravenous (IV) toxicology study, Good 
Laboratory Practices (GLP) 28-day rat and dog IV toxicology studies, in vitro and in vivo 
phototoxicity assay, an in vitro hemolysis assay, and in vitro safety pharmacology 
studies (human ether-à-go-go-related gene [hERG] and isolated rabbit heart) to 
characterize potential cardiovascular effects (AMG 176 IB). 
The doses selected for the 28-day IV dog and rat toxicology studies were intended to 
characterize the toxicity of AMG 176 and provide data to support a starting dose for the 
First-In-Human (FIH) study.  An IV route of administration and a dosing schedule of 
2 days of dosing followed by 5 days of non-dosing was used to support the anticipated 
clinical route and dosing schedule.  While no preclinical safety data exist for Once 
Weekly (QW) dosing, the twice weekly dosing data provide a conservative case and no 
additional safety concerns are anticipated with QW dosing.  In a 28-day rat IV infusion 
toxicology study the severely-toxic dose in 10 of the animals (STD10) was 60 mg/kg 
based on mortality at 120 mg/kg and in a 28-day IV toxicology study in dogs, the 
Highest-Non-Severely-Toxic Dose (HNSTD) was 10 mg/kg based on early deaths at 
20 mg/kg.  In both the rat and dog, morbidity and mortality were related to mucosal 
epithelial degeneration in the small and large intestines.  AMG 176 was phototoxic in an 
in vitro assay but not in an in vivo study, the latter of which is considered definitive.  
AMG 176 in vehicles containing hydroxypropyl-β-cyclodextrin caused hemolysis of whole 
blood at concentrations of 0.048, 0.12, 0.24, 1.2, and 2.4 mg/mL in rat blood and at 
0.1 and 1.0 mg/mL dog blood. 
2.2.2.4 
AMG 176 Clinical Experience 
AMG 176 is currently being investigated in 2 ongoing clinical studies:  Study 20150161, 
a phase 1, FIH, multicenter, nonrandomized, open-label, dose-exploration study in 


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subjects with R/R multiple myeloma and in subjects with R/R AML; and Study M16-785, 
a phase 1b study of venetoclax and AMG 176 in patients with R/R hematologic 
malignancies. 
A phase 1, FIH study of AMG 176 (Study 20150161) is ongoing.  As of 15 June 2021, 
preliminary data were available for 48 subjects with MM who had received at least 
1 dose of AMG 176:   
 
Thirty-six subjects in Part 1a (once daily for two consecutive days [QD2] dosing 
schedule) 
- 
In Part 1a: 
o Four subjects in the 50 mg/m2 cohort;  
o Three subjects each in the 30, 40, 60, and 120 mg/m2 cohorts,  
o Two subjects in the 240 mg/m2 cohort,  
o Four subjects each in the 120/180 mg/m2 and 120/240 mg/m2 cohorts, 
and  
o Five subjects each in the 120/360 mg/m2 and 120/480 mg/m2 cohorts. 
 
Twelve subjects in Part 1b (QW dosing schedule)   
- 
In Part 1b, 3 subjects each in 120/180, 120/240, 120/360, and 120/480 mg/m2 
cohorts.   
Preliminary data were also available for 37 subjects with AML who had received at least 
1 dose of AMG 176 (see also Section 2.3.1 for efficacy data):   
 
Fifteen subjects in Part 3a (QD2 dosing schedule)  
- 
In Part 3a, 5 subjects each treated in the 60, 120, and 120/180 mg/m2 cohorts. 
 
Two subjects in Part 3 QW Japan (a dose cohort described in a country-specific 
supplement) 
- 
In Part 3 QW Japan, 2 subjects were in 120/180 mg/m2 cohort 
 
Eight subjects in Part 3b (QW dosing schedule monotherapy at 120 mg/m2) 
 
Four subjects in Part 3c (QW dosing schedule monotherapy at 120 mg/m2 in Japan) 
 
Eight subjects in Part 4 (QW dosing schedule in combination at 60 mg/m2 with 
azacitidine). 
Since the safety cutoff, 5 Dose Level Review Meetings (DLRMs) have been held on 
Study 20150161 at the 120 mg/m2 and 180 mg/m2 monotherapy doses (Part 3b) and the 
60 mg/m2 and 120 mg/m2 combination doses (Part 4); no concerning safety events 
(including elevations of troponin) and no DLTs were observed.  Evaluation of the Part 4 
180 mg/m2 combination will be completed and results reviewed prior to opening 
enrollment at that dose level on this study. 
A detailed description of the chemistry, pharmacology, PK, efficacy, and safety of 
AMG 176 is provided in the Investigator’s Brochure. 


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2.2.3 
Non-Amgen Non-Investigational Product Background:  Azacitidine 
2.2.3.1 
Azacitidine Pharmacokinetics 
The pharmacokinetics of azacitidine were studied following a single 75 mg/m2 
Subcutaneous (SC) dose and a single 75 mg/m2 IV dose.  Azacitidine is rapidly 
absorbed after SC administration, with peak plasma concentrations achieved in 0.5 hour.  
Mean half-life (t1/2) after SC administration is 41  8 minutes. 
Urinary excretion is the primary route of elimination of azacitidine and its metabolites.  
In vitro studies indicate azacitidine may be metabolized in the liver.  No formal clinical 
DDI studies with azacitidine have been conducted.  In vitro studies indicate that 
azacitidine did not cause any inhibition of CYP2B6 and CYP2C8 or induction of 
CYP1A2, CYP2C19 or CYP3A4/5.  Refer to the United States Prescribing Information 
(USPI) for additional information.  
2.2.3.2 
Azacitidine Clinical Experience 
A randomized, open-label, controlled trial carried out in 53 U.S. sites compared the 
safety and efficacy of SC azacitidine plus supportive care with supportive care alone 
(“observation”) in subjects with any of the 5 French – American – British subtypes (FAB) 
of MDS:  Refractory Anemia (RA), RA with Ringed Sideroblasts (RARS), RA with Excess 
Blasts (RAEB), RAEB in Transformation (RAEB-T), and Chronic Myelomonocytic 
Leukemia (CMMoL).  Subjects with acute myelogenous leukemia were not intended to 
be included.  Baseline patient and disease characteristics of the 2 groups were similar.  
Azacitidine was administered at a SC dose of 75 mg/m2 daily for 7 days every 4 weeks.  
The dose was increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment 
cycles.  The dose was decreased and/or delayed based on hematologic response or 
evidence of renal toxicity.  
The ORR (CR  Partial Remission [PR]) of 15.7 (14 out of 89) in azacitidine-treated 
subjects without AML (16.2 for all azacitidine randomized subjects including AML) was 
statistically significantly higher than the response rate of 0 in the observation group 
(p  0.0001).  The majority of subjects who achieved either CR or PR had either 2 or 
3 cell line abnormalities at baseline (79; 11 out of 14) and had elevated bone marrow 
blasts or were transfusion dependent at baseline. 
Subjects in the observation group who crossed over to receive azacitidine treatment 
(47 subjects) had a response rate of 12.8. 


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Additionally, a multi-center, open-label, single-arm study of 72 subjects with RAEB, 
RAEB-T, CMMoL, or AML was also carried out.  Treatment with SC azacitidine resulted 
in a response rate (CR  PR) of 13.9, using criteria similar to those described above.  
The mean and median duration of clinical response of PR or better was estimated as 
810 and 430 days, respectively; 80 of the responding subjects were still in PR or better 
at the time of completion of study involvement. 
In another open-label, single-arm study of 48 subjects with RAEB, RAEB-T, or AML, 
treatment with IV azacitidine resulted in a response rate of 18.8, again using criteria 
similar to those described above.  The mean and median duration of clinical response of 
PR or better was estimated as 389 and 281 days, respectively; 67 of the responding 
subjects were still in PR or better at the time of completion of treatment.  Response 
occurred in all MDS subtypes as well as in subjects with adjudicated baseline diagnosis 
of AML in both of these studies.  Azacitidine dosage regimens in these 2 studies were 
similar to the regimen used in the controlled study. 
Benefit was seen in subjects who did not meet the criteria for PR or better but were 
considered “improved”.  About 24 of azacitidine-treated subjects were considered 
improved, and about 2/3 of those lost transfusion dependences.  In the observation 
group, only 5 out of 83 subjects met criteria for improvement; none lost transfusion 
dependence.  In all 3 studies, about 19 of subjects met criteria for improvement, with a 
median duration of 195 days.  Response rate estimates were similar regardless of age 
or gender. 
Azacitidine is commercial grade; refer to USPI for additional information. 
Refer to the regional manufacturer package insert for additional information. 
2.3 
Benefit/Risk Assessment 
Based on early evidence of clinical activity from the FIH study (20150161), nonclinical 
toxicity studies in AMG 176, and clinical safety experience, the overall benefit/risk profile 
supports the further clinical development of AMG 176 in combination therapy for 
subjects with HR-MDS/CMML.  Clinical signs and symptoms, along with other safety 
laboratory parameters, will be monitored during the study and at the appropriate time 
points to ensure subjects’ safety. 
The following benefit/risk assessment supports the conduct of this clinical trial.  
Reference should be made to the Investigator’s Brochure for further data on AMG 176. 


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2.3.1 
Key Benefits 
As AMG 176 is in early development and clinical experience is limited, key benefits are 
still being evaluated.  As of 23 April 2020, 17 subjects with R/R AML were enrolled in 
Part 3.  Of these 17 subjects, 2 subjects in dose escalation have achieved incomplete 
Count Recovery (CRi), with AMG 176 treatment at the 60 mg/m2 and 120 mg/m2 QD2 
dose levels.  One subject achieved a PR at the 60 mg/m2 QD2 dose.  Since the 
23 April 2020 data cut-off, additional subjects have been enrolled and analysis is 
ongoing.  There have been no additional risks identified.   
Preclinical data identified a synergistic effect with AMG 176 when given in combination 
with the HMA decitabine or venetoclax that resulted in an increase in anti-leukemic 
activity (see Section 2.2.2.1).  Based on preclinical data, AMG 176 in combination with 
azacitidine therapy, a similar HMA, is anticipated to provide a new treatment option with 
the potential for better disease control with more Durable Responses (DR) that will lead 
to improved clinical outcomes for subjects with MDS/CMML. 
2.3.2 
Key Risks 
At this time, there is limited clinical experience with AMG 176 in humans.  Based on 
biological plausibility, nonclinical toxicity studies of AMG 176, and clinical safety 
experience, Tumor Lysis Syndrome (TLS), increased troponins, neutropenia, nausea, 
vomiting, and diarrhea have been determined to be identified risks. 
Tumor Lysis Syndrome 
Administration of AMG 176 has been associated with TLS with a fatal outcome.  
Subjects with a high tumor burden or compromised renal function (eg, International 
Staging System [ISS] Stage II/III) may be at elevated risk for TLS.  The risk of TLS may 
increase in the setting of combinational therapy with azacitidine due to the anticipated 
increase in anti-leukemic activity.  To mitigate the risk of TLS, blood chemistry 
(potassium, uric acid, phosphorus, calcium, and creatinine) must be assessed in all 
subjects and any pre-existing abnormalities must be corrected prior to starting treatment 
with AMG 176.  In addition, subjects must be appropriately hydrated prior to each dose 
of AMG 176.  Refer to Section 11.9 (Appendix 9) for specific recommendations 
regarding the mitigation and management of TLS. 
Increased Troponin 
Administration of AMG 176 has led to elevations of serum troponins.  The exact cause 
and clinical effects of troponin increases observed during the use of AMG 176 are not 


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known.  A cardiac monitoring plan has been implemented to mitigate the risk of troponin 
elevations and potential for cardiac toxicity.  Refer to Section 11.10 (Appendix 10) and 
Section 11.11 (Appendix 11) for specific information regarding the cardiac monitoring 
plan and dose modification guidelines, respectively. 
Potential Risks 
In addition to the identified risks listed above, potential risks for AMG 176 based on 
nonclinical findings include reproductive toxicity-male, hepatobiliary toxicity, and 
cardiovascular toxicity (for details, see Section 2.2.2.3).  In addition, bone marrow 
toxicity has been observed in non-clinical studies.  While neutropenia has been identified 
as a risk, anemia and thrombocytopenia due to bone marrow toxicity remain a potential 
risk.  Additional DDI risk is unknown at this time.  Enrolled subjects will be advised on 
the risk associated with AMG 176 administration and signs and symptoms of the risks, 
along with other safety labs, will be monitored during the study and at the appropriate 
time points to ensure subjects’ safety. 
Please refer to the AMG 176 Investigator’s Brochure for further description of potential 
risks.   
There is significant clinical experience with azacitidine and it has an acceptable safety 
profile.  Hematological toxicity, hepatotoxicity, and TLS are associated with azacitidine.  
Tumor Lysis syndrome is an identified risk and bone marrow toxicity and hepatobiliary 
toxicity are potential risks for AMG 176.  The incidence and/or severity of these risks 
may increase when azacitidine and AMG 176 are given in combination.  Refer to 
Section 6.2 for dose modification guidelines for both AMG 176 and azacitidine, as well 
as the approved product label of azacitidine. 
Co-administration of AMG 176 with azacitidine is unlikely to result in DDIs based on 
in vitro studies (refer to azacitidine USPI and AMG 176 Investigators Brochure).   
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on AMG 176, and the 
respective Prescribing Information for further data on azacitidine. 
3. 
Objectives and Endpoints/Estimands 
 
Part 1A – QW Monotherapy (Dose Exploration) 
Objectives 
Endpoints 
Primary 


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 
Evaluate the safety and tolerability of 
AMG 176 once weekly (QW) 
monotherapy in subjects with R/R 
higher risk myelodysplastic 
syndrome (HR-MDS) 
 
Incidence of dose limiting toxicities 
(DLTs), treatment-related, 
treatment-emergent adverse events 
and clinically significant changes in 
vital signs, electrocardiogram (ECGs), 
and clinical laboratory tests 
Part 1B – QW Combination Therapy (Dose Exploration) 
 
Evaluate the safety and tolerability of 
AMG 176 in combination with 
azacitidine in subjects with R/R 
HR-MDS and determine the Optimal 
Biological Dose (OBD) and Minimum 
Safe and Biologically Effective Dose 
(MSBED) of AMG 176 in combination 
with azacitidine 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events 
and clinically significant changes in 
vital signs, ECGs, and clinical 
laboratory tests 
Part 2 – QW Combination Therapy (Dose Expansion) 
 
Evaluate the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with R/R 
HR-MDS/CMML in: 
- HMA Failure, Venetoclax-Naïve 
- HMA Failure, Venetoclax-Exposed 
 
To assess the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with Newly 
Diagnosed MDS/CMML 
 
Overall response rate (ORR), 
according to the Uniform Response 
Criteria for Myelodysplastic/ 
Myeloproliferative Neoplasms 
(MDS/MPN), including: 
 
Complete Remission (CR) 
 
Partial Remission (PR) 
 
Marrow CR 
 
Cytogenic response 
Secondary 
Part 1A – QW Monotherapy (Dose Exploration) 
 
Evaluate preliminary efficacy of 
AMG 176 QW when given as 
monotherapy in R/R MDS/CMML 
 
Overall response according to the 
Uniform Response Criteria for 
MDS/MPN, Event-Free Survival 
(EFS), time to response, and Duration 
of Response (DOR) 
 
Evaluate the pharmacokinetics (PK) 
of AMG 176 when administered as 
monotherapy 
 
PK parameters for AMG 176 
including, but not limited to, maximum 
observed concentration (Cmax), area 
under the concentration-time curve 
(AUC), clearance (CL), and half-life 
(t1/2) 
Part 1B – QW Combination Therapy (Dose Exploration) 
 
Evaluate preliminary efficacy of 
AMG 176 QW in combination with 
azacitidine in R/R MDS/CMML 
 
Overall response according to the 
Uniform Response Criteria for 
MDS/MPN, EFS, time to response, 
and DOR 


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 
Evaluate the PK of AMG 176 and 
azacitidine when administered in 
combination 
 
PK parameters for AMG 176 and 
azacitidine including, but not limited 
to, Cmax, AUC, CL, and t1/2 
Part 2 – QW Combination Therapy (Dose Expansion) 
 
Evaluate the preliminary efficacy of 
AMG 176 in combination with 
azacitidine in subjects with 
R/R HR-MDS/CMML in: 
- HMA Failure, Venetoclax-Naïve 
- HMA Failure, Venetoclax-Exposed 
- To assess the preliminary efficacy 
of AMG 176 in combination with 
azacitidine in subjects with Newly 
Diagnosed MDS/CMML 
 
Time to transformation to Acute 
Myeloid Leukemia (AML)  
 
Duration of Response (DOR)  
 
Overall Survival (OS)  
 
Time to Next MDS Treatment 
(TTNT)  
 
EFS 
 
Evaluate the PK of AMG 176 and 
azacitidine when administered in 
combination 
 
PK parameters for AMG 176 and 
azacitidine including, but not limited 
to, Cmax, AUC, CL, and t1/2 
 
 
4. 
Study Design 
4.1 
Overall Design 
This study is a phase 1 clinical trial designed to assess the safety, tolerability, and 
efficacy of AMG 176 in combination with the 7-day regimen of azacitidine for the 
treatment of HR-MDS/CMML.  Subjects will be treated with IV AMG 176 and IV or SC 
azacitidine.  The study consists of 2 parts. 
4.1.1 
Part 1 – Dose Escalation/Determination of Optimal Biological 
Dose (OBD) and Minimal Safe and Biologically Effective Dose 
(MSBED) 
In Part 1, the modified Toxicity Probability Interval (mTPI) design will be applied for dose 
escalation.  Three dose levels of AMG 176 monotherapy will first be tested, and after 
the OBD is found, three dose levels of AMG 176 in combination with azacitidine will be 
tested. 
After obtaining the monotherapy data from Part 1A, available data for monotherapy and 
combination therapy (with azacitidine) from the FIH study (Study 20150161) will also be 
leveraged to identify the MSBED for AMG 176.  Dose exploration for AMG 176 in 
combination with azacitidine in Part 1B will then begin at the monotherapy MSBED -1 for 
AMG 176.  The combination MSBED in Part 1B will be selected after an integrated 
assessment of all available clinical safety, efficacy, PK, and pharmacodynamic (PD) data 
for AMG 176 is performed, in order to select doses of AMG 176 that are likely to achieve 
the optimal benefit-risk profile.   


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Each dose cohort will initially enroll 3 to 4 subjects and up to 10 subjects per cohort may 
be enrolled.  After reviewing all available safety data, dose level decisions (eg, 
escalation, de-escalation) will be made by the DLRT using mTPI model (Ji et al, 2010) 
based on all subjects that have been enrolled at the current dose.  The DLRT may 
change the dose/dosing scheduled based on emerging data.  The OBD/MSBED is 
defined as the minimum safe and biologically effective combination dose with a 
probability of DLT lower than or close to a targeted toxicity probability of 0.2. 
Dose escalation is considered complete if one of the following rules is met: 
1. The highest planned dose level is evaluated, OBD has not been defined, and no 
DLTs occur at any dose level.  In this case, the Maximum Administered Dose (MAD) 
may be used for Part 2. 
2. An OBD is identified. 
Guidelines for dose level decisions can be found in Table 4-1.  Details regarding the 
mTPI model are described in Appendix 14 (see Section 11.14). 
Table 4-1.  Guidelines for Dose Level Decisions in Part 1 
 
Number of DLTs 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Escalate 
Stay at current dose 
De-escalateb 
3 
0 
1 
 2 
6 
0-1 
- 
 2 
9 
0-1 
2 
 3 
10c 
0-1 
2-3 
 4 
DLT  dose limiting toxicity. 
a A subject is considered DLT-evaluable if he/she experienced a DLT during the DLT evaluation period; or if 
he/she received 75 of the planned doses of AMG 176 and 100 of the planned doses of azacitidine, and 
completed the DLT evaluation period. 
b De-escalate guideline applies only when current dose level and enrollment is allowed to a lower dose level. 
c The maximum number of evaluable subjects at one dose level is 10. 
4.1.2 
Part 2 – Dose Expansion 
Upon completion of Part 1 of the study, the dose expansion phase will begin at the 
OBD/MSBED and drug administration schedule with the intention of confirming the 
safety and tolerability and determining the efficacy of AMG 176 in combination with 
azacitidine in not only R/R HR- MDS/CMML, but also in frontline HR-MDS/CMML.  An 
additional 60 subjects will be enrolled in Part 2 of the study as follows: 
 
HMA Failure Cohort:  stratified by venetoclax exposure history 
o HMA Failure, venetoclax-Naïve (n  20) 


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o HMA Failure, venetoclax-Exposed (n  20) 
 
Newly Diagnosed (n  20) – subjects will not be enrolled into this cohort until all 
previous cohorts have been completed and the data reviewed by the FDA. 
Toxicity will be monitored for each cohort using a Bayesian approach proposed by 
Thall, Simon, and Estey (1995). 
 
The incidence of grade 3 or higher treatment-related non-hematological adverse events 
will be evaluated once every 5 subjects have had the chance to receive at least 1 cycle 
of treatment at the determined dose level for Part 2.  Assuming a prior distribution of 
beta (1, 1), if the posterior probability that the incidence is greater than 20 is  80 at 
these interim analyses, the study will stop early.  The purpose of the safety interim 
analyses is to assess if the threshold for early termination has been reached.  The 
stopping rules and operating characteristics are described in Table 4-2 and Table 4-3. 
Table 4-2.  Stopping Boundary for Each Cohort in Part 2 
Number of subjects 
Stop study if observing this number of subjects with 
grade 3 or higher treatment-related non-hematological 
adverse event 
5  6 
 2 
7  10 
 3 
11  14 
 4 
15  19 
 5 
20 
Completes 
Table 4-3.  Operating Characteristics in Part 2 
True grade 3 or higher treatment-related 
non-hematological adverse event rate 
Probability of early stopping 
0.10 
15 
0.15 
32 
0.20 
51 
0.25 
69 
0.30 
82 
 
Duration of Therapy 
In the absence of treatment delays due to clinically significant study drug-related 
adverse events, treatment may continue until one of the following criteria applies: 
 
Clinically significant progressive disease.  Subjects may continue therapy with either 
or both AMG 176 and azacitidine as long as they have stable disease, as long as, in 
the opinion of the treating physician and/or Principal Investigator (PI), the subject 
continues to derive clinical benefit and has otherwise not had an event requiring 
permanent discontinuation. 
 
Inter-current illness that prevents further administration of treatment. 


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 
Subject decides to withdraw from the study. 
 
Excess toxicity that in the opinion of the PI would present a safety risk for further 
participation on the study. 
Subjects may receive further courses of therapy not earlier than 4 weeks from the 
previous course, provided the subject has recovered from myelosuppression considered 
to be related to chemotherapy. 
A minimum of one full course (or 4 weeks from the start of therapy) will be required for a 
subject to be considered as having received an adequate trial to evaluate efficacy.  All 
subjects receiving at least one dose of any of the two drugs will be considered evaluable 
for toxicity.  Subjects achieving a partial remission or with stable disease may continue 
on therapy until definite evidence of disease progression. 
4.2 
Patient Input into the Study Design 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
Approximately 120 subjects will be enrolled in the study, with up to 60 subjects in Part 1 
and up to 60 subjects in Part 2. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.3 
Justification for Dose 
4.3.1 
Justification for Investigational Product Dose 
The starting dose of AMG 176 will be 120 mg/m2 QW, which is based on prior clinical 
experience that demonstrated significant clinical safety and efficacy in subjects with AML 
(Section 2.2.2.4).  Increased troponin is an identified risk with AMG 176 (Section 2.3.2).  
Troponin elevations in AML and MM subjects studied to date (Study 20150161) were 
reported primarily at higher dose levels of AMG 176 of 360 and 480 mg/m2 as 
monotherapy when administered twice weekly using high sensitivity assays 
(Abbott Architect hs-cTnI) but were not observed for dose levels of 120 and 180 mg/m2 
administered weekly on a 3 out of 4 week dosing schedule.  Additionally, AMG 176 was 
well-tolerated with no DLTs reported in subjects treated with 120 mg/m2 monotherapy 
and 60 mg/m2 in combination with azacitidine when administered weekly for 
4 consecutive weeks each cycle.  In this study, AMG 176 will be administered QW for 
4 consecutive weeks each cycle.  This 28-day duration is considered 1 cycle.  Lead in 
dosing of 120 mg/m2 will be utilized whenever the target dose level is at 180 mg/m2 or 
higher. 


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4.3.2 
Justification for Non-investigational Product Dose 
The dose of azacitidine for the first treatment cycle, for all subjects regardless of 
baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, 
daily for the first 7 days of a 4-week cycle (as per local prescribing information).  
Prophylactic treatment to mitigate nausea and vomiting will be administered. 
4.4 
End of Study 
An individual subject is considered to have completed the study if he/she has completed 
the last visit or the last scheduled procedure shown in the Schedule of Activities.  The 
total study duration for an individual subject is 7.5 months from screening through the 
safety follow-up visit. 
The end of study (EOS) 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), including any additional parts in the study (eg, long-term follow-up, additional 
antibody testing), as 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 
Age  18 years of age. 
102 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
Refer to Section 11.11.1 for more details. 
103 
For Part 1, patients have R/R MDS post-HMA failure, defined as prior receipt of 
4 cycles of HMA therapy (including but not limited to decitabine, azacitidine, 
investigational HMAs such as SGI-110, and oral HMAs such as ASTX727 and 
CC-486) with failure to attain a response or progression of disease or relapse at 
any time after prior response to HMA therapy. 
Note:  


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1) Patients with HR-CMML (CMML, CMML-1 or 2 by World Health Organization 
[WHO]) are eligible.   
2) Hydroxyurea administration will be allowed on the study to lower the white 
cell count to  10 000/µL prior to the initiation of therapy. 
104 
For Part 2, patients will be divided into 2 cohorts: 
a. HMA Failure Cohort:  patients with R/R MDS post-HMA failure (defined as 
prior receipt of 4 cycles of HMA therapy with failure to attain a response or 
progression of disease or relapse at any time after prior response to HMA 
therapy) are eligible.  Patients who have previously received venetoclax are 
eligible and will be stratified accordingly in the HMA Failure Cohort.  
b. Newly Diagnosed Cohort:  patients with treatment-naïve newly diagnosed 
HR-MDS (IPSS score  3.5) are eligible.   
Note: 
1) Patients with HR-CMML (CMML-1 or 2 by WHO) are eligible.   
2) Hydroxyurea administration will be allowed on the study to lower the white 
cell count to  10 000/µL prior to the initiation of therapy.   
 
3) Patients who have previously received venetoclax are eligible and will be 
stratified accordingly in the HMA Failure Cohort. 
105 
Must be willing and able to undergo bone marrow aspirate at screening. 
106 
Life expectancy of  3 months, in the opinion of the investigator. 
107 
Hepatic function, as follows:  AST, and Alanine Aminotransferase (ALT) 
 3 X ULN, total bilirubin  1.5 X ULN (except subjects with Gilbert’s syndrome). 
108 
Cardiac function, as follows; Left Ventricular Ejection Fraction (LVEF)  50 
2D transthoracic ECHO is the preferred method of evaluation.  Multigated 
Acquisition (MUGA) scan is acceptable if ECHO is not available. 
109 
Calculated or measured Creatinine Clearance (CrCl) of  30 mL/minute 
calculated using the formula of Cockcroft and Gault ([140 – Age × Mass kg] / 
[72 × Creatinine mg/dL]).  Multiply result by 0.85 if female. 
110 
Females must be surgically or biologically sterile or postmenopausal 
(amenorrheic for at least 12 months) or if of childbearing potential, must have a 
negative serum or urine pregnancy test within 72 hours before the start of the 
treatment.  Female subjects of childbearing potential must agree to use highly 
effective methods of contraception (see Section 11.5) an adequate method of 
contraception during treatment and until 3 months after the last treatment. 
111 
Males must be surgically or biologically sterile or agree to use an adequate 
method of contraception during the study until 3 months after the last treatment. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Patients with newly diagnosed MDS with IPSS-R lower-risk category (IPSS score 
3.5). 
202 
Patients with CMML-0 by WHO. 
Other Medical Conditions 


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203 
Myocardial infarction within 6 months of enrollment  
204 
Moderate to severe heart failure (New York Heart Association [NYHA] Functional 
Classification III, IV at baseline).  
205 
History of other malignancy within the past 2 years prior to enrollment, with the 
following exceptions:   
 
Malignancy treated with curative intent and with no known active disease 
present for  2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
206 
History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
6 months prior to enrollment. 
207 
Active infection requiring IV anti-infective treatments within 1 week of enrollment. 
208 
Known or suspected Human Immunodeficiency Virus (HIV) infection or subjects 
who are HIV seropositive.  Testing will be performed if required by local 
regulatory authorities. 
209 
Patient has chronic respiratory disease that requires continuous oxygen, or 
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, or 
immunologic condition. 
210 
Exclusion of hepatitis B and C infection based on the following results: 
 
Positive for Hepatitis B Surface Antigen (HbsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B) 
 
Negative HbsAg and positive for Hepatitis B Core Antibody (HbcAb) and/or 
hepatitis B surface antibody:  hepatitis B virus DNA by polymerase chain 
reaction (PCR) is necessary.  Detectable hepatitis B virus DNA suggests 
occult hepatitis B.  Negative for PCR test can be enrolled in the study. 
 
Positive Hepatitis C Virus Antibody (HCVAb):  hepatitis C virus RNA by PCR 
is necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C.  
Negative for PCR test can be enrolled in the study. 
Prior/Concomitant Therapy 
211 
Treatment with medications known to cause corrected QT Interval (QTc) interval 
prolongation within 1 week prior to enrollment unless approved by the Amgen 
Medical Team.   
212 
Anti-tumor therapy:  chemotherapy within 14 days (or 5 half-lives, whichever is 
shorter) of enrollment, antibody therapy, molecular targeted therapy, or 
investigational agent within 21 days (or 5 half-lives, whichever is shorter) of 


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enrollment.  Exceptions:  hydroxyurea to control peripheral blood leukemic cell 
counts is allowed until prior to receiving the first dose of AMG 176.   
213 
Prior systemic radiation therapy must have been completed at least 28 days prior 
to enrollment.  Prior focal radiotherapy completed at least 14 days prior to 
enrollment.  
214 
Patient has received a live attenuated vaccine within 4 weeks prior to the first 
dose of study drug.  Patients who have received coronavirus disease 2019 
(COVID-19) vaccine within 14 days prior to dosing, or plan to receive a 
COVID-19 vaccine within 28 days postdose; from 29 days postdose through 
EOS, vaccination for COVID-19 may be deemed acceptable for a subject 
following discussion and agreement between the sponsor and the investigator. 
215 
Use of any medications (except anti-tumor medications), including herbal 
medicines (eg, St. John’s wort), vitamins, or supplements consumed by the 
subject within the 30 days prior to enrollment, and continuing use if applicable, 
that was not reviewed and approved by the PI and the Amgen Medical Monitor 
prior to enrollment.  Written documentation of this review and Amgen 
acknowledgment is required for subject participation. 
216 
Use of known strong inhibitors of CYP3A4/P-gp within the 14 days or 5 half-lives 
(whichever is longer) or products containing grapefruit juice, Seville oranges, or 
St. John’s wort within 7 days, prior to enrollment unless reviewed and approved 
by the principal investigator and the Amgen medical monitor prior to enrollment.  
Written documentation of this review and Amgen acknowledgment is required for 
subject participation. 
217 
Use of known CYP3A4 sensitive substrates with a narrow therapeutic window 
within 5 half-lives of the drug or its major active metabolite, whichever is longer, 
following the last dose of the drug prior to receiving the first dose of AMG 176 
unless reviewed and approved by the principal investigator and the Amgen 
medical monitor prior to enrollment.  Written documentation of this review and 
Amgen acknowledgment is required for subject participation.  Refer to 
prescribing information for any concomitant medications.  
218 
Use of known OATP1B1 and/or OATP1B3 or BCRP substrates with a narrow 
therapeutic window within 5 half-lives of the drug or its major active metabolite, 
whichever is longer, following the last dose of the drug prior to enrollment unless 
reviewed and approved by the principal investigator and the Amgen Medical 
Monitor prior to enrollment.  Written documentation of this review and Amgen 
acknowledgment is required for subject participation.  Refer to prescribing 
information for any concomitant medications. 
219 
Major surgery within 28 days of enrollment. 
Prior/Concurrent Clinical Study Experience 
220 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Diagnostic Assessments 
221 
Subjects with elevated cardiac troponin above the manufacturer’s 99th percentile 
upper reference limit for ADVIA Centaur XP TnI assay at screening performed by 
the central laboratory. 


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222 
Subjects with evidence of recent cardiac injury at screening based on Creatine 
Kinase-Muscle/Brain (CK-MB), N-Terminal Prohormone of Brain Natriuretic 
Peptide (NT-pro BNP), and Electrocardiogram (ECG) assessments at screening. 
223 
Patient has a white blood cell count  10 x 109/L.  Hydroxyurea or leukapheresis 
are permitted to meet this criterion. 
Other Exclusions 
224 
Female subjects of childbearing potential unwilling to use highly effective 
methods of contraception (see Section 11.5) during treatment and for an 
additional 3 months after the last dose of investigational product. 
225 
Female subjects who are breastfeeding or who plan to breastfeed while on study 
through 3 months after the last dose of investigational product. 
226 
Female subjects planning to become pregnant while on study through 3 months 
after the last dose of investigational product. 
227 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at Screening and/or day 1 by a highly sensitive urine or serum 
pregnancy test. 
228 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 4 months after the last dose 
of investigational product.  Refer to Section 11.5 for additional contraceptive 
information. 
229 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 4 months after the last dose 
of investigational product. 
230 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 4 months after the last dose of investigational product. 
231 
Subject is fit and deemed eligible by the investigator for intensive salvage 
therapy. 
232 
Subject is eligible for HSCT. 
233 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
234 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
235 
History or evidence of any other clinically significant disorder, condition, or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
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, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 


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The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
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 Subject Enrollment Case Report Form (CRF). 
Each subject who enters into the screening period for the study 14 days prior to 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 and concomitant (if subject experienced a serious adverse 
event) therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), 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. 


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A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 
 


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6.1.2 
Non-investigational Products 
The non-investigational product used in this study (azacitidine) may be considered 
investigational in some countries.  Refer to regional prescribing information for full 
details. 
Decisions regarding the AMG 176 lead-in dosing period regimen, lead-in period starting 
dose, dosing increments, will be made by DLRT and communicated to the IRB/IEC, as 
appropriate (see Section 11.3). 
Azacitidine will be administered at 75 mg/m2 IV over approximately 15 minutes or via 
subcutaneous injection daily for 7 days on days 1 to 7 of each treatment cycle.  
Treatment cycles will begin on day 1 of each new azacitidine cycle. 
Azacitidine will be dosed based on actual body weight.  However, at the treating 
physician’s discretion, an adjusted body weight may be used, if the actual body weight is 
greater than 40 over the ideal body weight. 
 
𝐴𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 
 0.4(𝑎𝑐𝑡𝑢𝑎𝑙 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡−𝑖𝑑𝑒𝑎𝑙 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡)  𝑖𝑑𝑒𝑎𝑙 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 
 
The patient’s baseline body weight will be used throughout treatment with consideration 
given to update the dosing weight for a weight change of greater than 10. 
After cycle 1, azacitidine may be subsequently administered at any of the Houston Area 
Locations (HALs) or at the patients’ local oncologists’ offices, and a schedule of 
7 azacitidine doses within 9 days is allowed due to possible weekend closure of local 
offices. Patients will receive one course every 4 to 8 weeks; however, delays of more 
than 8 weeks may be allowed if determined by the investigator to be in the best interest 
of the patient after discussion with the PI and the discussion documented in the patient’s 
medical record. 
Azacitidine will be obtained from commercial sources.  Please refer to the FDA 
prescribing information for azacitidine for further details. 
6.1.3 
Medical Devices 
There are no investigational devices in this study. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 


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Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
6.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies including, allopurinol, that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
6.1.4.1 
Tumor Lysis Prophylaxis (All Subjects) 
There is a potential for TLS in subjects, affected by hematologic malignancies especially 
in those with bulky disease, elevated pretreatment Lactate Dehydrogenase (LDH) levels, 
elevated leukocyte count, renal dysfunction, and dehydration.  To mitigate the risk of 
TLS, AMG 176 lead-in dosing (see Section 6.1.1) will be used and TLS prophylaxis must 
be initiated in all subjects prior to all lead-in dosing of AMG 176 and prior to all 
subsequent dose escalations (ie, first dose on the targeted cohort dose level).  Prior to 
administering these doses, all electrolyte values (including potassium, uric acid, 
phosphorous, calcium, and creatinine) should be reviewed and must be within normal 
range.  However, LDH is not mandatory. 
All other protocol-required therapies including, allopurinol, that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
All subjects will be hospitalized to monitor for TLS and all TLS monitoring assessments 
will be performed as outlined in the Schedule of Activities (see Section 1.3). 
The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be conducted per institutional protocols (Coiffier et al, 
2008; Cairo et al, 2004). 
Tumor lysis syndrome prophylaxis includes: 
 
Allopurinol or equivalent should be used to reduce uric acid level.  This should be 
initiated at least 72 hours prior to dosing.  Treatment may need to be continued 
for up to 5 weeks.  Other agents to reduce uric acid level, such as rasburicase, 


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may be used per principal investigator discretion and the institutional guidelines.  
Dosing per institutional guidelines. 
 
Hospitalization and monitoring, beginning the night before AMG 176 
administration until at least 24 hours post-first AMG 176 dose. 
 
IV hydration must be started the night before AMG 176 administration and to be 
continued until at least 24 hours post–dose during hospitalization as clinically 
tolerated (refer to Section 11.9.3 for more details about the level of IV hydration 
required). 
 
Monitoring of electrolyte values is required prior to dosing anytime a dose is 
higher than one previously given to the subject.  This will include at the following 
times: 
 
Prior to the week 1, day 1 dose. 
 
Prior to each dose during the lead-in period. 
 
Prior to the initial dosing at the target dose level. 
 
Prior to administering these doses, all electrolyte values (including LDH, 
potassium, uric acid, phosphorus, calcium, and creatinine) must be reviewed and 
within normal range (samples must be drawn within 24 hours prior to dosing of 
AMG 176).  The investigator's decision to proceed with AMG 176 treatment 
initiation will be based on these laboratory values. 
Within the first 24 hours after either the first dose or dose escalation, if any laboratory 
criteria for TLS are met, no additional AMG 176 doses should be administered until 
resolution.  A rapidly rising serum potassium is a medical emergency. 
Prophylactic dose reductions for potassium, phosphorus and/or uric acid values at 
the high end of normal range should be considered. 
If the potassium, uric acid, inorganic phosphate and/or creatinine values are higher 
than the normal range or the calcium is lower or higher than the normal range, this 
(these) value(s) can be approved following a discussion between the Amgen Medical 
Monitor and investigator. 
On the AMG 176 dosing days chemistry labs must be performed pre-dose (within 
4 hours before AMG 176 administration), 2, 4, 8, 12, and 24 hours after the start of 
AMG 176 infusion.  Pre-dose labs will be used as baseline to assess potential 
electrolytes abnormalities occurring post AMG 176 administration.  These labs must 
be reviewed in real time by the investigator. 
All 24-hour laboratory assessments may be taken  2 hours, if necessary. 
Monitor for signs and symptoms of TLS (eg, fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion, and seizures).  If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium, and 
creatinine within 1 hour. 
Additional information on the management recommendations of laboratory 
abnormalities can be found in Section 11.2. 
 
Nephrology (or acute dialysis service) consultation should be considered on 
admission (based on investigator discretion) for hospitalized subjects per 


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institutional guidelines to ensure emergency dialysis is available and the 
appropriate staff is aware and prepared. 
6.1.5 
Other Intervention Procedures 
There are no other treatment procedures in this protocol. 
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, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product provisioned and/or 
repackaged/modified by Amgen:  AMG 176. 
Any product complaint(s) associated with an investigational product or 
non-investigational product supplied by Amgen are to be reported. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications and/or therapies should not be administered within the 
timeframes specified prior to enrollment or during the study (unless otherwise specified 
below):   
 
Allogenic stem cell transplant. 
 
Autologous stem cell transplant. 
 
Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, 
retinoid therapy, or investigational agent or procedures); concurrent use of 
bisphosphonates or denosumab for bone loss are permitted. 
 
Treatment with medications known to cause QTc interval prolongation unless 
approved by the Amgen Medical Team. 
 
Any live vaccine therapies used for the prevention of infectious disease. 
 
Any major surgery or radiotherapy unless agreed upon by Amgen and 
investigator. 
 
Over the counter medication(s) that was not reviewed and approved by the 
principal investigator and the Amgen medical monitor. 
 
Herbal medicines (eg, St. John’s wort) that were not reviewed and approved by 
the principal investigator and the Amgen medical monitor. 
The use of certain medications and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 


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allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the Amgen medical monitor can approve such use. 
The following medications or non-drug therapies are prohibited:  
 
Use of known strong inhibitors of CYP3A4/P-gp such as ketoconazole, 
itraconazole, HIV protease inhibitors, nefazodone, cyclosporine, erythromycin, 
clindamycin, tetracycline, and clarithromycin within the 14 days or 5 half-lives 
(whichever is longer) or products containing grapefruit, Seville oranges, or St. 
John’s wort within 7 days, prior to enrollment.   
 
Use of known CYP3A4 sensitive substrates with a narrow therapeutic window 
(such as pimozide, and sirolimus) within 5 half-lives of the drug or its major active 
metabolite, whichever is longer, following the last dose of the drug prior to 
receiving the first dose of AMG 176.  Refer to prescribing information for 
concomitant medications. 
 
Use of known OATP1B1 and/or OATP1B3 substrates with a narrow therapeutic 
window within 5 half-lives of the drug or its major active metabolite, whichever is 
longer, following the last dose of the drug prior to enrollment.  Refer to 
prescribing information for concomitant medications.  
 
Use of known BCRP substrates with a narrow therapeutic window within 
5 half-lives of the drug or its major active metabolite, whichever is longer, 
following the last dose of the drug prior to enrollment.  Refer to prescribing 
information for concomitant medications. 
 
Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of levonorgestrel/injectable 
progesterone is prohibited in this study as it is not known if there is the potential 
of inhibition/induction of enzymes that affect the metabolism of estrogens and/or 
progestins. 
If use of any other prior or concomitant medication or procedure is in question, please 
refer to prescribing information and/or consult with the Amgen medical monitor. 
There are no prohibited therapies and procedures during the 30-day safety follow-up or 
the long-term follow-up. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Dose Level Determination 
A recommendation to escalate to a higher dose cohort will only occur when the previous 
dose regimen(s) has/have been found to be reasonably tolerated based on available 
study data through study day 28 for all subjects and upon unanimous agreement of the 
DLRT members.  Available data from previous cohorts will also be considered.  Dose 
level recommendations will be made on a treatment cohort basis (not on an individual 
basis).  After receiving the DLRT recommendation, Amgen will render a final decision 


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and will issue a written notification of the dose change decision to investigators.  Further 
information on DLRM is provided in Appendix 3 (Section 11.3). 
6.2.1.1 
Dose-limiting Toxicity Evaluation Period 
The minimum DLT evaluation period is defined as 28-days of treatment in cycle 1. 
The DLT evaluation period may also be extended to assess events starting within the 
evaluation period in case the DLT definition is time dependent (neutropenia or 
thrombocytopenia, see below). 
Subjects are considered DLT-evaluable if they experienced a DLT during the DLT 
evaluation period or if they received 75 of the planned doses of AMG 176 (and 100 
of the planned doses of azacitidine in Part 2) and completed the DLT evaluation period. 
Subjects who do not complete 75 of the planned doses of AMG 176 (and 100 of the 
planned doses of azacitidine) or discontinue from the study prior to completing the DLT 
evaluation period for reasons other than a DLT will be considered non DLT-evaluable for 
dose escalation decisions and OBD/MSBED determination and will be replaced by an 
additional subject at that same dose level.  Subjects who receive supportive care during 
the DLT evaluation period that confounds the evaluation of DLTs (not including 
supportive care described in Section 6.2.1.2 as part of the DLT definition) may be 
considered non evaluable for dose escalation decisions and MSBED determination and 
replaced at the discretion of the Medical Monitor. 
6.2.1.2 
Definition of Dose Limiting Toxicities 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT evaluation period and regarded by the investigators and/or Amgen Medical 
Monitor to be related to AMG 176.  Any adverse event occurring outside the DLT 
evaluation period that is determined by the investigator to be possibly related to the 
investigational product, which is seen more frequently or is more severe than expected 
or is persistent despite appropriate management, can be determined to be a DLT upon 
unanimous decision by the DLRT after review of the adverse event and all available 
safety data.  The grading of adverse events will be based on the guidelines provided in 
the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (available 
online at http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  For troponin elevation, refer to 
Section 6.2.1.2.2 for CTCAE grading interpretation.  Determination of the severity of 
adverse events will be consistent with CTCAE version 5.0.  The relationship of an 
adverse event to investigational product will be determined by the Investigator.  An event 


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should be considered related to treatment if, in the Investigator’s medical judgment, 
there is a reasonable possibility that the event may have been caused by AMG 176. 
6.2.1.2.1 
Dose Limiting Toxicities 
A DLT is defined as a grade 3 or higher non-hematological or a grade 4 hematologic 
adverse event that occurs during the DLT observation period (day 1 through day 28 after 
the administration of the first dose of AMG 176) in Part 1 unless clearly attributable to 
causes other than AMG 176 treatment. 
If a DLT of TLS is observed during the lead-in period, it will be attributed to the lead-in 
period and a modification may be made to the lead-in period regimen for subsequent 
groups.  Any other DLTs observed during the lead-in and/or designated group dosing 
period may require a modification of the designated cohort dose (and/or lead-in period 
regimen, if appropriate) as directed per the dose escalation guidelines. 
Available study data, including data collected after the initial DLT-observation period 
along with demographics, investigational product administration, medical history, 
concomitant medications, adverse events, ECG, vital signs, laboratory results, and PK 
information will be reviewed.  In addition to DLTs, all  grade 3 toxicities not meeting 
DLT criteria will be reviewed and may be considered in DLRT decisions.  Modeling of 
available potential safety risk data (eg, for thrombocytopenia) to predict safety risk for 
dose escalation decisions may also be considered.


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Table 6-2.  DLT Criteria 
 
All Subjects 
DLT Criteria 
 
Non-hematologic adverse events:   
- 
 grade 3 non-hematologic adverse event that is not clearly resulting from the underlying leukemia 
- 
recurrence within the DLT window of any adverse events listed under the non-hematologic adverse event 
exception (not including nausea and vomiting) 
- 
any grade 2 non-hematologic adverse event lasting  7 days that causes significant symptoms, dangerous 
medical repercussions, or warranting treatment interruption or dose reduction 
- 
 grade 3 nausea, vomiting or diarrhea persisting more than 3 days despite optimal medical support 
- 
 grade 3 fatigue persisting  7 days 
- 
any other  grade 3 adverse event 
 
Failure to recover from AMG 176 related toxicities to grade  1 or baseline severity after delaying next cycle up to 
14 days 
 
Hematological adverse events: 
- 
Any grade 4 neutropenia and/or thrombocytopenia lasting  28 days from the start of cycle in the absence of 
active MDS or CMML 
 
Any treatment-related death  
 
Clinical TLS per Cairo-Bishop criteria (see Section 11.9.1) grade  3 not resolved to grade  2 within 7 days 
without end-organ damage 
 
Severe DILI per the Hy’s Law criteria (ie, AST or ALT  3 x ULN and serum bilirubin  2 x ULN measured on the 
same day, without signs of cholestasis and in absence of any other explanation for the DILI).  See Section 6.2.3 
for hepatotoxicity management. 
 
Grade 3 elevation of troponin-I (see grading criteria in Section 6.2.1.2.2)a 
 
QTcF interval  501 ms or an increase of  60 ms from baseline on at least 2 separate ECG assessments 
 
Asymptomatic, absolute decrease in LVEF of  10% from baseline AND LVEF  50% 
 
Asymptomatic, absolute decrease in LVEF of  20% from baseline 
 
Symptomatic congestive heart failure 
 
Page 1 of 2 
Footnotes defined on last page of the table 
 


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Table 6 2.  DLT Criteria 
 
All Subjects 
Exceptions 
 
Infections and most hematologic adverse events 
 
Non-hematologic adverse events:   
- 
grade 3 weight gain or loss 
- 
grade 3 diarrhea despite optimal anti-diarrheal therapy that resolves to  grade 2 within  72 hours with or 
without clinical intervention 
- 
grade 3 or 4 isolated electrolyte abnormalities that is not clinically significant and resolves to  grade 2 within 
72 hours with or without clinical intervention 
- 
grade 3 nausea and vomiting that does not require tube feeding, total parenteral nutrition, or prolonged 
hospitalization and resolves to  grade 2 within  72 hours with or without clinical intervention 
- 
grade 3 or 4 serum lipase without clinical signs or symptoms of pancreatitis that returns to baseline within 
72 hours of interrupting study drug 
- 
infection grade 3 (with concurrent neutropenia grade 3 or 4) that resolves to  grade 2 within 7 days with or 
without clinical intervention 
- 
grade 3 fatigue or asthenia 
- 
grade 3 constipation that resolves to  grade 2 within 7 days with or without clinical intervention 
 
AE  adverse event; AML  acute myeloid leukemia; ALT  alanine aminotransferase; AST  aspartate aminotransferase; CMML = chronic myelomonocytic leukemia; 
DILI  drug-induced liver injury; DLT  dose limiting toxicity; ECG  electrocardiogram; LVEF  left ventricular ejection fraction; MDS = myelodysplastic syndrome; 
QTcF = QT interval with Fridericia's correction; TLS  tumor lysis syndrome; ULN  upper limit of normal. 
a Further treatment with AMG 176 may be considered for grade 1 elevations of troponin-I after a cardiology evaluation is completed and results are discussed with the 
Amgen Medical Monitor. 
 
 


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6.2.1.2.2 
Grading of Troponin-I Elevation 
Central testing of cardiac troponin-I will be performed for eligibility determination, 
grading, and withholding decisions.  The following criteria is developed based on 
CTCAE 5.0 to determine the grade of troponin-I elevation with ADVIA Centaur XP TnI 
assay performed by central lab: 
 
grade 1:  isolated elevation of troponin  99th percentile Upper Reference Limit 
(URL) of 0.04 ng/mL for females and 0.059 ng/mL for males 
 
grade 3:  troponin elevation greater than or equal to manufacturer’s defined cut-off 
for MI of 0.78 ng/mL 
Dose Cohort Stopping Rules 
The DLRT will recommend stopping or modifying dosing if suspected adverse drug 
reactions, changes in vital signs, ECG, or clinical laboratory results are observed and 
these changes pose a significant health risk.  The Amgen Medical Monitor may suspend 
dosing and convene a DLRM at any time based on emerging safety data. 
Clinically or medically significant suspected adverse drug reactions, and serious adverse 
events considered to be related to study procedures will be followed until resolved or 
considered stable. 
The study may be terminated at any point at the discretion of the sponsor. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
For Hematologic Drug-Related Adverse Events (AE) 
Dose reduction/interruption/discontinuation decisions should be based on the National 
Cancer Institute (NCI) CTCAE version 5.0 of the toxicity and the guidelines provided 
below.  Dose modifications outside of those provided in Table 6-3 are allowable after 
discussion with the PI and documentation in the medical record, if in the best interest of 
the patient. 
Patients with HR- MDS usually present with abnormal peripheral blood counts at the 
time therapy is started, and myelosuppression is an expected event during the course of 
therapy.  Thus, no dose adjustments or treatment interruptions for myelosuppression will 
be planned in the presence of residual MDS.  Dose-interruptions of azacitidine and 
AMG 176 in these patients should be considered on an individual case and discussed 
with the PI. 


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Patients with a response (with decline in blasts  5) who have prolonged ( 28 days) 
count recovery, may have the treatment with azacitidine and AMG 176 interrupted at the 
discretion of the treating physician after discussing with the PI until neutrophils recover 
to Absolute Neutrophil Count (ANC) is  500/μL and PLT to  50 x109/L.  Investigators 
should, whenever possible, determine which medication is causing the toxicity and 
interrupt or dose reduce azacitidine and/or AMG 176, as applicable.  After interruption, 
dose adjustment for azacitidine, AMG 176, or both can be made as follows: 
 
A reduction of two dose levels or holding of AMG 176 on day 22 may be considered 
if the myelosuppression or was deemed severe and life threatening by the treating 
physician, and if it is in the patient’s best interest. 
 
If additional dose reductions are thought to be necessary by the investigator, a 
discussion with the PI or co-PI is required on an individual case. 
For Non-Hematologic Drug-Related AEs 
Investigators should, whenever possible, determine which medication is causing the 
toxicity and interrupt or dose reduce azacitidine and/or AMG 176, as applicable.  Dose 
reductions will be as per Table 6-3 recommendations.  Dose reductions different than 
Table 6-3 are allowed if determined to be in the patient’s best interest and rationale 
documented in patient record.  The investigators will use their clinical judgment to 
determine whether toxicity is caused by azacitidine, AMG 176, or both.  Dose reductions 
of one of the agents, or both, are allowed after discussion with the PI or co-PI and 
documentation in the medical record. 


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Table 6-3.  Dose Adjustments for Non-hematologic AEs That Are at Least Possibly 
Related 
Grade 
Occurrence 
Dose Modification 
1 or 2 
Anytime 
No dose reduction 
3 or 4 
 
Persistent grade 2:  consider 
similar dose adjustments if 
persistent and not 
responding to optimal 
management in the opinion 
of PI and treating physician 
First and 
second time 
 Hold AMG 176  azacitidine. 
 Resume AMG 176  azacitidine at 
prior dose if recovery to  grade 1 
occurs within 14 days. 
 If toxicity persists for 
15 to 28 days, hold therapy and 
resume azacitidine and AMG 176 
at prior dose if recovery to 
 grade 1 or resume 
AMG 176  azacitidine at ONE 
dose level below current dose if 
recovery to  grade 2. 
Third and 
fourth time 
 Hold AMG 176  azacitidine. 
 Follow until toxicity  grade 2. 
 Resume AMG 176  azacitidine at 
ONE dose level below current 
dose. 
Fifth time 
 Hold AMG 176  azacitidine. 
 Follow until toxicity  grade 2. 
 Resume AMG 176  azacitidine at 
TWO dose levels below current 
dose. 
PI  Principal Investigator. 
Other Modifications of Dose Schedules 
 
Further dose reductions can be made to prevent adverse events and keep clinically 
significant toxicities grade  2. 
 
Dose adjustments by more than one dose level at a time can be considered when 
judged in the best interest of the patient (eg, severe myelosuppression) when toxicity 
has resolved.  The reason for this reduction will be discussed with the PI or co-PI and 
documented in the medical record. 
 
Treatment interruptions and dose modifications other than the ones mentioned above 
can be considered after discussion with the PI and proper documentation of the 
rationale.  Dose adjustment/delay of only one of the agents is permissible if the toxicity 
is most likely judged to be related to one of the agents by the investigator. 
Supportive Care 
Supportive care measures including blood products, infection prophylaxis, and growth 
factors will be administered according to institutional and Leukemia Department 
guidelines. 
6.2.2.1 
Amgen Investigational Product:  AMG 176 
The reason for dose change of AMG 176 is to be recorded on each subject’s CRF(s). 


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6.2.2.1.1 
Dosage Adjustments 
Upon completion of the lead-in dosing if applicable, the subject should continue on the 
same target dose of AMG 176 throughout the study unless the following events occur: 
 
For subjects experiencing an adverse event meeting the DLT definition or intolerable 
related adverse events BUT showing evidence of response, there will be an option to 
reduce the dose to the immediate next lower dose level shown to be safe and 
tolerable in the dose escalation part of the study. 
 
The study drug can be resumed once the adverse events recover to baseline or 
grade 1 and the reintroduction of AMG 176 is deemed safe by the Investigator and 
Amgen’s Medical Monitor. 
 
Subjects must be informed of the risk of continuing on therapy.  Each subject is only 
allowed a single dose reduction as a result of an adverse event.  Subjects showing 
evidence of response or subjects who in the opinion of the investigator may be 
responding to AMG 176, may have the option to have more than single dose 
reduction if deemed safe by the Investigator and Amgen’s medical monitor. 
 
For subjects who experience grade 3 arrhythmia possibly associated with AMG 176, 
AMG 176 dosing must be resumed at the immediate next lower dose level if the 
requirements mentioned below in rules for restarting are met. 
 
For subjects meeting the withholding criteria for elevation of cardiac troponin 
( 0.1 to  0.78 ng/mL), AMG 176 dosing can be resumed at the immediate next 
lower dose level if the requirements mentioned below in rules for dose withholding 
are met. 
Subjects should not be re-challenged with AMG 176 if the following AMG 176-related 
adverse events occur: 
 
Any life-threatening adverse events 
 
Drug-Induced Liver Injury (DILI) meeting Hy’s law (see Section 11.7) 
 
Persistent grade 3 adverse events that do not recover to baseline or grade 1 within 
4 weeks. 
 
Any AMG 176 related adverse event meeting DLT-criteria that recurs despite 2 dose 
level reductions. 
6.2.2.1.2 
Dosage Delays 
During the DLT evaluation period, if the dosing is delayed for more than 2 weeks the 
subject will be removed from the study and will be replaced.  After DLT evaluation 
period, if the dosing is delayed for  4 weeks, the subject should resume the treatment 
as soon as possible if deemed safe by the investigator.  The investigator should inform 
the Amgen Clinical team as soon as the unexpected dosing interruption occurs.  If the 
dosing of AMG 176 is delayed  4 weeks (missing 1 cycle) due to AMG 176-related 
adverse events, the subject will be permanently removed from AMG 176 treatment.  If 
the dosing delay occurred under conditions other than those associated with 


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AMG 176-related toxicities, the case will be reviewed by Amgen Medical Monitor to 
determine whether the subject will be allowed to resume AMG 176 treatment. 
6.2.2.1.3 
Rules for Dose Withholding 
AMG 176 should be withheld for any of the following: 
 
Suspected DLT (including adverse events that meet DLT definition outside DLT 
observation period). 
 
Aspartate aminotransferase or ALT greater than 3 x ULN or total bilirubin greater 
than 1.5 x ULN. 
 
Any grade 3 arrhythmia deemed possibly related to AMG 176.  Should dosing be 
resumed, AMG 176 should be given at the next lower dose level. 
 
Any central lab elevation of cardiac troponin  0.1 ng/mL (ADVIA Centaur XP TnI 
manufacturer’s prognostic cut-off) and  0.78 ng/mL, OR any change in the clinical 
status, above lab analytes (central or locally obtained), ECHO, or ECG deemed 
significant by the investigator or study subjects’ care team. 
 
Upon meeting withholding criteria for AMG 176, investigator/site physician should 
evaluate appropriateness of apparent benefit vs risk of re-initiating AMG 176.  
Based on the assessment, a subject may be continued drug at a reduced dose or 
permanently discontinue therapy. 
 
Low elevations from 0.04 to  0.1 ng/mL do not require withholding or dose 
reductions, though troponins should be monitored with subsequent doses. 
 
Elevations from  0.1 to  0.78 ng/mL should result in a dose withholding, and if 
further treatment is considered, should be restarted at one dose level below the dose 
where elevated troponins were observed. 
 
Permanently discontinue AMG 176 for elevations  0.78 ng/mL. 
 
Any consideration for continued treatment of AMG 176 after troponin elevations 
will require discussion between the investigator, subject, and Amgen medical 
monitor, and following normalization of all abnormalities. 
 
Study subjects that meet withholding criteria require continuous cardiac 
monitoring (telemetry) for at least 24 hours, and a cardiologist’s evaluation that 
includes transthoracic echocardiography to assess the study subject and provide 
recommendations for further cardiac care.  Monitoring should continue according 
to local SOC. 
6.2.2.1.4 
Rules for Restarting 
AMG 176 dosing can be resumed: 
 
If the adverse event resolves to grade  1 or return to subjects’ baseline values. 
 
For subjects meeting the withholding criteria for elevation of cardiac troponin 
( 0.1 to  0.78 ng/mL), AMG 176 dosing can be resumed at the immediate next 
lower dose level if the requirements mentioned above in Rules for Dose 
Withholding are met. 
 
If the restarting of therapy should be deemed safe by the investigators and Amgen’s 
Medical Monitor. 


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6.2.2.1.5 
Rules for Permanent Discontinuation 
Subjects will permanently discontinue from the investigational product if the following are 
observed: 
 
Subjects experience adverse events meeting the DLT criteria at any time.  Subjects 
will be followed until the DLT is resolved, returns to baseline value or is considered 
stable.  Subjects will be withdrawn from AMG 176 treatment and will be treated as 
deemed appropriate by the investigator or treating physician.  Except for: 
 
Subjects showing evidence of response or subjects who in the opinion of the 
investigator may be responding to AMG 176, may have the option to continue 
therapy once the adverse events recover to baseline or grade 1 and the 
re-introduction of AMG 176 is deemed safe by the investigator, and Amgen’s 
Medical Monitor.  The subject should restart at a reduced dose. 
 
Intolerability of AMG 176. 
 
Grade 3 central laboratory elevations of troponin. 
 
Any Grade 4 arrhythmia possibly associated with AMG 176. 
 
Symptoms of clinically significant cardiac dysfunction (defined in Table 6-2), ECG 
changes, or diagnostic evidence of decreased cardiac function or cardiac injury 
irrespective of any cardiac troponin level (centrally or locally obtained).  Study 
subjects that meet permanent discontinuation criteria require continuous cardiac 
monitoring (telemetry) for at least 24 hours, and a cardiologist evaluation that 
includes transthoracic echocardiography to assess the study subject and provide 
recommendations for further cardiac care.  Monitoring should continue according to 
local SOC. 
 
Hepatotoxicity (as defined in Section 11.7). 
The dosing is delayed  4 weeks due to AMG 176-related adverse events. 
6.2.2.2 
AMG 176 Management of Toxicities 
6.2.2.2.1 
Management of Infections 
Subjects with evidence of existing infection should be closely monitored while being 
treated with AMG 176.  Subjects with active systemic infections requiring IV antibiotics, 
antivirals, or antifungals should not be dosed with AMG 176 until infection has resolved 
and if being treated with an anti-infectious therapy, the course of such therapy should 
have been completed.  Management should be tailored to the appropriate prophylaxis 
and/or treatment for the underlying infection according to the local SOC and institutional 
guidelines with the exception of excluded medications detailed in Section 6.1.7. 
Infection Prophylaxis 
Subjects who may experience neutropenia are at a high risk for infectious complications.  
As appropriate, these subjects should be administered prophylactic antibacterial 
(eg, treatment with ciprofloxacin) and antifungal (treatment with amphotericin B or 
echinocandins). 


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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.  Subjects experiencing diarrhea should be closely monitored for their 
electrolyte levels. 
6.2.2.2.2 
Management of Cardiac Arrhythmia 
Subjects with risk factors for, or evidence of, existing heart disease should be closely 
monitored throughout their treatment with AMG 176.  Subjects should be clinically 
monitored on ongoing basis for cardiac function (blood pressure, heart rate, ECHO, and 
ECG) according to the Schedule of Activities (see Section 1.3).  The administration of 
AMG 176 should be withheld if grade 3 or 4 arrhythmias (including tachycardia) develop 
or appear to be exacerbated by AMG 176 treatment.  For any grade 3 arrhythmia related 
to AMG 176 administration, the AMG 176 dose should be reduced.  Treatment may be 
resumed once the signs and symptoms resolve to baseline value or grade 1.  
Management should be tailored to the appropriate treatment for the underlying cardiac 
disorder according to the local SOC and institutional guidelines.  For any grade 4 
arrhythmia related to AMG 176 administration, AMG 176 should be permanently 
discontinued. 
6.2.2.2.3 
Management of Gastrointestinal Toxicities 
Nausea, vomiting, and diarrhea have been observed in a phase 1 FIH dose finding study 
(Study 20150161).  AMG 176 must be withheld from subjects with grade 3 or 4 
gastrointestinal toxicity at any time during study treatment participation.  Management 
should be tailored to the appropriate treatment according to the local SOC and 
institutional guidelines.  AMG 176 can be restarted when the toxicity has improved to at 
least a grade 2. 
6.2.2.2.4 
Prophylaxis and Management of Tumor Lysis Syndrome 
Refer to Section 11.9 for guidance. 
6.2.2.2.5 
Management of Troponin and Other Cardiac Enzymes Elevation 
Subjects with risk factors for, or evidence of, existing heart disease should be closely 
monitored throughout their treatment with AMG 176.  Subjects should be clinically 
monitored with local and central cardiac monitoring tests for elevated troponin and 
cardiac enzymes diagnostic of cardiac injury.  Local troponin testing will be performed to 
guide immediate clinical care.  Central testing of troponin-I with ADVIA Centaur XP TnI 
assay will be performed for all screening, grading, and withholding decisions.   


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6.2.2.3 
Amgen/Non-Amgen Non-Investigational Product:  Azacitidine 
The reason for dose change of azacitidine is to be recorded on each subject’s CRF(s).  
For contraindications, warnings, precautions, and potential drug interactions please refer 
to the current prescribing information for azacitidine. 
Azacitidine dose adjustments based on hematology laboratory values: 
 
Hematological toxicity is defined as the lowest count reached in a given cycle (nadir) 
if platelets  50.0 x 109/L and/or ANC  1 x 109/L. 
Recovery is defined as an increase of cell line(s) where hematological toxicity was 
observed of at least half of the difference of nadir and the baseline count plus the 
nadir count (ie, blood count at recovery  to nadir count  (0.5 x [baseline 
count - nadir count]). 
 
Subjects without reduced baseline blood counts (ie, White Blood Cells 
[WBC]  3.0 x 109/L and ANC  1.5 x 109/L, and platelets  75.0 x 109/L) prior to the 
first treatment. 
For subjects with baseline (start of treatment) WBC  3.0 x 109/L, ANC  1.5 x 109/L, and 
PLT  75.0 x 109/L, adjust the dose as follows, based on nadir counts for any given cycle 
(see Table 6-4): 
Table 6-4.  Azacitidine Hematology Dose Reduction Guidance 
Nadir counts 
 Dose in the Next Cycle 
ANC (x 109/L) 
Platelets (x 109/L) 
 0.5 
 25.0 
50 
0.5 to 1.5 
25.0 to 50.0 
67 
 1.5 
 50.0 
100 
ANC  absolute neutrophil count. 
For patients whose baseline counts are WBC  3.0 x 109/L, ANC  1.5 x 109/L, or 
platelets  75.0 x 109/L, dose adjustments should be based on nadir counts and bone 
marrow biopsy cellularity at the time of the nadir as noted below (see Table 6-5), unless 
there is clear improvement in differentiation (percentage of mature granulocytes is higher 
and ANC is higher than at onset of that course) at the time of the next cycle, in which 
case the dose of the current treatment should be continued. 


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Table 6-5.  Azacitidine Dose Reduction Based on Bone Marrow Cellularity 
WBC or Platelet Nadir  
decrease in counts from baseline 
Bone Marrow Biopsy Cellularity at Time of Nadir () 
30 to 60 
15 to 30 
 15 
 
 Dose in the Next Cycle 
50 to 75 
100 
50 
33 
 75 
75 
50 
33 
WBC  white blood cell  
If a nadir as defined in the table above has occurred, the next course of treatment should 
be given 28 days after the start of the preceding course, provided that both the WBC and 
the platelet counts are  25 above the nadir and rising.  If a  25 increase above the 
nadir is not seen by day 28, counts should be reassessed every 7 days.  If a 25 
increase is not seen by day 42, then the subject should be treated with 50 of the 
scheduled dose. 
Following dose modifications, a new cycle will be started and duration should return to 
28 days.  
Dose adjustment based on renal function and serum electrolytes: 
 
Unexplained reduction of sodium bicarbonate to  20 mEq/L - reduce dose by 
50 on the next cycle 
 
Unexplained elevation of Blood Urea Nitrogen (BUN) or serum creatinine  2-fold 
above baseline - delay next cycle until values return to normal or baseline and 
dose reduce by 50 in the next treatment cycle. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding DILI 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 drug accountability for the investigational product and/or 
other protocol-required therapies and/or devices will be provided to the site. 
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 176. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF. 
An Amgen representative will notify the site in writing when a cohort is open to screen 
and enroll subjects.  The notification will include the cohort number and dose level in 


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which subjects will be enrolled.  Enrollment of subjects in Part 1A and Part 1B will be 
based on availability in the cohort and agreement between the investigator and Amgen 
Medical Monitor. 
6.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance 
When subjects are dosed at the site, they will receive AMG 176 and azacitidine directly 
from the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents and recorded in 
the CRF. 
6.6 
Treatment of Overdose 
Higher doses of AMG 176 may be associated with cardiac troponin elevation.  For 
management of troponin and other cardiac enzyme elevation, please refer to 
Sections 6.2.2.1 and 6.2.2.2.5. 
Refer to the approved product label for azacitidine for information related to azacitidine 
overdose. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken from 2 years prior to enrollment through the 
informed consent should be collected.  For prior therapies being taken for the disease 
under study (eg, steroids, chemotherapy on oncology studies), collect therapy name, 
indication, dose, unit, frequency, start date, and stop date. For all other prior therapies, 
collect therapy name, indication, dose, unit, frequency, route, start date, and stop date. 
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 informed consent through the 
30 days ( 3 days) after the last dose of protocol-required therapies.  For concomitant 
therapies being taken for the disease under study (eg, steroids, chemotherapy on 
oncology studies), assist in the evaluation of efficacy or safety endpoints, in a specific 
class, collect therapy name, indication, dose, unit, frequency, start date, and stop date. 


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For all other concomitant therapies, collect therapy name, indication, dose, unit, 
frequency, route, start date, and stop date.   
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit).  
Any concomitant medication(s), including herbal preparations, taken during the study will 
be recorded in the electronic Case Report Form (eCRF).  The minimum requirement is 
that drug name, dose, and the dates of administration are to be recorded.  Additionally, a 
complete list of all prior cancer therapies will be recorded in the eCRF. 
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, G-CSF and other care as deemed appropriate, and in accordance with 
their institutional guidelines.  Hydroxyurea may be administered according to standard 
practice prior to the first cycle of AMG 176 treatment for subjects with high 
WBC ( 15 000 cells/uL) and during the first cycle but not on days of AMG 176 
administration. 
6.7.2.1 
Antifungal Prophylaxis 
Use of micafungin and amphotericin B for antifungal prophylaxis is allowed for 
neutropenic subjects. 
6.7.2.2 
Concomitant Cautions to Consider 
Caution is recommended during concomitant use of known CYP1A2, CYP2D6, 
CYP2C9, or CYP2C8 sensitive substrates with a narrow therapeutic window (such as 
thioridazine) due to the potential of AMG 176 to inhibit these enzymes based on in vitro 
data. 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
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. 
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 Section 7. 


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7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/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) 
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 must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies and/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. 
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 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance (eg, procedural or dosing as defined in Section 6.1.1) 
 
Disease progression according to the Uniform Response Criteria for MDS/MPN, 
and/or per institutional guidelines as applicable 
 
Requirement for alternative therapy 
 
Pregnancy 
7.2 
Subject Discontinuation/Withdrawal 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 


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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) 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: 
 
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 should 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).  


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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.  After the subject has 
signed the informed consent form, the site will register the subject in the Interactive 
Response Technology (IRT) and screen the subject in order to assess eligibility for 
participation.  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 
re-screening 2 times. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 14 day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  On-study visits during 
cycles 1 and 2 should be done on the days specified, if possible.  All subsequent visits 
beginning on cycle 3 may be completed within  1 day unless otherwise specified.  The 
date of the first dose of AMG 176 is defined as day 1.  All subsequent doses and study 
visits will be scheduled based on the day 1 date.  Administration of AMG 176 is to be 
administered after all protocol-specific pre-dose assessments have been performed 
during each visit that it is required. 


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8.1.3 
End of Treatment 
The End of Treatment (EOT) visit will occur upon the decision to end treatment with 
protocol-required therapies.  For subjects who choose to discontinue investigational 
product treatment, the EOT visit should occur as soon as possible after the last dose of 
protocol-required therapies is administered ( 1 day).  Serious adverse events 
considered related to the investigational product, by the investigator, or Amgen will be 
followed until resolved or considered stable (see Section 11.4). 
8.1.4 
Safety Follow-up 
A safety follow-up visit must be performed 30 (3 days) after the last dose of 
protocol-required therapies.  All efforts should be made to conduct this visit.  If it is not 
possible to conduct the safety follow-up visit, documentation of efforts to complete the 
visit should be provided in the source documents and noted as not done in the eCRFs. 
8.1.5 
Long-term Follow-up 
Long-term follow-up (LTFU) assessments will occur every 3 months after EOT for 1 year 
and will include survival, subsequent anti-cancer therapy, and any cardiac associated 
serious adverse events or clinical diagnostic studies performed.  Additionally, the first 
LTFU visit will require an ECHO (see Section 8.4.5.1). 
8.1.6 
End of Study 
A subject is considered to have completed the study if he/she has completed all phases 
of the study including the last LTFU visit shown in the Schedule of Activities or dies, 
whichever occurs first. 
8.2 
General Assessments 
8.2.1 
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. 
8.2.2 
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 biomarkers variability 
and pharmacokinetics of the protocol-required therapies. 


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8.2.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started at least 2 years prior to enrollment through the first dose of AMG 176.  Medical 
history will include information on the subject’s concurrent medical health conditions, 
relevant past medical conditions, and surgical history.  Record all findings on the medical 
history eCRF. 
Relevant medical history, including antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, bleeding and infection (resolved and ongoing) will 
be collected.  The current toxicity grade will be collected for each condition that has not 
resolved. 
8.2.4 
Physical Examination  
Physical examination will be performed as per SOC.  Physical examination findings 
should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.5 
Physical Measurements 
Height (cm) will be measured without shoes at screening.  Weight (kg) without shoes will 
be obtained at screening and time points specified in the Schedule of Assessments (see 
Section 1.3).   
8.2.6 
Eastern Cooperative Oncology Group Performance Status  
Eastern Cooperative Oncology Group Performance Status (ECOG PS) (Section 11.11) 
assessments will occur at time points specified in the Schedule of Activities (see 
Section 1.3). 
8.3 
Efficacy Assessments 
8.3.1 
Bone Marrow 
Bone marrow aspirate will be performed for the following: 
1. Hematocytology and cytochemistry to establish WHO subtype of MDS – local site 
laboratory according to local procedures using slides of bone marrow and peripheral 
blood. 
2. Immunological phenotyping to verify myeloid leukemia.  Additional immunological 
phenotyping and/or Minimum Residual Disease (MRD) will be performed/done at the 
investigator’s discretion, for relapsed and/or for response confirmation. 
3. Cytogenetics (gene expressions, gene mutations, cell culture and banding analysis) - 
a local laboratory may perform cytogenetics to determine eligibility at screening.  
Previous bone marrow aspirate or biopsy performed within 6 months of day 1 may be 
used to determine eligibility for subjects.  A bone marrow biopsy or aspirate will still 
be required during screening for all subjects. 
4. Additional cytogenetics will be performed/done at the investigator’s discretion, for 
relapsed and/or for response confirmation. 


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Core bone marrow biopsies will also be collected for disease assessment unless these 
samples cannot be collected; for these institutions, the bone marrow aspirate is 
sufficient.  In case of dry tap or if there is concern of hemodilution, a bone marrow biopsy 
will be collected instead of aspirate sample. 
The degree of bone marrow infiltration defined by the percentage of leukemic blasts in 
bone marrow will be evaluated by the local laboratory as per cytological assessment. 
Additional bone marrow sampling may occur at other time points at the investigator’s 
discretion as clinically indicated.  Unscheduled bone marrow aspirate results will be 
captured in the respective eCRFs. 
8.3.2 
Peripheral Blood 
Blood samples will be collected for peripheral blood counts as per the Schedule of 
Activities (Section 1.3).  Peripheral blood counts will include ANC, platelets, blasts, and 
hemoglobin (Hgb). 
8.3.3 
Disease Response 
Disease response assessments will be based upon review of bone marrow aspirates, 
and peripheral blood count.  Refer to the Uniform Response Criteria for MDS/MPN in 
Section 11.12 for additional details.  Complete remission/CRi must be established from a 
bone marrow sample supplemented with neutrophil, platelet, and peripheral blast counts. 
In case of transplantation, a CR or CRi must be confirmed within 4 weeks prior to 
transplantation. 
8.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3). 
8.4.1 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, pulse oximetry and temperature.  Subject must be in a supine 
position in a rested and calm state for at least 5 minutes before blood pressure and 
pulse oximetry 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.  Oxygen saturation will be measured using a 
standard pulse oximeter.  The temperature location selected for a subject should be the 


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same that is used throughout the study and documented on the vital signs CRF.  Record 
all measurements on the vital signs CRF. 
Abnormal measurements may be repeated at the discretion of the investigator and must 
be reported on the corresponding eCRF page.  When vital signs and blood sample 
collection occur at the same time, vital signs should be performed before blood samples 
are drawn, where permitted. 
8.4.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. 
Electrocardiograms should be performed in a standardized method, in triplicate, and run 
consecutively.  Each triplicate, which consists of three 10-second tracings, should be 
completed within a total of five 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 interval (QRS), QT interval (QT), QTc, RR, and PR 
intervals (PR).  
 
Baseline ECGs should be collected at 3 timepoints  5 minutes apart, with each 
baseline ECG performed in triplicate, and with at least 5 minutes between the 
end of each triplicate and the start of the next (total 9 ECGs)  
 
Cycles 1 through 4:  Triplicate ECGs run consecutively (ie, all 3 ECGs should be 
completed within a total of 5 minutes from the start of the first to the completion 
of the third) 
 
 Cycle 5:  single ECG  
The PI or designated site physician will review all ECGs.  ECGs will be transferred 
electronically to an ECG central vendor for storage or for analysis per Amgen 
instructions.  Once signed, the original ECG tracing will be retained with the subject's 
source documents.  At the request of the sponsor, a copy of the original ECG will be 
made available to Amgen.  Standard ECG machines should be used for all study-related 
ECG requirements.  These will be provided to the site as ECG data will need to be 
transmitted to the selected vendor.  
8.4.3 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) 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.  


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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 
(Section 1.3).  
8.4.3.1 
Hepatitis Serology 
All subjects will be tested at screening for hepatitis B and hepatitis C infection as follows:  
 
HBsAg, total HBsAb, and total HBcAb. 
- If results are HBsAb and/or HBcAb positive and HBsAg positive, no additional 
testing is necessary. 
- If results are HBsAb and/or HBcAb positive and HBsAg negative, additional 
testing for hepatitis B virus DNA by PCR is necessary. 
 
HCVAb. 
- If results are HCVAb positive, additional testing for hepatitis C virus RNA by PCR 
is necessary. 
8.4.3.2 
Tumor Lysis Syndrome Laboratory Monitoring 
Tumor lysis syndrome prophylaxis must be initiated prior to all lead-in dosing of 
AMG 176 and prior to all subsequent dose escalations (ie, first dose on the targeted 
cohort dose level).  Subjects must be hospitalized and monitored the night before 
AMG 176 administration and will continue until at least 24 hours post-dose.  Chemistry 
labs must include serum potassium, phosphorous, calcium, uric acid, and creatinine, and 
be performed pre-dose (within 4 hours before AMG 176 administration), 2, 4, 8, 12, and 
24 hours after the start of AMG 176 infusion. 
8.4.3.3 
Cardiac Monitoring Tests 
Local and central cardiac monitoring test are required.  Local assessment should include 
troponin (I or T), CK-MB, and NT-pro-BNP.  Serum samples are collected for centralized 
assessment. 
8.4.4 
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. 


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8.4.5 
Other Safety 
8.4.5.1 
Echocardiogram (ECHO)/Multigated Acquisition (MUGA) 
Scan/Cardiac MRI 
Transthoracic echocardiography or MUGA that at least includes measures of both right 
and left atrial and ventricular structure and function will be performed at screening, with 
any clinically significant cardiac event, symptoms of cardiac dysfunction or clinically 
significant elevation of either cardiac troponin, CK-MB, or NT-pro-BNP during treatment, 
EOT, and the first long-term follow-up visit.  If available, cardiac Magnetic Resonance 
Imaging (MRI) at baseline, EOT, and the first long-term follow-up visit is recommended.  
If cardiac imaging was performed within 30 days of C1D1, one does not need to be 
performed again at screening as long as the same modality is used throughout the 
study. 
8.4.6 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events 
and serious adverse events, and the procedures for completing and transmitting 
serious adverse events are provided in Section 11.4. 
8.4.6.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.4.6.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) 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 the first dose of investigational 
product through the LTFU/EOS visit are reported using the Events CRF. 
8.4.6.1.2 
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 the safety follow-up visit or 30 days after last day of dosing 
interval of investigational product(s)/protocol-required therapies, whichever is 
later, are reported using the Events CRF. 
All serious adverse events will be collected, recorded, and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness 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. 


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Since the criteria of the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity grading 
scale criteria (eg, laboratory abnormality reported as grade 4 without manifestation of 
life-threatening status), it will be left to the investigator’s judgment to also report these 
abnormalities as serious adverse events.  For any adverse event that applies to this 
situation, comprehensive documentation of the event’s severity must be recorded in the 
subject medical records. 
8.4.6.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be related to 
investigational product after the protocol-required reporting period (as defined in 
Section 8.4.6.1.2) is complete, then these serious adverse events will be reported to 
Amgen within 24 hours following the investigator’s awareness of the event on the Events 
CRF. 
After End of Study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  However, if 
the investigator becomes aware of serious adverse events suspected to be related to 
investigational product, then these serious adverse events will be reported to Amgen 
within 24 hours following the investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  If further safety related data is needed to fulfill 
any regulatory reporting requirements for a reportable event, then additional information 
may need to be collected from the subject’s records after the subject ends the study. 
8.4.6.2 
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. 
8.4.6.3 
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. 


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All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
8.4.6.4 
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. 
8.4.6.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.6.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects will be collected after the 
start of study treatment and until 3 months after the last dose of investigational product. 
Details of all pregnancies and/or lactation in female partners of male subjects will 
be collected after the start of study treatment and until 4 months after the last 
dose of investigational product. 


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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. 
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. 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential. 
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, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
A pregnancy test should be performed should be performed as indicated in the Schedule 
of Activities (Section 1.3). 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.5 
Pharmacokinetic Assessments 
All subjects enrolled will have pharmacokinetic samples assessed. 
Blood samples of approximately 328 mL or 22.2 tablespoon will be collected for 
measurement of blood concentrations of AMG 176 as specified in the Schedule of 
Activities (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.  Sample collection, processing, storage, and shipping 
instructions are provided in a separate laboratory manual. 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The clinical hypothesis is that at least 1 dose level of AMG 176 administered in 
combination with azacitidine will achieve acceptable safety and tolerability in subjects 
with HR-MDS.  No formal statistical hypothesis will be tested. 
9.2 
Sample Size Determination 
It is anticipated that up to 120 subjects will be enrolled in the study, with up to 
60 subjects in Part 1 and 60 subjects in Part 2. 
For each part, the sample size is based on practical considerations and it is consistent 
with conventional oncology studies with the objective to identify the OBD/MSBED. 
9.3 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
Full Analysis Set (FAS) 
All subjects who are enrolled and receive at least one dose 
of the investigational product (AMG 176). 
DLT Evaluable Set 
Subjects are considered DLT-evaluable if they experience 
a DLT during the DLT evaluation period, or if they complete 
the DLT evaluation period and receive at least 75 of the 
planned doses of AMG 176 and 100 of the planned dose 
of azacitidine. 
 
9.3.1 
Covariates 
There are no planned covariates in this study. 
9.3.2 
Subgroups 
There are no planned subgroups in this study. 


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9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  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. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
No formal interim efficacy analysis is planned.  Safety data will be reviewed on an 
ongoing basis.  The DLRM will review all available data by cohort before making dose 
escalation recommendations.  Details of dose escalation and stopping rules are 
described in Section 4.1.1. 
9.4.1.2 
Primary Analysis 
A primary analysis will occur when the last subject has had opportunity to complete 
6 cycles of the treatment of AMG176. 
9.4.1.3 
Final Analysis 
A final analysis is planned after all subjects have had the opportunity to complete the last 
study visit. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, and 
biomarker data by dose, dose schedule, and time as appropriate.  Descriptive statistics 
on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may also be presented.  Unless otherwise specified, statistical 
analyses will be done using the FAS, which includes subjects that are enrolled and 
received at least 1 dose of AMG 176.  Data will be analyzed by dose level for each part. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The ORR with corresponding 2-sided exact 95 CI will be calculated. 
Secondary 
Kaplan-Meier (KM) curve will be presented for OS, TTNT, EFS, DOR, 
time to response and time to transformation to AML. 
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock. 


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9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The incidence of DLT will be summarized for the DLT Evaluable 
Subjects.  The primary analysis for each part will only include DLTs 
that occur within the protocol defined DLT evaluation period. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to discontinuation from investigational product or other 
protocol-required therapies, and  grade 3 TEAEs will also be provided. 
9.4.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics over time.  
Shifts in grades of safety laboratory values between baseline and the worst on-study 
value will be tabulated by cohorts. 
9.4.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics over time by cohort. 
9.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics over time by 
cohort. 
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 QTcF 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-AMG176 antibodies at any 
time will be tabulated. 
A listing of antibody results for all timepoints tested for each subject will be reported. 


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9.4.2.3.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to AMG 176.  The 
number of cycles initiated, the treatment duration, cumulative dose, and average dose of 
AMG 176 will be summarized. 
9.4.2.3.9 
Exposure to Non-investigational Product 
Descriptive statistics will be produced to describe the exposure to azacitidine.  The 
number of cycles initiated, the duration of therapy and cumulative dose will be 
summarized. 
9.4.2.3.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications of interest 
from study day 1 through safety follow-up will be summarized by preferred term as 
coded by the World Health Organization Drug (WHODRUG) dictionary. 
9.4.2.4 
Other Analyses 
9.4.2.4.1 
Pharmacokinetic Analyses 
The analysis of pharmacokinetic endpoints will include data from all subjects who have 
received at least 1 dose of the investigational product and have at least 
1 pharmacokinetic sample collected. 
Pharmacokinetic parameters for AMG 176 and azacitidine including, but not limited to, 
maximum observed concentration (Cmax), minimum observed concentration (Cmin), Area 
Under the plasma Concentration time curve (AUC), CL, and, if feasible, t1/2 will be 
estimated using standard noncompartmental PK methods and summarized by dose 
groups using means, standard deviations, medians, minimums, and maximums for 
intensive and peak/trough determinations.  Concentrations at each time point along with 
PK parameter values may be reviewed for each subject.  Individual concentration-time 
profiles will be plotted by dose groups.  Summary statistics will be computed for each 
sampling time and parameter as appropriate.  Analysis of the relationship between 
AMG 176 dose and exposure parameters (AUC and Cmax) will be conducted and plots of 
the relationship between AMG 176 dose and exposure parameters along with dose 
proportionality assessment will be provided, if feasible.  Additional analyses to explore 
relationship between exposure and safety and exposure and efficacy may also be 
performed. 


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10. 
References 
Albitar M, Manshouri T, Shen Y, et al. Myelodysplastic syndrome is not merely 
"preleukemia". Blood. 2002;100(3):791-798. 
AMG 176 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis 
discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 
2017;16(4):273-284. 
Bejar R, Steensma DP.  Recent developments in myelodysplastic syndromes.  Blood.  
2014;124:2793-2803.  
Beroukhim R, Mermel CH, Porter D, et al.  "The landscape of somatic copy-number 
alteration across human cancers."  Nature.  2010;463(7283):899-905. 
Bose P, Grant S.  MCL1 as a therapeutic target in acute myelogenous leukemia (AML).  
Leukemia Research Reports.  2013;2(1):12-14. 
Caenepeel S, Brown SP, Belmontes B, et al.  AMG 176, a selective MCL1 inhibitor, is 
effective in Hematological Cancer models alone and in combination with established 
therapies. Cancer Discovery. 2018;8:1582–1597.  
Cairo MS, Bishop M.  Tumour lysis syndrome:  new therapeutic strategies and 
classification.  Br J Haematol.  2004;127(1):3-11. 
Cheson BD, Greenberg PL, Bennett JM, et al.  Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in 
myelodysplasia.  Blood.  2006;108:419-425.  
Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric and adult 
tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-2778. 
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 
protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 
2014;15(1):49-63. 
Doll DC, List AF. Myelodysplastic syndromes. West J Med. 1989;151(2):161-167. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with 
that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol. 
2009;10(3):223-232. 
Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 
2017;7(5):1016-1036. 
Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the 
development and sustained growth of acute myeloid leukemia. Genes Dev. 
2012;26(2):120-125. 
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088. 
Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring 
system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. 
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. 


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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  
International Conference on Harmonisation; S9 Guidance on Nonclinical Evaluation for 
Anticancer Pharmaceuticals.  Fed Regist.  2010;Mar 8;75(44):10487-10488. 
Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic 
syndrome after failure of decitabine therapy. Cancer. 2010;116(16):3830-3834. 
Ji Y, Liu P, Li Yisheng, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials. 2010; 7:653-663.  
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myelodysplastic syndromes. Semin Oncol. 2011; 38(5):682-692. 
Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer. 
2006;106(8):1794-1803. 
Kasper S, Breitenbuecher F, Heidel F, et al.  Targeting MCL1 sensitizes 
FLT3-ITD-positive leukemias to cytotoxic therapies.  Blood Cancer J.  2012;2:e60. 
Kaufmann SH, Karp JE, Svingen PA, et al.  Elevated Expression of the Apoptotic 
Regulator MCL1 at the Time of Leukemic Relapse.  Blood.  1998;91(3):991-1000.  
Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and 
effective in diverse cancer models. Nature. 2016;538(7626):477-482. 
Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in 
programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl 
Acad Sci U S A. 1993;90(8):3516-3520.  
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2005;3(11):832-834. 
Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival 
in the United States. Cancer. 2007;109(8):1536-1542. 
Merino D, Whittle JR, Vaillant F, et al. Synergistic action of the MCL-1 inhibitor S63845 
with current therapies in preclinical models of triple-negative and HER2-amplified breast 
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Peperzak V, Vikström I, Walker J, et al.  MCL1 is essential for the survival of plasma 
cells.  Nat Immunol.  2013;14(3):290-297. 
Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome 
after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322-3327. 
Roberts AW, Davids MS, Pagel JM, et al.  Targeting BCL2 with venetoclax in relapsed 
chronic lymphocytic leukemia.  N Engl J Med. 2016;374:311-322.  DOI:  
10.1056/NEJMoa1513257. 
Steensma DP. Can hypomethylating agents provide a platform for curative therapy in 
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clinical trials with multiple outcomes. Stat Med. 1995;14(4):357-79.  
Thomas RL, Roberts DJ, Kubli DA, et al. Loss of MCL-1 leads to impaired autophagy 
and rapid development of heart failure. Genes Dev. 2013;27(12):1365-1377. 
van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective 
Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. 
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Wang X, Bathina M, Lynch J, et al. Deletion of MCL-1 causes lethal cardiac failure and 
mitochondrial dysfunction. Genes Dev. 2013;27(12):1351-1364. 
Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is 
regulated by MCL1 and FBW7. Nature. 2011;471(7336):110-114. 
Xiang Z, Luo H, Payton J E, et al.  Mcl1 haploinsufficiency protects mice from 
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Youle, RJ, Strasser A.  The BCL2 protein family:  opposing activities that mediate cell 
death.  Nat Rev Mol Cell Biol.  2008;9(1):47-59. 
  
 


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11. 
Appendices 
 


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11.1 
Appendix 1.  List of Abbreviations 
 
Abbreviation 
Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ASTX727 
cedazuridine 
AUC 
area under the curve 
BAK 
pro-apoptotic effector proteins BCL2 homologous 
antagonist/killer 
BAX 
pro-apoptotic effector proteins BCL2-associated X 
BCL2 
B-cell lymphoma/leukemia 2 
BCRP 
breast cancer resistance protein 
BH3 
pro-apoptotic BCL2 homology 3 
BIM 
BCL2-interacting mediator of cell death 
BUN 
blood urea nitrogen 
CC-486 
azacitidine 
CFR 
U.S. Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK-MB 
creatine kinase-muscle/brain 
CL 
clearance 
Cmax 
maximum concentration 
CMML/CMMoL 
chronic myelomonocytic leukemia 
COVID-19 
Coronavirus Disease 2019 
CR 
complete remission 
CrCl 
creatinine clearance 
CRF 
case report form 
CRi 
incomplete count recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 


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DOR 
duration of response 
DR 
durable response 
ECG 
electrocardiogram 
Echo 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
EOS 
end of study 
EOT 
end of treatment 
FAB 
French – American – British subtypes 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FIH 
first in human 
 
 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
good laboratory practices 
GSO 
Global Safety Officer 
HALs 
Houston Area Locations 
HbcAb 
hepatitis B core antibody 
HbsAb 
hepatitis B surface antibody 
HbsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
hERG 
human ether-à-go-go-related gene 
Hgb 
hemoglobin 
HI 
hematologic improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HNSTD 
highest-non-severely-toxic dose 
HR 
higher-risk 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPSS 
International Prognostic Scoring System 
IPSS-R 
Revised IPSS 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISS 
International Staging System 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
intravenous 
IWG-MDS 
International Working Group for the Prognosis of MDS 
Ki 
mean inhibitory constant 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MAD 
maximum administered dose 
MCL1 
Myeloid Leukemia Cell 1 
mCR 
marrow/morphologic complete remission 
MDS 
myelodysplastic syndrome 
MDSCs 
Myeloid Derived Suppressor Cells 
MM 
Multiple Myeloma 
MOA 
mechanism of action 
MOLM 
acute monocytic leukemia (AML-M5a) cell lines 
MOMP 
mitochondrial outer membrane permeabilization 
MPN 
myeloproliferative neoplasm 
MPN-SAF 
MPN Symptoms Assessment Form 
MRD 
minimum residual disease 
MRI 
magnetic resonance imaging 
MSBED 
minimum safe and biologically effective dose 
mTPI 
modified Toxicity Probability Interval 
MUGA scan 
Multigated Acquisition scan 
NCI 
National Cancer Institute 
NCT 
National Clinical Trials 
 
 
NK cells 
natural killer cells 


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NT-pro BNP 
N-terminal prohormone of brain natriuretic peptide 
NYHA 
New York Heart Association 
OATP 
organic anion polypeptide transporters 
OBD 
optimal biological dose 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PFS 
progression free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PLT 
platelets 
PR 
partial remission 
PUMA 
p53-upregulated modulator of apoptosis 
Q2W 
every 2 weeks 
QD2 
once daily for 2 consecutive days 
QRS 
QRS interval is the interval between the Q wave and the S wave 
in the heart's electrical cycle as measured by ECG; represents 
the time it takes for the depolarization of the ventricles 
QTc 
corrected QT interval  
QTcF 
QT interval with Fridericia's correction 
QW 
once weekly 
R/R 
relapsed or refractory 
RA 
refractory anemia 
RAEB 
refractory anemia with excess blasts 
RAEB-T 
refractory anemia with excess blasts in transformation 
RARS 
refractory anemia with ringed sideroblasts 
RBC 
red blood cell 
SAP 
statistical analysis plan 
SC 
subcutaneous 
siRNA 
small interfering RNA 
SOC 
standard of care 
STD 
severely-toxic dose 
t1/2 
half-life 
TBL 
total bilirubin 
TI 
transfusion independence 
TLS 
tumor lysis syndrome 
TSS 
Total Symptom Score 


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TTNT 
time to next treatment 
ULN 
upper limit of normal 
UPM 
Unit Probability Mass 
URL 
Upper Reference Limit 
USPI 
United States Prescribing Information 
Ven 
venetoclax 
WBC 
white blood cells 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug 
 
 


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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.  Additional analyte test results may be reported by the local or central 
laboratory, in accordance with standard laboratory procedures (eg, components of a 
hematology panel).  All locally obtained test results are to be recorded in the eCRF.  
Pharmacokinetic, 
 
.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Blood samples will be obtained by venipuncture before study drug administration.  All 
laboratory tests must be reviewed by the investigator or qualified designee.  Additional 
safety laboratory assessments may be performed if clinically indicated at the discretion 
of the investigator.  The following tests listed in Table 11-1 will be conducted on samples 
collected by standard laboratory procedures. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 11-1.  Analyte Listing 
Central Laboratory 
PK  
 
Bone marrow aspirate 
Bone marrow biopsy 
Cardiac enzymes including troponin-I, CK-MB, and NT-pro-BNP 
Local Laboratory 
Chemistry 
Hematology 
Urinalysis 
Albumin 
ALP 
ALT 
AST 
Bicarbonate (optional) 
NT-pro-BNP (or BNP if 
NT-pro-BNP not available)  
BUN or Urea 
Calcium 
Chloride 
CK-MB 
Creatinine 
Direct bilirubin 
GGT 
Glucose 
LDH 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Troponin (I or T) 
Uric acid 
Haptoglobin 
ANCa 
Hematocrit 
Hemoglobina 
MCH 
MCHC 
MCV 
Plateletsa 
RBCs 
WBCs 
Differential: 
▪ 
Neutrophils 
▪ 
Lymphocytes 
▪ 
Monocytes  
▪ 
Eosinophils 
▪ 
Basophils 
Blastsa 
Specific gravity 
pH 
Blood 
Protein 
Ketones 
Bilirubin 
Glucose 
Leucocytes esterase (WBC) 
Microscopic exam (only needed for 
positive dipstick and should include the 
following):  
▪ Epithelial 
▪ Bacteria 
▪ Casts 
▪ Crystal 
▪ RBCs 
WBCs 
Coagulation 
Other Labs 
PT or INR 
aPTT 
Pregnancy 
HBsAg 
HBsAb 
HBcAb 
Hepatitis C antibody 
HCV PCR (if applicable) 
HBV PCR (if applicable) 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; ANC  absolute neutrophil count; 
aPTT  activated partial thromboplastin time; AST  aspartate aminotransferase; BNP  B type natriuretic 
protein; BUN  blood urea nitrogen; CK-MB  creatinine kinase muscle/brain; DILI  drug induced liver 
injury; GGT  gamma-glutamyl transferase; HBcAb  hepatitis B core antibody; HBsAb  hepatitis B 
surface antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; 
INR  international normalized ratio; LDH  lactate dehydrogenase; MCH  mean cell hemoglobin; 
MCHC  mean cell hemoglobin concentration; MCV  mean cell volume; NT-pro-BNP  N-terminal 
prohormone of brain natriuretic peptide; PCR  polymerase chain reaction; PK  pharmacokinetics; 
PT  prothrombin time; PTT  partial thromboplastin time; RBC  red blood cell; WBC  white blood cell.  
a Peripheral blood counts for MDS disease assessments will include ANC, platelets, hemoglobin, and blasts. 
If the subject is being followed for possible DILI, the following analytes may be tested at 
the local laboratory depending on the clinical situation (see Section 11.7): 


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Table 11-2.  DILI Potential Analyte Listing 
Chemistry 
Total bilirubin, direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT), 
creatine kinase, ferritin, gamma-glutamyl transferase, haptoglobin 
Hematology 
Hemoglobin, Platelets, RBC Morphology, WBC Count, WBC Differential 
Coagulation 
PT, INR 
Immunology 
5 Prime Nucleotidase, Alpha-1 Antitrypsin, Antinuclear Antibodies, 
Anti-Smooth Muscle Antibody, Anti-Soluble Liver Ag/Liver-Pancreas Ag, 
Cytomegalovirus IgG Antibody, Cytomegalovirus IgM Antibody, Endomysial 
IgA Antibody, Epstein-Barr Virus EDA IgG Antibody, Epstein-Barr Virus NA 
IgG Antibody, Epstein-Barr Virus VCA IgG Antibody, Epstein-Barr Virus 
VCA IgM Antibody, Hepatitis A Virus IgG Antibody, Hepatitis A Virus IgM 
Antibody, Hepatitis B Core Antibodies, Hepatitis B Core IgM Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Virus DNA Genotyping, Hepatitis B 
Virus Surface Antibody, Hepatitis C Antibodies, Hepatitis C Virus RNA 
Genotyping, Hepatitis D Virus Antibody, Hepatitis E IgG Antibody, Hepatitis 
E IgM Antibody, Herpes Simplex Virus Type 1_2 IgG AB, Herpes Simplex 
Virus Type 1_2 IgM AB, Human Herpes Virus 6 DNA, Human Herpes Virus 
7 DNA, Human Herpes Virus 8 DNA, Immunoglobulin G, Liver Kidney AB 1,  
Parvovirus IgM/IgG Antibody, Serum Caeruloplasmin, Tissue 
Transglutaminase IgA Antibody, Toxoplasma IgM/IgG, Varicella Zoster 
Virus Antibody 
Toxicology 
Acetaminophen 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
DILI  drug induced liver injury; EDA  ectodysplasin; Ig  immunoglobulin; INR  international normalized 
ratio; LDH  lactate dehydrogenase; NA  nuclear antigen; PT  prothrombin time; PTT  partial 
thromboplastin time; RBC  red blood cell; SGOT  serum glutamic-oxaloacetic transaminase; 
SGPT  serum glutamic-pyruvic transaminase; WBC  white blood cell 
 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Team 
Dose Level Review Meetings (DLRM) 
A DLRM is conducted to review and interpret safety data for the purposes of making 
recommendations about dose-level escalation (either to the next planned dose or to an 
intermediate dose), dose level de-escalation, cohort continuation, or cohort expansion; 
making recommendations about non-dose escalation cohorts (eg, expanded, highest 
dose and/or final cohort); and evaluating safety signals for purposes of applying Dose 
Cohort Stopping Rules.  The required DLRT members are the Medical Monitor, Global 
Safety Officer (GSO), and Site Investigators.  The DLRT will include all Site 
Investigators.  The 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; additional members may be added as 
needed (eg, clinical pharmacologist). 
The 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 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 greater than or equal to 50 of the participating investigators or their qualified 
designee (ie, sub-investigator, research nurse or study coordinator possessing a hard 
copy document [eg, email] of the Investigator’s vote regarding the dose level review; this 
email is required to be submitted to Amgen).  The DLRM will be rescheduled if these 
requirements are not met. 
All available study data, including demographics, IP administration, medical history, 
concomitant medications, adverse events, ECG, vital signs, laboratory results, and PK 
information will be reviewed.  Data to be reviewed will be cleaned. 
DLRM voting will occur as follows:  there will be a total of 3 votes, 1 for the Medical 
Monitor, 1 for the GSO or delegate, and 1 for all of the Site Investigators or delegates 
combined.  Regardless of how many Site Investigators there are, all of the Site 


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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, or to an intermediate 
cohort, 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 
or to an intermediate cohort, then this should be reflected in the DLRM Memo.  Other 
recommendations, such as expanding a cohort or lowering a dose will be made by a 
majority vote. 
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 (CIOMS) 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, 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 informed consent form 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 protocol amendments and changes 
to the informed consent document that Amgen distributes to the site.  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. 
During the course of the study, if new information becomes available that alters the 
benefit-risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
The investigator will be responsible for the following: 


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 
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. 
 
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 informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form 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 or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study 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 (HIPAA) 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 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 


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of the subject’s participation in the clinical study 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 informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative 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 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9). 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 14 days from the previous informed consent form signature 
date. 
The Informed Consent Form (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 


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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. 
The 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 informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, 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.   
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. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 
Sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 


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has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
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 (ICJME) 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 


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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. 
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. 


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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. 
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. 
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 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 or certain 
demographic information, such as gender, race, and ethnicity). 
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. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list. 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the IRB/IEC 
and Amgen. 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
 
Non-investigational product documentation, as applicable. 
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 a separate 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 will be defined in the SAP. 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, 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 MDS 
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 


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Other medically important serious event 
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 mandatory adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product(s), other 
protocol-required therapies, and/or study-mandated activity and/or procedures; 
o Action taken; and 
o Outcome of event. 
 
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event 
electronic case report form (eCRF). 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the 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 


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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. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment 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, version 5.0 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product(s), protocol-required therapies, and/or study-mandated activity and/or 
procedure(s) 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. 
 
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. 


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 
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. 
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based Serious Adverse Event 
Contingency Report Form (also referred to as the electronic Serious Adverse 
Event (eSAE) Contingency Report Form) (see Figure 11-1) within 24 hours of the 
investigator’s awareness 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 system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product should be reported to Amgen if the investigator becomes 
aware of a serious adverse event.  The investigator should use the paper-based 
Serious Adverse Event Contingency Report Form to report the event. 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
(paper-based 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 females of childbearing potential 
are outlined in Section 5.2.  Contraceptive use and methods should be consistent with 
local regulations for subjects participating in clinical studies. 
Female subjects of childbearing potential should be advised of the pregnancy prevention 
requirements and the potential risk to the fetus if they become pregnant during treatment 
and for 3 months after the last dose of protocol-required therapies. 
Male subjects should be advised of the pregnancy prevention requirements and 
the potential risk to the fetus if they father a child during treatment and for 
4 months after the last dose of protocol-required therapies. 
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 documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR  
 
A woman age  55 years with no menses for at least 12 months and with a 
follicle-stimulating hormone (FSH) level within the definition of “postmenopausal 
range” for the laboratory involved.  In the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal). 


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 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable). 
 
Intrauterine device (IUD). 
 
Intrauterine hormonal-releasing system (IUS). 
 
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 trial 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 trial and the 
preferred and usual lifestyle of the subject) 
 
Use a condom during treatment and for an additional 4 months after the last dose of 
protocol-required therapies. 
The female partner should consider using a method of contraception for female subjects 
stated above (a female condom should not be used 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. 
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 3 months after the last 
dose of investigational product. 
 
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 the 
site’s awareness 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 consent 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 3 months after 
the last dose of the study drug.  This information will be forwarded to Amgen Global 


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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 elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, 
congenital anomalies) 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. 
 
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 
 
In the event a male subject fathers a child during treatment, and for an additional 
4 months 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). 
 
Males with pregnant partners or whose partners become pregnant during treatment 
and for an additional 4 months after discontinuing protocol-required therapies must 
practice sexual abstinence or use a condom through 4 months after discontinuing 
protocol-required therapies. 
 
The investigator will attempt to obtain a signed consent 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 consent 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. 


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Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 3 months after the last dose of 
investigational product. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 225. 
 
With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 3 months 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 and tumor 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) 
 
 
  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.   
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or tumor samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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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 biomarkers (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, rhabdomyolysis, hemolysis) 


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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.  
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 11-3.  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 AMG 176 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 Case Report Form (CRF) (eg, Events 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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o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
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 Appendix 11.4. 
Anticipated Serious Adverse Events for Study 20200392.02 
Preferred Term1 
Acute myeloid leukaemia 
Acute myeloid leukaemia recurrent 
Acute myeloid leukaemia refractory 
Neutropenia 
Anaemia 
Thrombocytopenia 
Leukocytosis 
Leukopenia 
White blood cell decreased 
Hemoglobin decreased 
Platelet count decreased 
White blood cell increased 
1 MedDRA Version 24.0 
 
 


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11.9 
Appendix 9.  Tumor Lysis Syndrome 
11.9.1 
Cairo-Bishop Tumor Lysis Syndrome Definition and Grading 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 classifies tumor 
lysis syndrome (TLS) in grade 3 (present), grade 4 (life threatening consequences; 
urgent intervention indicated) and grade 5 (death).  Presence of TLS is not clearly 
defined by CTCAE version 5.0.  Cairo and Bishop developed a system for defining and 
grading TLS based on Hande-Garrow classification of laboratory or clinical TLS 
(Coiffier et al, 2008).  For this trial the Cairo-Bishop classification will be used to define 
presence of TLS, ie, presence of laboratory TLS (see Table 1-1) and clinical TLS (see 
Table 11-5) including grading as detailed below. 
Based on the Cairo and Bishop system, laboratory TLS is present when levels of 2 or 
more serum values of uric acid, potassium, phosphorus, or calcium are more than or 
less than normal at presentation or if they change by 25 within 3 days before or 7 days 
after initiation of treatment (Section 1.3). 
Table 11-4.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
Element 
Value 
Change from Baseline 
Uric acid 
 476 µmol/L or 8 mg/dL 
25 increase 
Potassium 
 6.0 mmol/L or 6 mg/L 
25 increase 
Phosphorus 
 2.1 mmol/L for children or 
 1.45 mmol/L for adults 
25 increase 
Calcium 
 1.75 mmol/L 
25 decrease 
Note:  Two or more laboratory changes within 3 days before or 7 days after cytotoxic therapy will constitute 
laboratory tumor lysis syndrome. 
Clinical TLS requires the presence of laboratory TLS in addition to 1 or more of the 
following significant complications:  renal insufficiency, cardiac arrhythmias/sudden 
death, and seizures (Table 11-5).  The grade of clinical TLS is defined by the maximal 
grade of the clinical manifestations as detailed in Table 11-5. 


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Table 11-5.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Grade 
Creatininea, b 
Cardiac Arrhythmiaa 
Seizurea 
0 
 1.5 x ULN 
none 
none 
1 
1.5 x ULN 
intervention not indicated 
-- 
2 
 1.5 – 3.0 x ULN 
non urgent medical 
intervention indicated 
one brief, generalized seizure; 
seizure(s) well controlled by 
anticonvulsants or infrequent focal 
motor seizures not interfering with 
ADL 
3 
 3.0 – 6.0 x ULN 
symptomatic and 
incompletely controlled 
medically or controlled 
with device (eg, 
defibrillator)  
seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; with breakthrough 
generalized seizures despite medical 
intervention 
4 
 6.0 x ULN 
life-threatening (eg, 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
seizure of any kind which are 
prolonged, repetitive or difficult to 
control (eg, status epilepticus, 
intractable epilepsy) 
5 
Death 
death 
death 
Note:  Laboratory TLS and at least 1 clinical complication will constitute clinical TLS. 
ADL  activities of daily living; CHF  congestive heart failure; TLS  tumor lysis syndrome, ULN  upper 
limit of normal 
a not directly or probably attributable to therapeutic agent 
b if no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:   1 to  12 years of 
age, both male and female, 61.6 µmol/L;  12 to  16 years, both male and female, 88 µmol/L;  16 years, 
female 105.6 µmol/L, male 114.4 µmol/L. 
11.9.2 
Tumor Lysis Syndrome Laboratory Monitoring 
Tumor lysis syndrome prophylaxis must be initiated prior to all lead-in dosing of 
AMG 176 and prior to all subsequent dose escalations (ie, first dose on the targeted 
cohort dose level).  Subjects must be hospitalized and monitored the night before 
AMG 176 administration and will continue until at least 24 hours post-dose.  Chemistry 
labs must include serum potassium, phosphorous, calcium, uric acid, and creatinine, and 
be performed for the following timepoints:  
 
AMG 176:  pre-dose (within 4 hours before AMG 176 administration), 2, 4, 8, 12, and 
24 hours after the start of AMG 176 infusion.  Note:  For AMG 176 180 mg/m2 with 
lead-in dose:  Subjects will also be hospitalized in week 2. 
 
Azacitidine:  pre-dose, 6 to 8 hours after each new dose during ramp-up and 
24 hours after reaching final dose  
Since subjects on this trial may be at risk for developing TLS, measures will be 
implemented to help reduce and manage this risk, including staggered initiation of the 
two BH3 mimetics, ramp up dosing, and hospital admission during cycle 1 during the first 
doses of AMG 176 and azacitidine. 


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To further mitigate any possible risk of TLS, several measures will be implemented: 
 
Electrolyte levels, including serum potassium, calcium, phosphorous, and uric acid 
will be checked prior to treatment to make sure they are within the normal range.  
Hyperkalemia (Potassium  5.0) should be corrected prior to starting therapy.  
Phosphate binders should be started (unless contraindicated) in subjects with 
elevated phosphorous.   
 
Subjects with medium (white blood cell [WBC] 10 to 20) risk for tumor lysis should be 
initiated on allopurinol (or other uric acid lowering treatment) prior to therapy.  
Subjects with n  20 should have cytoreduction (with hydrea) or delay therapy to 
make sure the WBC to less than 20 prior to starting therapy in protocol.  If the uric 
acid is elevated above 9, the patient should be given a dose of rasburicase per 
institutional protocol. 
 
Oral and when needed, IV hydration, will also be implemented per institutional 
standards to help mitigate the risk for TLS. 
11.9.3 
Prophylaxis and Management of Tumor Lysis Prophylaxis 
The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be conducted per institutional protocols 
(Coiffier et al, 2008; Cairo et al, 2004). 
Tumor lysis syndrome prophylaxis includes: 
 
Allopurinol or equivalent should be used to reduce uric acid level per SOC.  This 
should be initiated at least 72 hours prior to dosing.  Treatment may need to be 
continued for up to 5 weeks.  Other agents to reduce uric acid level, such as 
rasburicase, may be used per principal investigator discretion and the institutional 
guidelines.  Dosing per institutional guidelines. 
 
All patients should have WBC count less than 25 x 109/L prior to initiation of 
azacitidine.  Cytoreduction prior to treatment may be required. 
 
Hospitalization and monitoring:  beginning the night before AMG 176 administration 
until at least 24 hours post-first AMG 176 dose. 
 
Intravenous hydration must be started the night before AMG 176 administration and 
to be continued until at least 24 hours post–dose during hospitalization as clinically 
tolerated (see below for more details about the level of IV hydration required) 
 
Monitoring of electrolyte values is required prior to dosing anytime a dose is higher 
than one previously given to the subject.  This will include at the following times for: 
AMG 176:   
- Prior to the week 1, day 1 dose 
- Prior to each dose during the lead-in period 
- Prior to the initial dosing at the target dose level 
Azacitidine: 
- Pre-dose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after 
reaching final dose 
 
Prior to administering these doses, all electrolyte values (including lactate 
dehydrogenase [LDH], potassium, uric acid, phosphorus, calcium, and creatinine) 
must be reviewed and within normal range (samples must be drawn within 24 hours 


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prior to dosing of AMG 176).  The investigator's decision to proceed with AMG 176 
treatment initiation will be based on these laboratory values. 
- Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria for TLS are met, no additional AMG 176 doses should be 
administered until resolution.  A rapidly rising serum potassium is a medical 
emergency. 
- Prophylactic dose reductions for potassium, phosphorus and/or uric acid values 
at the high end of normal range should be considered. 
- If the potassium, uric acid, inorganic phosphate and/or creatinine values are 
higher than the normal range or the calcium is lower or higher than the normal 
range, this (these) value(s) can be approved following a discussion between the 
Amgen medical monitor and investigator. 
- On the AMG 176 dosing days chemistry labs must be performed pre-dose (within 
4 hours before AMG 176 administration), 2, 4, 8, 12, and 24 hours after the start 
of AMG 176 infusion.  Pre-dose labs will be used as baseline to assess potential 
electrolytes abnormalities occurring post AMG 176 administration.  These labs 
must be reviewed in real time by the investigator.  
- All 24-hour laboratory assessments may be taken ± 2 hours, if necessary. 
- Perform hematology labs at pre-dose (within 4 hours before AMG 176 
administration) and 24 hours after the start of AMG 176 infusion. 
- Monitor for signs and symptoms of TLS (eg, fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion, and seizures).  If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour. 
 
Nephrology (or acute dialysis service) consultation should be considered on 
admission (based on investigator discretion) for hospitalized subjects per institutional 
guidelines to ensure emergency dialysis is available and the appropriate staff is 
aware and prepared. 
All subjects will receive TLS prophylaxis as described above.  Allopurinol or equivalent 
should be used to reduce uric acid level.  This should be initiated at least 72 hours prior 
to dosing.  Treatment may need to be continued for up to 5 weeks.  Other agents to 
reduce uric acid level, such as rasburicase, may be used per investigator discretion and 
institutional guidelines. 
Within the first 24 hours after either the first dose or dose escalation, if any laboratory 
criteria below are met, no additional AMG 176 doses or azacitidine should be 
administered until resolution.  A rapidly rising serum potassium is a medical emergency.  
Nephrology (or other acute dialysis service) should be contacted/consulted (per 
institutional guidelines to ensure emergency dialysis is available) on admission for any 
subject hospitalized prophylactically or in response to laboratory changes.  
Intravenous (IV) fluids (eg, D5 1/2 normal saline) should be initiated at a rate of at least 
1 mL/kg/hr rounded to the nearest 10 mL (target 150 to 200 mL/hr; not  50 mL/hr).  


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Modification of fluid rate should also be considered for individuals with specific medical 
needs.  
Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, vomiting, 
diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental 
status changes, confusion, and seizures).  If any clinical features are observed, recheck 
potassium, phosphorus, uric acid, calcium, and creatinine within 1 hour and perform 
ECG. 
Vital signs should be taken at time of all blood draws or any intervention.  
For subjects with risk factors for TLS (eg, circulating blasts, high burden of leukemia 
involvement in bone marrow, elevated pre-treatment LDH levels, or reduced renal 
function), consider additional measures, including increased laboratory monitoring and 
reducing azacitidine starting dose. 
The management recommendations below focus on the minimum initial responses 
required (Roberts et al, 2016).  If a diagnosis of TLS is established, ongoing intensive 
monitoring and multi-disciplinary management will be per institutional protocols. 


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Table 11-6.  Tumor Lysis Syndrome Management Recommendations 
Abnormality 
Management Recommendations 
Hyperkalemia (including rapidly rising potassium) 
 Potassium  0.5 mmol/L 
increase from prior value 
(even if potassium within 
normal limits [WNL]) 
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.  If further  0.2 mmol/L 
increase in potassium, but still  upper limit of normal 
(ULN), manage as per potassium  ULN.  Otherwise 
recheck in 1 hour. 
 Resume per protocol testing if change in potassium is 
 0.2 mmol/L, and potassium  ULN, and no other 
evidence of tumor lysis. 
 At discretion of Investigator, may recheck prior to 
hospitalization.  If stable or decreased, and still WNL, 
hospitalization is at discretion of the Investigator.  
Potassium phosphorus, uric acid, calcium and creatinine 
must be rechecked within 24 hours.  
 Potassium  upper limit of 
normal 
 Perform STAT ECG and commence telemetry. 
 Nephrology notification with consideration of initiating 
dialysis. 
 Administer Kayexalate 60 g (or Resonium A 60 g).  
 Administer furosemide 20 mg IV x 1 
 Administer calcium gluconate 100 - 200 mg/kg IV slowly if 
there is ECG/telemetry evidence of life-threatening 
arrhythmias. 
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT. 
If potassium  ULN 1 hour later, repeat potassium 
phosphorus, uric acid, calcium and creatinine 1, 2, 
and 4 hours, if no other evidence of tumor lysis. 
 Potassium  6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic (eg, muscle 
cramps, weakness, 
paresthesias, nausea, 
vomiting, diarrhea) 
 Perform STAT ECG and commence telemetry. 
 Nephrology (or other acute dialysis service) assessment 
with consideration of initiating dialysis.  
 Administer Kayexalate 60 g (or Resonium A 60 g).  
 Administer furosemide 20 mg IV x 1.  
 Administer insulin 0.1 U/kg IV  D25 2 mL/kg IV. 
 Administer sodium bicarbonate 1 to 2 mEq/kg IV push.  
If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate 
precipitation.  
 Administer calcium gluconate 100 to 200 mg/kg IV slowly 
if there is ECG/telemetry evidence of life-threatening 
arrhythmias.  Do not administer in same IV line as sodium 
bicarbonate.  
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine every hour STAT. 
Page 1 of 3 


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Table 11-6.  Tumor Lysis Syndrome Management Recommendations 
Hyperuricemia 
 Uric acid  8.0 mg/dL 
(476 mol/L) 
 Consider rasburicase (0.2 mg/kg as an intravenous 
infusion over 30 minutes).  
If rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate 
precipitation. 
Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.  
 Uric acid  10 mg/dL 
(595 mol/L)  
 
OR 
 
 Uric acid  8.0 mg/dL 
(476 mol/L) with 25 
increase and creatinine 
increase  0.3 mg/dL 
( 0.027 mmol/L) from 
pre-dose level 
 Administer rasburicase (0.2 mg/kg as an intravenous 
infusion over 30 minutes).  
When rasburicase is used, sodium bicarbonate should 
not be used as this may exacerbate calcium phosphate 
precipitation.  
 Consult nephrology (or other acute dialysis service).  
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT. 
 If uric acid  8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hours later, if no other evidence of tumor lysis. 
Hypocalcemia 
 Calcium  7.0 mg/dL 
(1.75 mmol/L) 
 
AND 
 Patient symptomatic (eg, 
muscle cramps hypotension, 
tetany, cardiac arrhythmias) 
 Administer calcium gluconate 50 to 100 mg/kg IV slowly 
with ECG monitoring. 
 Telemetry. 
 Recheck potassium phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT. 
 If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hours later, if no other evidence of tumor lysis. 
 Calculate corrected calcium and check ionized calcium if 
albumin low. 
Hyperphosphatemia 
 Phosphorus  5.0 mg/dL 
(1.615 mmol/L) with 
 0.5 mg/dL (0.16 mmol/L) 
increase 
 Administer a phosphate binder (eg, aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate).  
 Nephrology (or other acute dialysis service) notification 
(dialysis required for phosphorus uric  10 mg/dL). 
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT. 
 If phosphorus  5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hours later, if no other evidence of tumor lysis. 
Page 2 of 3 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 139 of 149 
CONFIDENTIAL  
 
 
Table 11-6.  Tumor Lysis Syndrome Management Recommendations 
Creatinine 
 Increase  25 from baseline 
 Start or increase rate of IV fluids. 
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 to 2 hours STAT. 
Page 3 of 3 
ECG  electrocardiogram; IV  intravenous; ULN  upper limit of normal 
Reference:  Protocol for:  Roberts AW, Davids MS, Pagel JM, et al.  Targeting BCL2 with venetoclax in 
relapsed chronic lymphocytic leukemia.  N Engl J Med.  2016;374:311-322.  DOI:  
10.1056/NEJMoa1513257 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 140 of 149 
CONFIDENTIAL  
 
 
11.10 
Appendix 10:  Cardiac Monitoring 
11.10.1 
Management of Troponin and Other Cardiac Enzymes Elevation 
Subjects with risk factors for, or evidence of, existing heart disease should be closely 
monitored throughout their treatment with AMG 176.  Subjects should be clinically 
monitored with local and central cardiac monitoring tests for elevated troponin and 
cardiac enzymes diagnostic of cardiac injury.  Local troponin testing will be performed to 
guide immediate clinical care. Local assessment should include troponin (I or T), 
CK-MB, and NT-pro-BNP.  Serum samples are collected for centralized assessment.  
Central testing of troponin-I with ADVIA Centaur XP TnI assay will be performed for all 
screening, grading, and withholding decisions.   
Grading of Troponin-I Elevation: 
Central testing of cardiac troponin-I will be performed for eligibility determination, 
grading, and withholding decisions.  The following criteria is developed based on CTCAE 
version 5.0 to determine the grade of troponin-I elevation with ADVIA Centaur XP TnI 
assay performed by central lab:  
grade 1:  isolated elevation of troponin  99th percentile URL of 0.04 ng/mL for females 
or 0.059 ng/mL for males 
grade 3:  troponin elevation greater than or equal to manufacturer’s defined cut-off for MI 
of 0.78 ng/mL 
11.10.2 
Management of Cardiac Arrhythmia 
Subjects with risk factors for, or evidence of, existing heart disease should be closely 
monitored throughout their treatment with AMG 176.  Subjects should be clinically 
monitored on ongoing basis for cardiac function (blood pressure, heart rate, ECHO and 
ECG) according to the Schedule of Activities (Section 1.3).  The administration of 
AMG 176 should be withheld if grade 3 or 4 arrhythmias (including tachycardia) develop 
or appear to be exacerbated by AMG 176 treatment.  For any grade 3 arrhythmia related 
to AMG 176 administration, the AMG 176 dose should be reduced.  Treatment may be 
resumed once the signs and symptoms resolve to baseline value or grade 1.  
Management should be tailored to the appropriate treatment for the underlying cardiac 
disorder according to the local SOC and institutional guidelines.  For any grade 4 
arrhythmia related to AMG 176 administration, AMG 176 should be permanently 
discontinued. 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 141 of 149 
CONFIDENTIAL  
 
 
11.11 
Appendix 11:  ECOG Performance Status and NYHA Classification 
11.11.1 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light housework, office work) 
2 
Ambulatory and capable of all 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 out any selfcare.  Totally confined to bed or 
chair 
5 
Dead  
ECOG  Eastern Cooperative Oncology Group; NYHA  New York Heart Association.  
 
11.11.2 
New York Heart Association Functional Classification 
Class I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation or dyspnea. 
Class II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea. 
Class III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or dyspnea. 
Class IV 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 142 of 149 
CONFIDENTIAL  
 
 
11.12 
Appendix 12.  Uniform Response Criteria for Myelodysplastic/ 
Myeloproliferative Neoplasms (MDS/MPN) 
CR (presence of all of the following improvements)a 
Bone marrow:   5 myeloblasts (including monocytic blast equivalent in case of 
CMML) with normal maturation of all cell lines and return to normal cellularitya 
 
Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” ( grade 1 fibrosis)b 
- Peripheral bloodc 
▪ 
WBC  10 x 109 cells/L 
▪ 
Hgb  11 g/dL 
▪ 
Platelets  100 x 109/L;  450 x 109/L 
▪ 
Neutrophils  1.0 x 109/L 
▪ 
Blasts 0 
▪ 
Neutrophil precursors reduced to  2 
▪ 
Monocytes  1 x 109/L 
Extramedullary disease:  Complete resolution of extramedullary disease present 
before therapy (eg, cutaneous disease, disease-related serous effusions), including 
palpable hepatosplenomegaly 
Provisional category of CR with resolution of symptomsc:  CR as described above, and 
complete resolution of disease-related symptoms as noted by the MPN Symptoms 
Assessment Form (MPN-SAF) Total Symptom Score (TSS) 
Persistent low-level dysplasia is permitted given subjectivity of assignment of 
dysplasiaa 
Complete Cytogenetic Remission 
Resolution of previously present chromosomal abnormality (known to be associated 
with myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN), as seen 
on classic karyotyping with minimal of 20 metaphases or FISHd 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 143 of 149 
CONFIDENTIAL  
 
 
Partial Remission 
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts 
(and blast equivalents) reduced by 50, but remaining  5 of cellularity except in 
cases of MDS/MPN with  5 bone marrow blasts at baseline 
Marrow Response 
Optimal marrow response:  Presence of all marrow criteria necessary for CR without 
normalization of peripheral blood indices as presented above 
Partial marrow response:  Bone marrow blasts (and blast equivalents) reduced by 
50, but remaining  5 of cellularity, or reduction in grading of reticulin fibrosis from 
baseline on at least 2 bone marrow evaluations spaced at least 2 months apart 
Clinical Benefit 
Requires 1 of the following in the absence of progression or CR/partial response and 
independent of marrow response (cord blood response must be verified at  8 weeks) 
to be considered a clinical benefit 
 
Erythroid Response 
- Hemoglobin (Hgb) increase by  2.0 g/dL 
- Transfusion independence (TI) for  8 weeks for patients requiring at least 4 
packed red blood cell transfusions in the previous 8 weeks 
- Only red blood cell transfusions given based on physician’s judgment for a 
pretreatment Hgb of  8.5 g/dL will count in the red blood cell TI response 
evaluatione 
 
Platelet Response 
- Transfusion independence when previously requiring platelet transfusions of at 
least a rate of 4 platelet transfusions in the previous 8 weeks 
- Pretreatment  20 x 109/L:  increase from  20 x 109/L to  20 x 109/L and by at 
least 100 
- Pretreatment  20 x 109/L but  100 x 109/L:  absolute increase of  30 x 109/Le 
 
Neutrophil Response 
- Pretreatment  0.5 x 109/L at least 100 increase and an absolute increase 
 0.5 x 109/L 
- Pretreatment  0.5 x 109/L and  1.0 x 109/L at least 50 increase and an 
absolute increase  0.5 x 109/Le 
 
Spleen Response 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 144 of 149 
CONFIDENTIAL  
 
 
- Either a minimum 50% reduction in palpable splenomegaly of a spleen that is 
at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at 
baseline becomes not palpable 
 
Symptom Response 
- Improvement in symptoms as noted by decrease of  50 as per the 
MPN-SAF TSS scoring  20 were not considered eligible for measuring clinical 
benefitf 
Progression 
Requires at least one of the following in the absence of another explanation (eg, 
infection, bleeding, ongoing chemotherapy, etc.): 
 
 50 reduction from maximum response levels in granulocytes or platelets 
 
Reduction in hemoglobin by  1.5 g/dL 
Transfusion dependence  
Relapse 
Requires at least one of the following: 
 
Return to pre-treatment bone marrow blast percentage 
 
Decrease of  50 from maximum response levels in granulocytes or 
platelets 
 
Transfusion dependence or hemoglobin level  1.5 g/dL lower than prior to 
therapy 
CMML = chronic myelomonocytic leukemia; CR = complete response; FISH = fluorescence in situ 
hybridization; Hgb = hemoglobin; IWG = International Working Group; MDS = myelodysplastic syndrome; 
MPN = myeloproliferative neoplasm; MPN-SAF = MPN Symptoms Assessment Form; TI = transfusion 
independence; TSS = Total Symptom Score; WBC = white blood cells 
aPresence of dysplastic changes, which may be interpreted within the scope of normal range of dysplastic 
changes, may still exist in the presence of CR as allowed in MDS IWG.  Marrow should exhibit 
age-adjusted normocellularity in CR. 
bIf there is no significant fibrosis present on the initial bone marrow biopsy, a second biopsy is not required 
to prove resolution of fibrosis.  Grading of fibrosis in measurement of treatment response should be 
according to the European Consensus System. 
cGiven the current lack of a validated tool to assess complete resolution of symptoms in MDS/MPN, “CR 
with resolution of symptoms” (a complete resolution of disease-related symptoms as noted by the 
MPN-SAF TSS in presence of CR) will be a provisional category of disease response. 
dLoss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to adversely affect 
prognosis is required to reach complete cytogenetic remission.  Decrease in the cytogenetic burden of 
disease must be by  50% (via FISH or classic karyotyping) to be indicative of a partial cytogenetic 
response.  Given variability of fluorescent probes used in FISH, cytogenetic normalization via FISH will 
depend on the performance characteristics of the specific probes used. 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 145 of 149 
CONFIDENTIAL  
 
 
eResolution of abnormal peripheral blood counts must persist for at least 2 separate analyses over at least 
8 weeks.  In the case of proliferative MDS/MPN, CR will include resolution of thrombocytosis to a normal 
platelet count (150 to 450 x 109/L) and resolution of leukocytosis to WBC  10 x 109 cells/L but  1.5 x 
109/L.  Hemoglobin should be maintained  11 g/dL and platelets  100 x 109/L without the support of 
transfusions.  Clinical benefit may occur when these changes occur in absence of other changes required 
for CR or marrow response.  Platelet and packed red blood cell TI would be considered for clinical benefit, 
and duration of TI should be monitored.  Reduction in myeloid precursors (promyelocytes, myelocytes, 
metamyelocytes, nucleated red blood cells) to less than appreciable levels ( 2 to 3%) and/or 1 x 109/L 
monocytosis in the absence of infection, cytokine treatment, or other reactive causes. 
fMPN-SAF TSS validation among patients with MDS/MPN is currently under way (Mesa, 2014). 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 146 of 149 
CONFIDENTIAL  
 
 
11.13 
Appendix 13.  Medications That may Cause QTc Prolongation 
List of medications known to cause corrected QT interval (QTc) interval prolongation is 
available at the following link:  http://www.azcert.org/medical-pros/drug-lists/drug-
lists.cfm 
If participant in this study does not have access to the internet, they can contact the 
institution investigational pharmacy or contact their study physician to obtain a list. 
The following table presents a list of drugs that may prolong the QTc.  This is not an 
inclusive list of drugs and is provided for guidance only.  The participant is encouraged 
to follow the list in this link above for the most up-to-date information.  These drugs are 
prohibited during the study with the exception of ciprofloxacin for use in neutropenic 
subjects with acute myeloid leukemia.  Washout period is based on roughly 5 half-lives 
and rounded to a convenient interval.  This list includes (but is not limited to) the 
following: 
Compounds 
Compound Half-life 
Possible 
Washout 
Period – Hours 
Possible 
Washout Period - 
Days 
Alfuzosin 
 10 hours 
 
7 
Amantadine 
17  4 hours (10-25) 
 
4 
Amiodarone 
(cordarone) 
58 days (15 142) 
36 days (active metabolite) 
 
180 
Amitriptylinea 
 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26 to 64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol 
(active metabolite t1/2  7 to 10 hours) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30  7 hours 
 
 
Clarithromycin 
Non-linear PK3 to 4 hr (250 mg Q12) 
5 to 7 hr (500 mg Q12) 
36 
 
Chloroquine 
6 to 60 days; mean 20 days 
 
 
Desipraminea 
 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4 to 10) 
36 
 
Dofetilide 
10 hours 
48 
 
Dolasetron 
 
8.1 hours 
 
 
Domperidone 
7 to 8 hours 
48 
 
Doxepina 
 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Page 1 of 3 
Footnotes defined on the last page of the table. 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 147 of 149 
CONFIDENTIAL  
 
 
Compounds 
Compound Half-life 
Possible Washout 
Period – Hours 
Possible Washout 
Period - Days 
Erythromycin 
Each salt form has different 
Half-Lifea 
 
 
Felbamate 
20 to 23 hours 
 
5 
Flecainide 
20 hours (12 to 27) 
 
5 
Foscarnet 
87.5  41.8 hours 
distribution and release from bonea 
 
20 
Fosphenytoin 
12 to 29 hours 
 
6 
Gatifloxacin 
7 to 14 hours 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hours 
 
3 
Halofantrine 
6 to 10 days (variable among 
individual) 
 
45 
Haloperidol 
18  5 hours 
 
5 
Ibutilide 
6 hours (2 to 12) variable among 
subjecta 
36 
 
Imipramine* 
 24 hours, wide interpatient 
variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours (multiple metabolites) 
48 
 
Levofloxacin 
6 to 8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active 
metabolite 
2.6 days for LAAM, 2 day for 
nor-LAAM, 4 day for dinor-LAAM 
 
20 
Lithium 
24 hours (10 to 50) 
 
7 
Mesoridazine 
24 to 48 hours (animal study) 
 
10 
Methadone 
15 to 30 hours 
 
7 
Moexipril/HCTZ 
2 to 9 hours (include active 
metabolite) for moexipril;  
5.6 to 14.8 hours for HCTZ 
48 
 
Moxifloxacin 
12  1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
 2 hour post IV infusion 
12 
 
Nortriptylinea 
 24 hours, wide interpatient 
variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4  1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3 to 4 hours for PA and NAPA (active 
metabolite) 
24 
 
Protriptylinea 
 24 hours, wide interpatient 
variability 
 
 
Page 2 of 3 
Footnotes defined on the last page of the table.


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 148 of 149 
CONFIDENTIAL  
 
 
Compounds 
Compound Half-life 
Possible Washout 
Period – Hours 
Possible Washout 
Period - Days 
Quetiapine 
6 hours 
36 
 
Quinidine 
6 to 8 hours in adult; 3 to 4 hours in 
children 
36 
 
Quinine 
4 to 5 hours 
 
 
Risperidone 
3 to 20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active 
metabolite) t1/2  21 to 30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours (only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16 to 30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
 34 hours in healthy; 19 hours in 
Kidney transplant 
 
7 
Tamoxifen 
5 to 7 days (biphasic) 
 
30 
Telithromycin 
2 to 3 hours 
24 
 
Thioridazine 
20 to 40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenafil 
4 to 5 hours 
 
 
Venlafaxine 
5  2 hours for parent comp. 
11  2 hours for OVD (active 
metabolite) 
60 
 
Voriconazole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hours 
36 
 
Zolmitriptan 
2.8 to 3.7 hours (higher in female) 
18 
 
Page 3 of 3 
HCTZ  hydrochlorothiazide; IV  intravenous; IM  intramuscular; LAAM  levo-alpha-acetylmethadol; 
NAPA  N-acetylprocainamide; OVD  O-desmethylvenlafaxine; PA  procainamide; 
PK  pharmacokinetics; PO  once daily; Q12  every 12 hours; QT  QT interval; t1/2  elimination 
half-life. 
a Weakly associated with Torsades de pointes and/or QT prolongation but that are unlikely to be a risk for 
Torsades de pointes when used in usual recommended dosages and in subjects without other risk factors 
(eg, concomitant QT prolonged drugs, bradycardia, electrolyte disturbances, congenital long QT 
syndrome, concomitant drugs that inhibit metabolism). 
References: 
Physician’s Desk Reference 2002 
Facts and Comparison (update to June 2005) 
The Pharmacological Basis of Therapeutics 9th Edition, 1999 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  28 April 2022 
Page 149 of 149 
CONFIDENTIAL  
 
 
11.14 
Appendix 14.  Modified Toxicity Probability Interval Design 
A modified Toxicity Probability Interval (mTPI) design will be used to guide dose 
exploration.  The OBD/MSBED is defined as the minimum safe and biologically effective 
combination dose with a probability of DLT lower than or close to a targeted toxicity 
probability of 0.2.  The doses are considered close to the OBD if the toxicity probabilities 
belong to the proper dosing interval (0.25, 0.35) which corresponds to staying at the 
current dose (S).  The underdosing interval is defined as (0, 0.25) in which the doses are 
deemed lower than the OBD and corresponds to a dose escalation (E).  The overdosing 
interval is (0.35, 1) in which the doses are deemed higher than the OBD and 
corresponds to a dose de-escalation (D). 
The dose-finding decisions are guided based on Bayesian decision rule by minimizing 
the posterior expected loss through calculating the Unit Probability Mass (UPM).  At 
each dose level, the UPM is computed for the dosing intervals using the observed data 
enrolled at current dose.  The dose-finding decision is determined as the interval with 
maximum UPM.  A set of independent and non-informative prior Beta (1,1) is used for 
each dose level, which provides equal prior expected loss for the decisions 
(Ji et al, 2010).  Dose escalation will not occur unless at least 6 subjects are treated at 
the current dose level.  In addition, any dose whose posterior probability of toxicity is 
greater than the target toxicity exceeds 80 will be considered as unacceptable toxicity.  
This dose and higher doses will not be used again in the trial.  Dose exploration will 
continue until either the maximum number of subjects (up to 30 subjects in monotherapy 
part and up to 30 subjects in combination therapy part) are treated or all doses are 
determined to be intolerable. 


Product:  AMG 176 
Protocol Number:  20200392 
Date:  11 April 2022 
Page 1 of 12 
Amendment 3 
Protocol Title:  A Phase 1 Study of AMG 176 as Monotherapy and in 
Combination with Azacitidine in Higher-Risk Myelodysplastic Syndrome 
and Chronic Myelomonocytic Leukemia 
 
Amgen Protocol Number AMG 176 20200392 
 
Amendment Date: 
11 April 2022 
 
Rationale: 
The protocol has been amended to incorporate minor changes based on the 
need to replace the assay used to evaluate troponin-I elevations with a new 
high-sensitivity assay.  The current cardiac monitoring plan for AMG 176 employs 
testing of troponin-I with Troponin-I Ultra assay for all screening, grading, and 
withholding decisions.  The manufacturer has decided to retire Troponin-I Ultra 
assay effective on end of year 2021 due to low tolerance and sensitivity issues 
and has recommended to transition to High-Sensitivity Troponin-I (TNIH) assay.  
Both assays use the ADVIA Centaur XP system which is specified on the study 
protocol.  An assay verification study was conducted at Q2 laboratory to evaluate 
the accuracy and clinical performance of the new High-Sensitivity Troponin-I 
(TNIH) assay and to compare it to Troponin-I Ultra assay.  The comparison 
report demonstrated consistency between the two assays and support the 
replacement of Troponin-I Ultra assay with High-Sensitivity Troponin-I (TNIH) 
assay.  Based on the acceptable correlation data and the urgent need for 
continued cardiac monitoring, Amgen requested to replace Troponin-I Ultra 
assay with the new High-Sensitivity Troponin-I (TNIH) assay and continue to use 
the current grading criteria with the exception of increasing the male 99th 
percentile upper reference limit (URL) to 0.059 ng/mL per manufacturer’s 
guideline.  Since the protocol only refers to the system (ADVIA Centaur XP 
system) used to perform the troponin-I assay and not to the specific name of the 
assay, the only update made to the protocol relates to increasing the male 99th 
percentile URL to 0.059 ng/mL and maintaining the URL of 0.04 ng/mL for 


Product:  AMG 176 
Protocol Number:  20200392 
Date:  11 April 2022 
Page 2 of 12 
females in relevant sections of the protocol.  Minor changes were also made to 
clarify/correct other items in the protocol.  
Changes include: 
 
Update to inclusion criterion #103 to separate the note for clarity. 
 
Update to inclusion criterion #104 to remove prior cohort completion and 
data review by FDA since the statement does not define eligibility, and to 
separate the note. 
 
Update exclusion criterion #214 to reduce COVID-19 vaccination time 
point prior to dosing from 28 days to 14 days. 
 
A clarification to remove biomarker from central lab testing was made to 
the schedule of activities (section 1.3) as the standard of care would be 
performed by the local laboratory.  
 
Remove reference to central testing of troponin-I with high sensitivity 
Abbott ARCHITECT assay used for exploratory purposes to evaluate 
biological variations of troponin-I in oncology subjects (section 6.2.2.2.5) 
and (section 11.10.1). 
 
Update to grading of troponin-I elevation (section 6.2.2.2.5) and 
(section 11.10.1) to align female and male requirements with assay 
manufacturer guidelines. 
 
Update to Uniform Response Criteria for 
Myelodysplastic/Myeloproliferative Neoplasm (section 11.12) to clarify the 
definition of progression and relapse 
 
Administration, typographical, and formatting changes were made 
throughout the protocol. 


Product:  AMG 176 
Protocol Number:  20200392 
Date:  14 February 2022 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 1 Study of AMG 176 as Monotherapy and in Combination 
with Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic 
Myelomonocytic Leukemia 
 
Amgen Protocol Number AMG 176 20200392 
EudraCT number:  TBD 
NCT Number:  TBD 
 
Amendment Date: 
14 February 2022 
 
Rationale: 
This protocol is being amended to include changes as described in Amgen’s response to 
the Food and Drug Administration (FDA) potential hold comments and deficiencies 
received on 19 November 2021.  Changes include the following: 
 
Addition of a 240 mg/m2 dose level to Part 1A and Part 1B. 
 
Minor formatting, administrative, and typographical edits. 


Product:  AMG 176 
Protocol Number:  20200392 
Date:  25 October 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Phase 1 Study of AMG 176 as Monotherapy and in Combination with 
Azacitidine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic 
Leukemia 
 
Amgen Protocol Number AMG 176 20200392 
EudraCT number:  TBD 
NCT Number:  TBD 
 
Amendment Date: 
25 October 2021 
 
Rationale: 
This protocol is being amended to include changes as described in Amgen’s response to the 
Food and Drug Administration (FDA) potential hold comments and deficiencies received on 
06 October 2021.  Additionally, required safety template language was added in Section 8.4.6.  
Changes include the following: 
 
Revision of dose-limiting toxicity (DLT) criteria as per FDA’s recommendations, 
specifically cardiac DLTs, hematologic DLTs, and DLTs related to tumor lysis syndrome 
(TLS). 
 
Revision of the targeted toxicity probability to 0.2 as well as revision of the modified 
Toxicity Probability Interval (mTPI) based guidelines for dose level decisions. 
 
Revision of dose expansion stopping rules. 
 
Revision of the protocol to indicate the primary objective is to find the Optimal Biological 
Dose (OBD), rather than the maximum tolerated dose (MTD), escalating to the Minimum 
Safe and Biologically Effective Dose (MSBED).   
 
Clarified the number of dose reductions a subject is eligible for. 


Product:  AMG 176 
Protocol Number:  20200392 
Date:  25 October 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Revision of protocol Section 2.2.2.4, AMG 176 Clinical Experience, to summarize the 
available data from the ongoing Study 20150161, Part 4, for AMG 176 (60 and 
120 mg/m2 dose) in combination with azacitidine.  
 
Revision throughout the protocol to clarify that subjects will not be enrolled into the 
“Newly Diagnosed” cohort in Part 2 until all previous cohorts have been completed and 
the data reviewed by the FDA.  
 
Revision of the response criteria to utilize the Uniform Response Criteria for 
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) as included in Appendix 12 
of the protocol. 
 
Revision to Section 4.1.2 to clarify that subjects may remain on treatment with either or 
both AMG 176 and azacytidine as long as, in the opinion of the investigator, the subject 
continues to derive clinical benefit and has otherwise not had an event requiring 
permanent discontinuation. 
 
Revision to remove the enrollment requirement of blast count of  5 in patients who 
are otherwise eligible.  
 
Revision to include required template safety reporting language in Section 8.4.6. 
 
Administrative, typographical, and formatting changes throughout the protocol. 

SAP_001.pdf: 
Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 1 of 33 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1 Study of AMG 176 as Monotherapy and 
in Combination with Azacitidine in Higher-Risk 
Myelodysplastic Syndrome and Chronic 
Myelomonocytic Leukemia. 
Short Protocol Title: 
Phase 1 Study of AMG 176 with Azacitidine in 
Subjects with MDS/CMML 
Protocol Number: 
20200392 
NCT Number: 
Not available at the time of amendment 
Authors: 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Amendment 1 (v2.0) 
10 May 2024 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
20OCT2021 
Original Version 
Amendment 1 (v2.0) 
10MAY2024 

CMML is added along with R/R
MDS in the secondary objectives.

Secondary endpoint ‘Evaluate the
pharmacokinetics (PK) of the
AMG 176 when administered as
monotherapy’ is added.

Overall response according to
Uniform Response Criteria is now
changed to overall response
according to International Working
Group (2006) -MDS/MPN
Response criteria throughout the
SAP except for objectives and
endpoints.
NCT Number: NCT05209152
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 2 of 33 
CONFIDENTIAL  
 
 
 
 
The description for Part 1 changed 
from ‘Dose Escalation/ 
Determination of Maximum 
Tolerated Combination Dose 
(MTCD) and Recommended 
Phase 2 Dose (RP2D)’ to ‘Dose 
Escalation/Determination of Optimal 
Biological Dose (OBD) and 
Minimum Safe and Biologically 
Effective Dose (MSBED)’ 
 
Two dose levels in part 1 changed 
to three dose levels. 
 
The text of MTDC/RP2D definition 
is now replaced with ‘The DLRT 
may change the dose/dosing 
scheduled based on emerging 
data.  The OBD/MSBED is defined 
as the minimum safe and 
biologically effective combination 
dose with a probability of DLT 
lower than or close to a targeted 
toxicity probability of 0.2’ 
 
In Part 2 the enrollment in newly 
diagnosed subjects is changed as 
‘subjects will not be enrolled 
into this cohort until all 
previous cohorts have been 
completed and the data 
reviewed by the FDA. Toxicity 
will be monitored for each 
cohort using a Bayesian 
approach proposed by Thall, 
Simon, and Estey (1995).’ 
 
Prior distribution parameters are 
changed to beta (1,1) whereas 
initially it was beta (0.50, 1.50). 
 
The posterior probability that the 
incidence is greater than 30 is  
90 is changed to ‘20 is greater 
than 80. 
 
The sample size changed from 
110 subjects to 120 subjects and 
number of subjects in part 1 
changed from 50 to 60 
 
BOR definition is updated as BOR 
is defined as the first response 
category achieved as responders 
and non-responders. Responders 
will include CR or PR, whereas 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 3 of 33 
CONFIDENTIAL  
 
 
 
 
non-responders will include SD, 
PD, NE or NA. 
 
Section 10- changes from protocol 
specified analysis is updated. 
 
Section 9.1- Updated the general 
considerations. 
 
Section 9.5.2- Updated to 
include listings for 
responder/non-responder. 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 4 of 33 
CONFIDENTIAL  
 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Introduction ........................................................................................................... 11 
2. 
Objectives, Endpoints/Estimands and Hypotheses ............................................... 11 
2.1 
Objectives and Endpoints/Estimands ........................................................ 11 
2.2 
Hypotheses and/or Estimations ................................................................. 12 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 15 
3.3 
Adaptive Design ........................................................................................ 15 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates ................................................................................... 15 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 15 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
Full Analysis Set........................................................................................ 18 
6.2 
DLT Evaluable Analysis Set ...................................................................... 18 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 18 
7. 
Planned Analyses ................................................................................................. 18 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 18 
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 ......................................... 19 
8.3 
Handling of Missing and Incomplete Data ................................................. 19 
8.4 
Detection of Bias ....................................................................................... 19 
8.5 
Outliers ..................................................................................................... 19 
8.6 
Distributional Characteristics ..................................................................... 19 
8.7 
Validation of Statistical Analyses ............................................................... 19 
9. 
Statistical Methods of Analysis.............................................................................. 20 
9.1 
General Considerations ............................................................................. 20 
9.2 
Subject Accountability ............................................................................... 20 
9.3 
Important Protocol Deviations ................................................................... 20 
9.4 
Demographic and Baseline Characteristics ............................................... 20 
9.5 
Efficacy Analyses ...................................................................................... 21 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 21 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
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CONFIDENTIAL  
 
 
 
9.5.2 
Analyses of Secondary Efficacy 
Endpoint(s)/Estimand(s) ............................................................ 21 
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 ............................................................ 21 
9.6.4 
Vital Signs ................................................................................. 22 
9.6.5 
Physical Measurements ............................................................ 22 
9.6.6 
Electrocardiogram ..................................................................... 22 
9.6.7 
Antibody Formation ................................................................... 22 
9.6.8 
Exposure to Investigational Product .......................................... 22 
9.6.9 
Exposure to Non-investigational Product(s)/Auxiliary 
Medicinal Product(s).................................................................. 22 
9.6.10 
Exposure to Concomitant Medication ........................................ 22 
9.7 
Other Analyses ......................................................................................... 22 
9.7.2 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 22 
9.7.3 
Analyses of Clinical Outcome Assessments .............................. 22 
9.7.4 
Analyses of Health Economic Endpoints ................................... 23 
 
 
10. 
Changes From Protocol-specified Analyses.......................................................... 23 
11. 
Literature Citations / References ........................................................................... 24 
12. 
Prioritization of Analyses....................................................................................... 26 
13. 
Data Not Covered by This Plan............................................................................. 26 
14. 
Appendices ........................................................................................................... 27 
Appendix A.  Code Fragments .............................................................................. 27 
Appendix B.  Modified Toxicity Probability Interval Design .................................... 28 
Appendix C.  Last Known Alive Date..................................................................... 29 
Appendix D.  Handling of Dates, Incomplete Dates and Missing Dates ................. 31 
Appendix E. MDS Diagnostic and Response Criteria ............................................ 33 
 
 
 
 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 6 of 33 
CONFIDENTIAL  
 
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ASTX727 
Cedazuridine 
AUC 
area under the curve 
BAK 
pro-apoptotic effector proteins BCL2 homologous 
antagonist/killer 
BAX 
pro-apoptotic effector proteins BCL2-associated X 
BCL2 
B-cell lymphoma/leukemia 2 
BCRP 
breast cancer resistance protein 
BH3 
pro-apoptotic BCL2 homology 3 
BIM 
BCL2-interacting mediator of cell death 
BUN 
blood urea nitrogen 
CC-486 
Azacitidine 
CFR 
U.S. Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK-MB 
creatine kinase-muscle/brain 
CL 
Clearance 
Cmax 
maximum concentration 
CMML/CMMoL 
chronic myelomonocytic leukemia 
COVID-19 
Coronavirus Disease 2019 
CR 
complete remission 
CrCl 
creatinine clearance 
CRF 
case report form 
CRi 
incomplete count recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 7 of 33 
CONFIDENTIAL  
 
 
 
DLT 
dose limiting toxicity 
DOR 
duration of response 
DR 
durable response 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
EOS 
end of study 
EOT 
end of treatment 
FAB 
French – American – British subtypes 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FIH 
first in human 
 
 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
good laboratory practices 
GSO 
Global Safety Officer 
HALs 
Houston Area Locations 
HbcAb 
hepatitis B core antibody 
HbsAb 
hepatitis B surface antibody 
HbsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
hERG 
human ether-à-go-go-related gene 
Hgb 
Hemoglobin 
HI 
hematologic improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HNSTD 
highest-non-severely-toxic dose 
HR 
higher-risk 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 8 of 33 
CONFIDENTIAL  
 
 
 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPSS 
International Prognostic Scoring System 
IPSS-R 
Revised IPSS 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISS 
International Staging System 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
Intravenous 
Ki 
mean inhibitory constant 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MAD 
maximum administered dose 
MCL1 
Myeloid Leukemia Cell 1 
mCR 
marrow/morphologic complete remission 
MDS 
myelodysplastic syndrome 
MDSCs 
Myeloid Derived Suppressor Cells 
MM 
Multiple Myeloma 
MOA 
mechanism of action 
MOLM 
acute monocytic leukemia (AML-M5a) cell lines 
MOMP 
mitochondrial outer membrane permeabilization 
MPN 
myeloproliferative neoplasm 
MPN-SAF 
MPN Symptoms Assessment Form 
MRD 
minimum residual disease 
MRI 
magnetic resonance imaging 
MSBED 
minimum safe and biologically effective dose 
mTPI 
modified Toxicity Probability Interval 
MUGA scan 
Multigated Acquisition scan 
NCI 
National Cancer Institute 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 9 of 33 
CONFIDENTIAL  
 
 
 
NCT 
National Clinical Trials 
 
 
NE 
Not evaluable 
NK cells 
natural killer cells 
NT-pro BNP 
N-terminal prohormone of brain natriuretic peptide 
NYHA 
New York Heart Association 
OATP 
organic anion polypeptide transporters 
OBD 
optimal biological dose 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression free survival 
PI 
principal investigator 
PK 
Pharmacokinetics 
PLT 
Platelets 
PR 
partial remission 
PUMA 
p53-upregulated modulator of apoptosis 
Q2W 
every 2 weeks 
QD2 
once daily for 2 consecutive days 
QRS 
QRS interval is the interval between the Q wave and the S wave 
in the heart's electrical cycle as measured by ECG; represents 
the time it takes for the depolarization of the ventricles 
QTc 
corrected QT interval  
QTcF 
QT interval with Fridericia's correction 
QW 
once weekly 
R/R 
relapsed or refractory 
RA 
refractory anemia 
RAEB 
refractory anemia with excess blasts 
RAEB-T 
refractory anemia with excess blasts in transformation 
RARS 
refractory anemia with ringed sideroblasts 
RBC 
red blood cell 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SD 
stable disease 
siRNA 
small interfering RNA 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 10 of 33 
CONFIDENTIAL  
 
 
 
SOC 
standard of care 
STD 
severely-toxic dose 
t1/2 
half-life 
TBL 
total bilirubin 
TI 
transfusion independence 
TLS 
tumor lysis syndrome 
TSS 
Total Symptom Score 
TTNT 
time to next treatment 
ULN 
upper limit of normal 
UPM 
Unit Probability Mass 
URL 
Upper Reference Limit 
USPI 
United States Prescribing Information 
Ven 
Venetoclax 
WBC 
white blood cells 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug 
 
 






Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 13 of 33 
CONFIDENTIAL  
 
 
 
azacitidine for the treatment of HR-MDS/CMML.  Subjects will be treated with 
Intravenous (IV) AMG 176 and IV or Subcutaneous (SC) azacitidine.  The study consists 
of two parts.  
Part 1 – Dose Escalation/Determination of Optimal Biological Dose (OBD) and 
Minimum Safe and Biologically Effective Dose (MSBED) 
In Part 1, the modified Toxicity Probability Interval (mTPI) design will be applied for dose 
escalation. 
Three dose levels of AMG 176 monotherapy will first be tested in Part 1A, and after the 
OBD or MSBED is found, three dose levels of AMG 176 in combination with azacitidine 
will be tested in Part 1B. 
Each dose cohort will initially enroll 3 to 4 subjects and up to 10 subjects per cohort may 
be enrolled.  After reviewing all available safety data, dose level recommendations (eg, 
escalation, de-escalation) will be made by the Dose Level Review Team (DLRT) using 
an mTPI model (Ji et al, 2010) based on all subjects that have been enrolled at the 
current dose.  The DLRT may change the dose/dosing scheduled based on 
emerging data.  The OBD/MSBED is defined as the minimum safe and biologically 
effective combination dose with a probability of DLT lower than or close to a 
targeted toxicity probability of 0.2. 
Dose escalation is considered complete if one of the following rules is met:  
1. The highest planned dose level is evaluated, OBD has not been defined, and no 
DLTs occur at any dose level. In this case, the Maximum Administered Dose 
(MAD) may be used for Part 2.  
2. An OBD is identified. 
Guidelines for dose level decisions can be found in Table 3-1. Details regarding the 
mTPI model are described in Appendix B. 
Table 3-1.  Guidelines for Dose Level Decisions in Part 1 
 
Number of DLTs 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Escalate 
Stay at current dose 
De-escalateb 
3 
0 
1 
 2 
6 
0-1 
- 
 2 
9 
0-1 
2 
 3 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 14 of 33 
CONFIDENTIAL  
 
 
 
 
Number of DLTs 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Escalate 
Stay at current dose 
De-escalateb 
10c 
0-1 
2-3 
 4 
DLT  dose limiting toxicity. 
a A subject is considered DLT-evaluable if he/she experienced a DLT during the DLT evaluation period; or if 
he/she received 75 of the planned doses of AMG 176 and 100 of the planned doses of azacitidine and 
completed the DLT evaluation period. 
b De-escalate guideline applies only when current dose level and enrollment is allowed to a lower dose level. 
c The maximum number of evaluable subjects at one dose level is 10. 
Part 2 – Dose Expansion (Not Applicable, did not enroll) 
Upon completion of Part 1 of the study, the dose expansion phase will begin at the 
OBD/MSBED and drug administration schedule with the intention of confirming the 
safety and tolerability and determining the efficacy of AMG 176 in combination with 
azacitidine in not only R/R HR- MDS/CMML, but also in frontline HR-MDS/CMML.  An 
additional 60 subjects will be enrolled in Part 2 of the study as follows: 
 
HMA Failure Cohort:  stratified by venetoclax exposure history 
o HMA Failure, venetoclax-Naïve (n  20) 
o HMA Failure, venetoclax-Exposed (n  20) 
 
Newly Diagnosed (n  20) – subjects will not be enrolled into this cohort until all 
previous cohorts have been completed and the data reviewed by the FDA. 
Toxicity will be monitored for each cohort using a Bayesian approach 
proposed by Thall, Simon, and Estey (1995).  
The incidence of grade 3 or higher treatment-related non-hematological adverse events 
will be evaluated once every 5 subjects have had the chance to receive at least 1 cycle 
of treatment at the determined dose level for Part 2.  Assuming a prior distribution of 
beta (1, 1), if the posterior probability that the incidence is greater than 20 is  80 at 
these interim analyses, the study will stop early.  The purpose of the safety interim 
analyses is to assess if the threshold for early termination has been reached.  The 
stopping rules and operating characteristics are described in Protocol Table 3-2 and 
Table 3-3. 
Table 3-2.  Stopping Boundary for Each Cohort in Part 2 
Number of subjects 
Stop study if observing this number of subjects with grade 3 or 
higher treatment-related non-hematological adverse event 
5  6 
 2 


Product:  AMG 176  
Protocol Number:  20200392 
Date:  10 May 2024 
Page 15 of 33 
CONFIDENTIAL  
 
 
 
7  10 
 3 
11  14 
 4 
15  19 
 5 
20 
Completes 
Table 3-3.  Operating Characteristics in Part 2 
True grade 3 or higher treatment-related non-hematological 
adverse event rate 
Probability of early stopping 
0.10 
15 
0.15 
32 
0.20 
51 
0.25 
69 
0.30 
82 
 
3.2 
Sample Size 
It is anticipated that up to 120 subjects will be enrolled in the study, with up to 
60 subjects in Part 1 and 60 subjects in Part 2. 
For each part, the sample size is based on practical considerations and it is consistent 
with conventional oncology studies with the objective to identify the OBD/MSBED. 
3.3 
Adaptive Design 
NA 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
There are no planned covariates in this study. 
4.2 
Subgroups 
There are no planned subgroups in this study. 
5. 
Definitions 
Age at Enrollment: 
Age at Enrollment: Subject age at enrollment will be collected in [years] in the clinical 
database 


Product:  AMG 176  
Protocol Number:  20200392 
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Page 16 of 33 
CONFIDENTIAL  
 
 
 
Baseline: 
Unless otherwise specified, baseline will be defined as the last assessment with 
nonmissing value before the first dose of investigational product (AMG 176). 
Baseline and Post-Baseline ECG Values in Triplicate: 
The baseline ECG is defined as the mean of all pre-dose assessments, the mean of 
values in a triplicate should be calculated before taking the mean of the triplicate 
averages. 
For all post-baseline ECG, the mean value for measurements taken at the same 
assessment will be calculated and used in the analysis. 
When an ECG is missing within a triplicate, all available data will be averaged for that 
time point. 
Bazett-corrected QT Interval (QTcB): 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec): QTcB=QT/(RR/1000)1/2 
Best Overall Response (BOR):  
BOR for a subject is the best observed post-baseline disease response based on 
investigator assessment.  
BOR is defined as the first response category achieved as responders and non-
responders. Responders will include CR or PR, whereas non-responders will 
include SD, PD, NE or NA.  
Response criteria to be used for MDS/MPN are International Working Group (IWG)-MDS 
Response Criteria (2006).  
Change From Baseline: 
Change from baseline is the arithmetic difference between post-baseline and baseline.  
Duration of Treatment: 
Date of last administration of investigational product – Study Day 1 + 1  


Product:  AMG 176  
Protocol Number:  20200392 
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Page 17 of 33 
CONFIDENTIAL  
 
 
 
DLT Observation Period:  
The DLT observation period is defined as day 1 through day 28 after the administration 
of the first dose of AMG 176.  
Fridericia-corrected QT Interval (QTcF):  
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec): QTcF=QT/(RR/1000)1/3.  
Investigational Product (IP):  
IP is used in reference to AMG 176.  
Last known alive date:  
Last known alive date is described in Appendix C.  
Study Day:  
Post study day 1: study day = (date – date of Study Day 1) + 1  
Pre study day 1: study day = (date – date of Study Day 1)  
Study Day 1:  
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Day -1. 
Transfusion independence: 
Transfusion independence is defined as no transfusion for at least 8 consecutive weeks 
(56 days). 
Treatment-Emergent Adverse Event (TEAE): 
A treatment-emergent adverse event is any adverse event starting on or after the first 
dose of investigational product, as determined by "Did event start before first dose of 
investigational product" equal to "No" or missing on the Events eCRF, and up to and 
including 30 days after the last dose of investigational product excluding events reported 
after end of study date. 
Treatment-related Treatment-emergent Adverse Event (TRAE): 
A TRAE is any TEAE whose causal relationship is marked as "Related" on the eCRF. 


Product:  AMG 176  
Protocol Number:  20200392 
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CONFIDENTIAL  
 
 
 
Event with missing relationship will be assumed to be treatment-related. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The FAS is defined as all subjects who are enrolled and receive at least 1 dose of AMG 
176. 
6.2 
DLT Evaluable Analysis Set 
Subjects are considered DLT-evaluable if they experience a DLT during the DLT 
evaluation period, or if they complete the DLT evaluation period and receive at least 
75% of the planned doses of AMG 176 and 100% of the planned dose of azacitidine. 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
The PK Analysis Set defined as all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected. These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
As the decision was made to terminate the study early, no formal interim analysis will be 
performed for this study.  
7.2 
Primary Analysis 
No formal primary analysis will be performed due to early close out of the study. 
7.3 
Final Analysis 
A final analysis is planned after all available subjects have had the opportunity to 
complete the last study visit. 
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. 


Product:  AMG 176  
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CONFIDENTIAL  
 
 
 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
receive and store 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 D.  
Non-pharmacokinetic measurements (
) that are above or 
below the quantification limits will be considered equal to the upper or lower limit of 
quantification for all analyses unless specified otherwise. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
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 Pharmacokinetics 
and Drug Metabolism (PKDM) practices. 
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 
Datasets, tables, figures, and listings will be produced and validated in accordance with 
SOP-430399. Standard macros will be used when available.   


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The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.2 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics on required continuous data like Troponin I and Troponin T 
will include means, medians, standard deviations, first and third quartiles and 
ranges.  
When data are summarized by time, the values recorded against the scheduled 
time points listed in the protocol will be used. When assessing 
minimum/maximum increases or decreases over the study, all assessments, 
including unscheduled assessments will be used.  
No formal statistical analysis will be performed for the study and listings will be provided.  
9.2 
Subject Accountability 
No summary of subject accountability will be required to provided. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
No listing of IPDs and eligibility deviations will be provided 
9.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristic will be listed. 


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9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
No formal statistical analyses will be performed for primary efficacy endpoints 
due to early termination of the study which resulted in insufficient number of 
subjects.   
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)/Estimand(s) 
The listing of responder/non-responder will be provided for Part 1A- QW 
Monotherapy (Dose Exploration) subjects. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
NA 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
No summary analysis tables will be provided for the safety endpoints. More details are 
mentioned in sections from 9.6.2 to 9.6.10 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 26.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
Subject listing of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to discontinuation of investigational product, treatment related 
adverse events, DLTs and fatal adverse events will be provided. 
Subject listing of Troponin increased adverse events serious adverse events, adverse 
events leading to discontinuation of investigational product, treatment related adverse 
events, and fatal adverse events will be provided. 
The grading of adverse events will be based on the guidelines provided in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
9.6.3 
Laboratory Test Results 
The subject listing of clinical laboratory will be provided for the full analysis set. The 
analyses of safety laboratory data for Troponin will be included as summary statistics 
over time by dose level 


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9.6.4 
Vital Signs 
The listing of vital signs including systolic/diastolic blood pressure, heart rate, respiratory 
rate and temperature will be provided. 
9.6.5 
Physical Measurements 
The subject listing will be provided which will include parameters of physical 
measurements. 
9.6.6 
Electrocardiogram 
The listing of all on-study ECG data will be provided. 
9.6.7 
Antibody Formation 
No summary tables or listing will be provided. 
9.6.8 
Exposure to Investigational Product 
The subject listings will be provided with IP start and end date. The listing will also 
include planned dose, actual dose and reason for change or withheld of the planned 
dose. 
9.6.9 
Exposure to Non-investigational Product(s)/Auxiliary Medicinal 
Product(s)  
NA 
9.6.10 
Exposure to Concomitant Medication 
No summary tables and listings will be provided. 
9.7 
Other Analyses 
9.7.1.1.1 
Pharmacokinetic Analyses 
The analysis of pharmacokinetic endpoints will include data from all subjects who have 
received at least 1 dose of the investigational product and have at least 
1 pharmacokinetic sample collected. 
PK parameters for AMG 176 including, but not limited to, maximum observed 
concentration (Cmax), area under the concentration-time curve (AUC) and half-life (t1/2) 
will be estimated, if feasible. 
9.7.2 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
NA 
9.7.3 
Analyses of Clinical Outcome Assessments 
NA 


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9.7.4 
Analyses of Health Economic Endpoints 
NA 
9.7.5 
 
NA 
10. 
Changes From Protocol-specified Analyses 
During the initial development of this document, it was realized that there are protocol-
specified analyses that cannot be implemented/performed and the protocol is not 
required to be amended.  Following changes are required- 
 
Though protocol states that the Uniform Response criteria were used for 
deriving the responses; however, International Working Group MDS Response 
Criteria (2006) (Appendix E) were used to classify responses for patients with 
MDS (based on NCCN guidelines Jan 2024). No patients with CMML were 
enrolled.  
 
Tables based on the primary analysis endpoints and secondary endpoints will not be 
generated due to the limited number of subjects and early close out of the study. 
These changes will also be documented in the Clinical Study Report. 
Primary endpoints will not be analyzed using tables; however, listings will be provided 
only for clinical laboratory tests, vital signs, ECG, and adverse events including DLTs, 
treatment-related and treatment-emergent adverse events.  
1. Part 1A – QW Monotherapy (Dose Exploration)- Incidence of dose limiting 
toxicities (DLTs), treatment-related, treatment-emergent adverse events and 
clinically significant changes in vital signs, electrocardiogram (ECGs), and clinical 
laboratory tests. 
No analysis will be performed for below secondary endpoints: 
1. Part 1B – QW Combination Therapy (Dose Exploration) – Overall response 
according to the IWG-MDS Response criteria for MDS/MPN (2006), EFS, time 
to response, and DOR 
2. Part 2 – QW Combination Therapy (Dose Expansion) –  
a. Time to transformation to Acute Myeloid Leukemia (AML)  
b. Duration of Response (DOR)  
c. Overall Survival (OS)  
d. Time to Next MDS Treatment (TTNT) 
e. EFS 


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11. 
Literature Citations / References 
Albitar M, Manshouri T, Shen Y, et al. Myelodysplastic syndrome is not merely 
"preleukemia". Blood. 2002;100(3):791-798. 
AMG 176 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis 
discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 
2017;16(4):273-284. 
Bejar R, Steensma DP.  Recent developments in myelodysplastic syndromes.  Blood.  
2014;124:2793-2803.  
Beroukhim R, Mermel CH, Porter D, et al.  "The landscape of somatic copy-number 
alteration across human cancers."  Nature.  2010;463(7283):899-905. 
Bose P, Grant S.  MCL1 as a therapeutic target in acute myelogenous leukemia (AML).  
Leukemia Research Reports.  2013;2(1):12-14. 
Caenepeel S, Brown SP, Belmontes B, et al.  AMG 176, a selective MCL1 inhibitor, is 
effective in Hematological Cancer models alone and in combination with established 
therapies. Cancer Discovery. 2018;8:1582–1597.  
Cairo MS, Bishop M.  Tumour lysis syndrome:  new therapeutic strategies and 
classification.  Br J Haematol.  2004;127(1):3-11. 
Cheson BD, Greenberg PL. Clinical application and proposal for modification of the 
International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 
108 (2): 419-425. 
Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric and adult 
tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-2778. 
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 
protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 
2014;15(1):49-63. 
Doll DC, List AF. Myelodysplastic syndromes. West J Med. 1989;151(2):161-167. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with 
that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol. 
2009;10(3):223-232. 
Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 
2017;7(5):1016-1036. 
Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the 
development and sustained growth of acute myeloid leukemia. Genes Dev. 
2012;26(2):120-125. 
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088. 
Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring 
system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. 
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. 


Product:  AMG 176  
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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 
International Conference on Harmonisation; S9 Guidance on Nonclinical Evaluation for 
Anticancer Pharmaceuticals.  Fed Regist.  2010;Mar 8;75(44):10487-10488. 
Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic 
syndrome after failure of decitabine therapy. Cancer. 2010;116(16):3830-3834. 
Ji Y, Liu P, Li Yisheng, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials. 2010; 7:653-663.  
Kadia TM, Jabbour E, Kantarjian H. Failure of hypomethylating agent-based therapy in 
myelodysplastic syndromes. Semin Oncol. 2011; 38(5):682-692. 
Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer. 
2006;106(8):1794-1803. 
Kasper S, Breitenbuecher F, Heidel F, et al.  Targeting MCL1 sensitizes 
FLT3-ITD-positive leukemias to cytotoxic therapies.  Blood Cancer J.  2012;2:e60. 
Kaufmann SH, Karp JE, Svingen PA, et al.  Elevated Expression of the Apoptotic 
Regulator MCL1 at the Time of Leukemic Relapse.  Blood.  1998;91(3):991-1000.  
Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and 
effective in diverse cancer models. Nature. 2016;538(7626):477-482. 
Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in 
programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl 
Acad Sci U S A. 1993;90(8):3516-3520.  
List AF. New agents in the treatment of MDS. Clin Adv Hematol Oncol. 
2005;3(11):832-834. 
Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival 
in the United States. Cancer. 2007;109(8):1536-1542. 
Merino D, Whittle JR, Vaillant F, et al. Synergistic action of the MCL-1 inhibitor S63845 
with current therapies in preclinical models of triple-negative and HER2-amplified breast 
cancer. Sci Transl Med. 2017;9(401). 
Mesa RA, personal communication, 2014. 
Peperzak V, Vikström I, Walker J, et al.  MCL1 is essential for the survival of plasma 
cells.  Nat Immunol.  2013;14(3):290-297. 
Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome 
after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322-3327. 
Roberts AW, Davids MS, Pagel JM, et al.  Targeting BCL2 with venetoclax in relapsed 
chronic lymphocytic leukemia.  N Engl J Med. 2016;374:311-322.  DOI:  
10.1056/NEJMoa1513257. 
Steensma DP. Can hypomethylating agents provide a platform for curative therapy in 
myelodysplastic syndromes?  Best Pract Res Clin Haematol. 2012;25(4):443-451. 
Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to 
improve therapy of cancer and other diseases. EMBO J. 2011;30(18):3667-3683. 


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Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med. 1995;14(4):357-79.  
Thomas RL, Roberts DJ, Kubli DA, et al. Loss of MCL-1 leads to impaired autophagy 
and rapid development of heart failure. Genes Dev. 2013;27(12):1365-1377. 
van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective 
Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. 
Cancer Cell. 2006;10(5):389-399. 
Wang X, Bathina M, Lynch J, et al. Deletion of MCL-1 causes lethal cardiac failure and 
mitochondrial dysfunction. Genes Dev. 2013;27(12):1351-1364. 
Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is 
regulated by MCL1 and FBW7. Nature. 2011;471(7336):110-114 
Xiang Z, Luo H, Payton J E, et al.  Mcl1 haploinsufficiency protects mice from 
Myc-induced acute myeloid leukemia.  J Clin Investigation.  2010;120(6):2109-2118. 
Youle, RJ, Strasser A.  The BCL2 protein family:  opposing activities that mediate cell 
death.  Nat Rev Mol Cell Biol.  2008;9(1):47-59 
12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
The analyses of PK are not covered by this plan. 


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14. 
Appendices 
Appendix A.  Code Fragments 
The ORR and its 95% CI can be calculated in SAS using PROC FREQ. The sample 
code is provided below, where RESP is the status of response (eg., 1=responder, 
2=non-responder). The CI using the exact method can be found in the OUT data labeled 
as ‘Exact Conf Limits’.  
proc freq data=TEST;  
tables RESP / binomial alpha=0.05;  
ods output Binomial=OUT;  
run; 
 
 


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Appendix B.  Modified Toxicity Probability Interval Design 
A modified Toxicity Probability Interval (mTPI) design will be used to guide dose 
exploration.  The OBD/MSBED is defined as the minimum safe and biologically effective 
combination dose with a probability of DLT lower than or close to a targeted toxicity 
probability of 0.2.  The doses are considered close to the OBD if the toxicity probabilities 
belong to the proper dosing interval (0.25, 0.35) which corresponds to staying at the 
current dose (S).  The underdosing interval is defined as (0, 0.25) in which the doses are 
deemed lower than the OBD and corresponds to a dose escalation (E).  The overdosing 
interval is (0.35, 1) in which the doses are deemed higher than the OBD and 
corresponds to a dose de-escalation (D). 
The dose-finding decisions are guided based on Bayesian decision rule by minimizing 
the posterior expected loss through calculating the Unit Probability Mass (UPM).  At 
each dose level, the UPM is computed for the dosing intervals using the observed data 
enrolled at current dose.  The dose-finding decision is determined as the interval with 
maximum UPM.  A set of independent and non-informative prior Beta (1,1) is used for 
each dose level, which provides equal prior expected loss for the decisions 
(Ji et al, 2010).  Dose escalation will not occur unless at least 6 subjects are treated at 
the current dose level.  In addition, any dose whose posterior probability of toxicity is 
greater than the target toxicity exceeds 80 will be considered as unacceptable toxicity.  
This dose and higher doses will not be used again in the trial.  Dose exploration will 
continue until either the maximum number of subjects (up to 30 subjects in monotherapy 
part and up to 30 subjects in combination therapy part) are treated or all doses are 
determined to be intolerable. 
 


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Appendix C.  Last Known Alive Date 
For subjects who do not have death date available i.e., subject was alive throughout, 
derive last known alive date as the latest of all the date variables below:  
1. Events form: Date Started, Date Ended or Resulted in Death, hospitalization 
admission date, hospitalization date discharged.  
2. Date collected on Chemistry (Local lab), Chemistry (Local lab) (Unsched), 
Coagulation (Local Lab), Coagulation (Local Lab) (Unsched), Hematology (Local Lab), 
Hematology (Local Lab) (Unsched), Urinalysis (Local Lab), Urinalysis (Local Lab) 
(Unsched), Immunology (Local Lab), Reproductive Status and Pregnancy Test (Local 
Lab), Male Reproductive Status, Liver Biopsy Results, Liver Biopsy - Abnormal Findings, 
Liver Biopsy - Abnormal Architecture Findings, Liver Biopsy - Abnormal Liver Cell or 
Hepatocyte Findings, Liver Biopsy - Liver Cell or Hepatocyte Inclusion or Vacuole Types, 
Liver Biopsy - Hepatocyte or Liver Cell Nuclear Abnormality Types, Liver Biopsy - Liver 
or Lobular Infiltrate Types, Liver Biopsy - Portal Tract Inflammation Types, Liver Biopsy - 
Abnormal Bile Duct Findings, Liver Biopsy - Abnormal Portal Vein Findings, Liver Biopsy 
- Liver Infection Findings, Liver Biopsy - Parasite or Ova Findings, Liver Biopsy - 
Histological Staining or Additional Study Details, Liver Imaging Results, Hepatic Event 
Labs, Chemistry (Local Lab) (DILI), Coagulation (Local Lab) (DILI), Hematology (Local 
Lab) (DILI), Immunology (Local Lab) (DILI), Toxicology (Local Lab) (DILI), Chemistry 
(Local Lab) (Non-TP), Hematology (Local Lab) (Non-TP), Urinalysis (Local Lab) (Non-
TP), Coagulation (Local Lab) (Non-TP), 
, 
 (Non-TP) (Cardiac monitoring tests), Chemistry (Local Lab) (TLS 
monitoring tests), Chemistry (Local Lab) (Cardiac monitoring tests), Bone Marrow 
Aspirate for MDS, Chemistry (Local Lab) (Unsched) (TLS monitoring tests), Chemistry 
(Local Lab) (Unsched) (Cardiac monitoring tests), Hematology (Local Lab) (Peripheral 
Blood Counts), Hematology (Local Lab) (Unsched) (Peripheral Blood Counts), 
Hematology (Local Lab) (Peripheral Blood Counts) (Non-TP) forms.  
3. Date first taken, Date last taken on the Concomitant medications, Other Protocol 
Required Therapy (Allopurinol or equivalent), Anti-Cancer Therapies (On Study) forms.  
4. Date performed on CT or MRI, ECOG performance status, Electrocardiogram - 
Triplicate (On-study), Electrocardiogram (on-study), Procedure, Transfusions,  
NYHA Classification, Vital signs, Vital Signs (DILI), MUGA Scan or Echocardiogram, 
MUGA Scan or Echocardiogram (DILI), Electrocardiogram (On-study) (Non-TP), 


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Electrocardiogram - Triplicate (On-study) (Non-TP), Vital Signs Log (VS200), Vital Signs 
Log (VS200) (Non-TP) forms.  
5. Date subject has ended IP, End of Investigational Product Administration, End of Non-
Investigational Product Administration (Azacitidine), End of Safety Follow-up, EOS forms 
only if the status is not dead or lost to follow-up.  
6. Hospitalization admission and dfischarge dates on hospitalization form  
7. Date first taken, Date last taken, Progression Date, Best Response Date on the Anti-
cancer therapies form.  
8. Start and stop dates on Investigational Product administration, Non- Investigational 
Product Administration (Azacitidine) forms.  
9. Date of examination on physical measurement, Physical Measurement (Weight), 
Physical Measurement (Height/Weight/BMI_C) forms.  
10. Date consent signed, Date consent withdrawn on additional consents/withdrawals of 
consent form  
11. Date of contact/search, subject status date on the Survival Status form if the subject 
status is not unknown.  
12. Date of assessment on Disease Response (MDS) form.  
13. All the date fields on Best Overall Response/Progression form.  
14. All dates from NDB data. 
 


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


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


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Appendix E. MDS Diagnostic and Response Criteria 
Proposed modified International Working Group response criteria for altering 
natural history of MDS