Conditions: Relapsed or Refractory Multiple Myeloma Relapsed or Refractory Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 141
Healthy volunteers: no

Brief summary:
The main objectives are to evaluate the safety and tolerability of AMG 176 monotherapy in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia.

Detailed description:
This is a Phase 1, first-in-human, multicenter; non-randomized, open-label and dose-exploration study of AMG 176 administered IV in participants with relapsed or refractory multiple myeloma and participants with relapsed or refractory acute myeloid leukemia The study will be conducted in five parts.

Arms:
arm 1: Part 1a - Participants with muliple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion for two-consecutive days (QD2) followed by a 5 days break. arm 2: Part 1b - Participants with multiple myeloma (MM) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break. arm 3: Part 3a - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion once a day, for two-consecutive days (QD2) followed by a 5 day break. arm 4: Part 3b - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break. arm 5: Part 3c - Participants in Japan only with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW) followed by 6 days break. arm 6: Part 3d - Participants in the United States with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, once a week (QW), for 3 weeks, in combination with itraconazole. arm 7: Part 4 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine. arm 8: Part 5 - Participants with acute myeloid leukemia (AML) administered AMG 176 as an intravenous (IV) infusion at the maximum tolerated combination dose from Part 4, either once a week (QW) followed by 6 days break, or once a day, for two-consecutive days (QD2), in combination with azacitidine.

Interventions: intervention 1: AMG 176 intervention 2: Azacitidine intervention 3: Itraconazole
Intervention descriptions: intervention 1: Study Drug intervention 2: Non-investigational product intervention 3: Non-investigational product

Protocol document:
Prot_000.pdf: 
Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 1 of 219 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 176 in Subjects With 
Relapsed or Refractory Multiple Myeloma and 
Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia 
Protocol Number: 
20150161 
Investigational Product: 
AMG 176 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+1-805-447-1000 
Key 
Sponsor 
Contacts 
Name: 
, MD, PhD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
 
Protocol 
Approver 
Name: 
, MD 
Function: 
Vice President, Early Development 
EudraCT Number: 
2015-004777-32 
NCT Number: 
NCT02675452 
Protocol Version Date: 
Document Version 
Date 
Original 
21 August 2015 
Amendment 1 
11 November 2015 
Amendment 2 
25 February 2016 
Amendment 3 
10 January 2017 
Amendment 4 
07 March 2017 
Amendment 5 
14 December 2017 
Amendment 6 
25 April 2018 
Amendment 7 
12 February 2019 
Amendment 8 
18 June 2019 
Amendment 9 
30 July 2019 
Amendment 10 
30 March 2020 
Amendment 11 
05 February 2021 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 2 of 219 
CONFIDENTIAL  
 
 
Superseding 
Amendment 11 
18 February 2021 
Amendment 12 
16 September 2021 
Amendment 13 
20 January 2022 
Amendment 14 
16 March 2022 
Amendment 15 
09 February 2023 
Amendment 16 
13 July 2023 
Data Elements Standards 
Version:  
5.0 
 
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:  20150161  
Date:  13 July 2023 
Page 3 of 219 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects 
With Relapsed or Refractory Multiple Myeloma and Subjects With Relapsed or 
Refractory Acute Myeloid Leukemia, dated 13 July 2023, and agree to abide by all 
provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse [or legal partner] and dependent children) and my 
subinvestigators (including, if applicable, their spouses [or legal 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:  20150161  
Date:  13 July 2023 
Page 4 of 219 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 11 
1.1 
Synopsis ................................................................................................... 11 
1.2 
Study Schema ........................................................................................... 22 
1.3 
Schedule of Activities (SoA) ...................................................................... 32 
2. 
Introduction ........................................................................................................... 57 
2.1 
Study Rationale ......................................................................................... 57 
2.2 
Background ............................................................................................... 59 
2.2.1 
Disease ..................................................................................... 59 
2.2.1.1 
Multiple Myeloma Background ................................ 59 
2.2.1.2 
Acute Myeloid Leukemia Background ..................... 61 
2.2.1.3 
Combination Therapy in Multiple Myeloma 
and Acute Myeloid Leukemia .................................. 62 
2.2.2 
Amgen Investigational Product Background:  
AMG 176 ................................................................................... 62 
2.2.2.1 
AMG 176 Preclinical Pharmacodynamic 
and Antitumor Studies ............................................. 63 
2.2.2.2 
AMG 176 Pharmacokinetics .................................... 65 
2.2.2.3 
AMG 176 Nonclinical Toxicology ............................. 65 
2.2.2.4 
AMG 176 Clinical Experience .................................. 66 
2.3 
Benefit/Risk Assessment ........................................................................... 68 
2.3.1 
Key Benefits .............................................................................. 68 
2.3.2 
Key Risks .................................................................................. 68 
2.3.2.1 
Tumor Lysis Syndrome ........................................... 68 
2.3.2.2 
Increased Troponin ................................................. 69 
2.3.2.3 
Other Risk ............................................................... 69 
3. 
Objectives and Endpoints ..................................................................................... 70 
4. 
Study Design ........................................................................................................ 75 
4.1 
Overall Design .......................................................................................... 75 
4.1.1 
AMG 176 Monotherapy (Part 3b) and Combination 
with Azacitidine (Parts 4 and 5) for AML .................................... 80 
4.1.2 
AMG 176 Tolerability in Subjects with AML in Japan 
(Part 3c) .................................................................................... 82 
4.1.3 
Drug-drug interaction Assessments with Itraconazole 
in the United States (Part 3d) .................................................... 83 
4.2 
Number of Subjects ................................................................................... 83 
4.2.1 
Replacement of Subjects ........................................................... 84 
4.2.2 
Number of Sites ......................................................................... 84 
4.3 
Justification for Investigational Product Dose ............................................ 84 
4.3.1 
Starting and Maximum Planned Doses ...................................... 85 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 5 of 219 
CONFIDENTIAL  
 
 
4.3.1.1 
Multiple Myeloma .................................................... 86 
4.3.1.2 
Acute Myeloid Leukemia ......................................... 86 
4.3.2 
Justification for the AML Conventional Dosing 
Schedule (5 Consecutive Days) ................................................ 89 
4.3.3 
Justification of the Monotherapy Recommended 
Phase 2 Dose (RP2D) ............................................................... 90 
4.3.4 
Dose Optimization Plan to Inform Combination 
Recommended Phase 2 Dose (RP2D) ...................................... 91 
4.4 
Justification for Non-investigational Product Dose ..................................... 92 
4.4.1 
Azacitidine ................................................................................. 92 
4.4.2 
Itraconazole ............................................................................... 92 
4.5 
End of Study ............................................................................................. 93 
4.5.1 
End of Study Definition .............................................................. 93 
4.5.2 
Study Duration for Subjects ....................................................... 93 
5. 
Study Population .................................................................................................. 93 
5.1 
Inclusion Criteria ....................................................................................... 94 
5.2 
Exclusion Criteria ...................................................................................... 95 
5.3 
Subject Enrollment .................................................................................... 98 
5.4 
Screen Failures ....................................................................................... 100 
6. 
Treatments ......................................................................................................... 100 
6.1 
Treatment(s) Administered ...................................................................... 100 
6.1.1 
Investigational Product:  AMG 176 .......................................... 100 
6.1.2 
Non-investigational Products:  Azacitidine and 
Itraconazole ............................................................................ 102 
6.1.2.1 
Azacitidine (Parts 4 and 5) .................................... 103 
6.1.2.2 
Itraconazole (Part 3d) ............................................ 104 
6.1.3 
Medical Devices ...................................................................... 105 
6.1.4 
Other Protocol-required Therapies .......................................... 105 
6.1.4.1 
Tumor Lysis Prophylaxis (All Subjects).................. 105 
6.1.5 
Other Treatment Procedures ................................................... 107 
6.1.6 
Product Complaints ................................................................. 107 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................. 108 
6.1.8 
Concomitant Medications with Itraconazole (Part 3d 
only) ........................................................................................ 109 
6.2 
Dose Modification .................................................................................... 110 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules ........................................................................ 110 
6.2.1.1 
Dose-Limiting Toxicity Evaluation Period ............... 110 
6.2.1.2 
Definition of Dosage Limiting Toxicities ................. 110 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ................................... 115 
6.2.2.1 
Amgen Investigational Product:  AMG 176 ............ 115 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 6 of 219 
CONFIDENTIAL  
 
 
6.2.2.2 
AMG 176 Management of Toxicities ...................... 118 
6.2.2.3 
Non-Investigational Products:  Azacitidine 
and Itraconazole .................................................... 123 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ..................... 124 
6.3 
Preparation/Handling/Storage/Accountability .......................................... 124 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ....................... 125 
6.4.1 
Method of Treatment Assignment ............................................ 125 
6.4.2 
Blinding ................................................................................... 125 
6.5 
Treatment Compliance ............................................................................ 125 
6.6 
Treatment of Overdose ........................................................................... 125 
6.7 
Prior and Concomitant Treatment ........................................................... 125 
6.7.1 
Prior Treatment ....................................................................... 125 
6.7.2 
Concomitant Treatment ........................................................... 126 
6.7.2.1 
Bone Disease Therapy (Multiple Myeloma 
Subjects Only) ....................................................... 126 
6.7.2.2 
Antifungal Prophylaxis ........................................... 127 
6.7.2.3 
Concomitant Cautions to Consider ........................ 127 
6.7.2.4 
Vaccines ............................................................... 127 
7. 
Discontinuation Criteria ....................................................................................... 127 
7.1 
Discontinuation of Study Treatment......................................................... 128 
7.2 
Discontinuation From the Study .............................................................. 129 
7.2.1 
Reasons for Removal From Study ........................................... 129 
7.3 
Lost to Follow-up ..................................................................................... 129 
8. 
Study Assessments and Procedures .................................................................. 130 
8.1 
General Study Periods ............................................................................ 130 
8.1.1 
Screening, Enrollment and/or Randomization .......................... 130 
8.1.2 
Treatment Period ..................................................................... 131 
8.1.3 
End of Treatment ..................................................................... 132 
8.1.4 
Safety Follow-up ...................................................................... 132 
8.1.5 
Long-term Follow-up ................................................................ 132 
8.1.6 
End of Study ............................................................................ 132 
8.2 
Description of General Study Assessments and Procedures ................... 132 
8.2.1 
General Assessments ............................................................. 132 
8.2.1.1 
Informed Consent .................................................. 132 
8.2.1.2 
Demographics ....................................................... 132 
8.2.1.3 
Medical History ...................................................... 133 
8.2.1.4 
Physical Examination ............................................ 133 
8.2.1.5 
Physical Measurements ........................................ 133 
8.2.1.6 
Eastern Cooperative Oncology Group 
Performance Status............................................... 133 
8.2.2 
Efficacy Assessments .............................................................. 133 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 7 of 219 
CONFIDENTIAL  
 
 
8.2.2.1 
Multiple Myeloma Tumor Assessment and 
Disease Assessment ............................................. 133 
8.2.2.2 
Acute Myeloid Leukemia Tumor 
Assessment and Disease Assessment .................. 136 
8.2.3 
Safety Assessments ................................................................ 138 
8.2.3.1 
Vital Signs ............................................................. 138 
8.2.3.2 
Electrocardiograms (ECGs) ................................... 138 
8.2.3.3 
Vital Status ............................................................ 139 
8.2.3.4 
Other Safety .......................................................... 139 
8.2.4 
Adverse Events and Serious Adverse Events .......................... 140 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information ................ 140 
8.2.4.2 
Relationship to Study Drug .................................... 142 
8.2.4.3 
Method of Detecting Adverse Events and 
Serious Adverse Events ........................................ 142 
8.2.4.4 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 142 
8.2.4.5 
Regulatory Reporting Requirements for 
Serious Adverse Events ........................................ 143 
8.2.4.6 
Safety Monitoring Plan .......................................... 143 
8.2.4.7 
Pregnancy and Lactation ....................................... 143 
8.2.5 
Clinical Laboratory Assessments ............................................. 144 
8.2.5.1 
Hepatitis Serology ................................................. 144 
8.2.5.2 
Tumor Lysis Syndrome Laboratory 
Monitoring ............................................................. 144 
8.2.5.3 
Cardiac Monitoring Tests ...................................... 145 
8.2.5.4 
Pregnancy Testing ................................................ 145 
8.2.6 
Pharmacokinetic Assessments ................................................ 145 
8.2.7 
Pharmacogenetic Assessments............................................... 145 
8.2.8 
8.2.9 
Optional Substudies ................................................................ 147 
9. 
Statistical Considerations .................................................................................... 148 
9.1 
Statistical Hypotheses ............................................................................. 148 
9.2 
Sample Size Determination ..................................................................... 148 
9.3 
Analysis Sets, Subgroups, and Covariates .............................................. 149 
9.3.1 
Analysis Sets ........................................................................... 149 
9.3.2 
Covariates ............................................................................... 149 
9.4 
Statistical Analyses ................................................................................. 149 
9.4.1 
Planned Analyses .................................................................... 150 
9.4.1.1 
Interim Analyses .................................................... 150 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 8 of 219 
CONFIDENTIAL  
 
 
9.4.1.2 
Primary Analysis ................................................... 151 
9.4.1.3 
Final Analysis ........................................................ 151 
9.4.2 
Methods of Analyses ............................................................... 151 
9.4.2.1 
General Considerations ......................................... 151 
9.4.2.2 
Efficacy Analyses .................................................. 152 
9.4.2.3 
Safety Analyses .................................................... 152 
9.4.2.4 
Other Analyses ...................................................... 154 
10. 
References ......................................................................................................... 155 
11. 
Appendices ......................................................................................................... 159 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 160 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 166 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 169 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 177 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 188 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 194 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 196 
11.8 
Appendix 8.  Additional Guidance for Tumor Lysis Syndrome ................. 200 
11.8.1 
Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor 
Lysis Syndrome (TLS) ............................................................. 200 
11.8.2 
Cairo-Bishop Definition of Laboratory Tumor Lysis 
Syndrome ................................................................................ 203 
11.8.3 
Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading ............................................................. 203 
11.9 
Appendix 9.  International Myeloma Working Group Uniform 
Response Criteria for Multiple Myeloma (IMWG-URC) ............................ 204 
11.10 Appendix 10.  ECOG Performance Status and NYHA 
Classification ........................................................................................... 206 
11.11 Appendix 11.  Medications That may Cause QTc Prolongation ............... 207 
11.12 Appendix 12.  Definition of Relapsed or Refractory Progressive 
Disease and Line of Therapies ................................................................ 210 
11.13 Appendix 13.  Peripheral Neuropathy Assessment .................................. 212 
11.14 Appendix 14.  World Health Organization Classification for Acute 
Myeloid Leukemia ................................................................................... 213 
11.15 Appendix 15.  European LeukemiaNet (ELN) Response Criteria 
in Acute Myeloid Leukemia (2017) .......................................................... 215 
11.16 Appendix 16.  Modified Toxicity Probability Interval Design ..................... 217 
 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 9 of 219 
CONFIDENTIAL  
 
 
List of Tables 
Table 1-1.  AMG 176 Dosing Schedule.......................................................................... 19 
Table 1-2.  Schedule of Activities:  Part 1a (Multiple Myeloma BIW) and 
Part 3a (AML BIW) ................................................................................. 33 
Table 1-3.  Schedule of Activities:  Part 1b (Multiple Myeloma QW), Part 3b 
(AML QW; Cohorts 1-3 Only), and Part 3c (AML QW in Japan) .............. 37 
Table 1-4.  Schedule of Activities:  Part 3d (AML in United States) DDI 
Assessment With Itraconazole ................................................................ 41 
Table 1-5.  Schedule of Activities:  Parts 4 (Cohorts 1-4 Only) and 5A (AML) 
AMG 176 QW in Combination With Azacitidine ....................................... 42 
Table 1-6.  Schedule of Activities:  Parts 4 (Cohorts 5a and 5b Only) and 5A 
(AML) AMG 176 BIW in Combination With Azacitidine ........................... 45 
Table 1-7.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – 
Regimen 1 (Days 1 Through 3 In Week 1 And BIW In Weeks 2 
And 3 Only) ............................................................................................ 47 
Table 1-8.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – 
Regimen 2 (Days 1 Through 5 In Week 1 and BIW 
In Week 2 Only) ...................................................................................... 50 
Table 1-9.  Schedule of Activities Notes and Abbreviation Definitions ........................... 53 
Table 2-1.  Study 20150161 Best Overall Response – Acute Myeloid 
Leukemia ................................................................................................ 67 
Table 4-1.  Overview of Study Design............................................................................ 77 
Table 4-2.  Guidelines for Dose-level Decisions for Part 3b and Part 4 .......................... 81 
Table 6-1.  DLT Criteria ............................................................................................... 112 
Table 6-2.  Azacitidine Hematology Dose-Reduction Guidance ................................... 123 
Table 6-3.  Azacitidine Dose Reduction Based on Bone Marrow Cellularity ................. 124 
Table 9-1.  Summary of Interim Analyses .................................................................... 150 
Table 11-1.  Analyte Listing ......................................................................................... 167 
Table 11-2.  Expected Disease-related Events by System Organ Class (SOC) 
for Multiple Myeloma............................................................................. 186 
Table 11-3.  Expected Disease-related Events by System Organ Class (SOC) 
for Acute Myeloid Leukemia .................................................................. 187 
Table 11-4.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 197 
Table 11-5.  True Probability of DLT by Scenario for Simulated Studies 
Estimating MTD for Part 3b................................................................... 218 
Table 11-6.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using the mTPI Design for Part 3b ....................... 218 
Table 11-7.  True Probability of DLT by Scenario for Simulated Studies 
Estimating MTD for Part 4 .................................................................... 218 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 10 of 219 
CONFIDENTIAL  
 
 
Table 11-8.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using the mTPI Design for Part 4 ......................... 219 
List of Figures 
Figure 1-1.  Overall Study Design and Treatment Schema ............................................ 22 
Figure 1-2.  Study Design and Treatment Schema – Multiple Myeloma 
Part 1a AMG 176 BIW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) ............................................................... 23 
Figure 1-3.  Study Design and Treatment Schema – Multiple Myeloma 
Part 1b AMG 176 QW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) ............................................................... 24 
Figure 1-4.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 3a AMG 176 BIW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) ............................................................... 25 
Figure 1-5.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 3b AMG 176 QW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) ............................................................... 26 
Figure 1-6.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 3c AMG 176 QW Monotherapy Dose Escalation in Japan 
(COMPLETED) ....................................................................................... 27 
Figure 1-7.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 3d – DDI Assessment With Itraconazole in the United 
States ..................................................................................................... 28 
Figure 1-8.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 4 AMG 176 QW and BIW in Combination With Azacitidine 
(DOSE EXPLORATION) ......................................................................... 29 
Figure 1-9.  Study Design and Treatment Schema – Acute Myeloid Leukemia 
Part 5A AMG 176 QW or BIW in Combination With Azacitidine 
(DOSE EXPANSION) ............................................................................. 30 
Figure 1-10.  Study Design and Treatment Schema – Acute Myeloid 
Leukemia Part 5B AMG 176 Conventional Dosing .................................. 31 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 183 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 192 
 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 11 of 219 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or 
Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid 
Leukemia 
Study Phase:  1 
Indication:  Multiple myeloma (MM) and acute myeloid leukemia (AML) 
Rationale 
Acute Myeloid Leukemia (AML) is a clonal disorder characterized by ineffective 
hematopoiesis and an accumulation of abnormal blasts in the bone marrow 
(Albitar et al, 2002; Doll and List, 1989).  The combination of azacitidine and venetoclax 
represents the current standard frontline therapy for newly diagnosed patients 
considered unfit for intensive chemotherapy due to either age or medical comorbidity 
(DiNardo et al, 2020).  While remission rates and median overall survival (OS) represent 
a significant improvement compared to prior therapy, the regimen is not curative.  
Primary resistance may occur, with a mean OS of less than 3 months observed for 
patients upon relapse (Prebet et al, 2011; Jabbour et al, 2010; Fenaux et al, 2009).  
Recent studies demonstrate that the myeloid cell leukemia sequence 1 (MCL1) protein, 
an intrinsic anti-apoptotic protein within the B-cell lymphoma/leukemia 2 (BCL2) family, 
may drive the resistance to BCL2 inhibition by venetoclax.   
The upregulation of MCL1 has been described in many human malignant subtypes, 
including AML and myelodysplastic syndromes (MDS) (Fischer et al, 2023; 
Caenepeel et al, 2018), highlighting MCL1 as a promising target for the next generation 
of therapy for these malignancies.  MCL1-dependency was observed in AML mouse 
models as well as in human AML-derived cell lines (Glaser et al, 2012), and inhibition of 
MCL1 induced leukemic cell death in these models.  Preclinical investigations have also 
demonstrated that MCL1 inhibition synergizes with standard of care (SOC) therapy and 
increases antileukemic activity by sensitizing leukemic cells towards apoptosis 
(Kelly et al, 2014; Phillips et al, 2015; Caenepeel et al, 2018).  As evidence of this, 
combination of MCL1 inhibition with venetoclax overcomes BCL2 inhibitor resistance 
and is active in venetoclax-resistant cell lines and patient samples (Zhang et al, 2020).  
In the current study, AMG 176, an MCL1 inhibitor, is combined with azacitidine to 
overcome treatment resistance in subjects with relapsed or refractory AML.  In support 
of this expectation, preliminary efficacy results demonstrate clinical responses in 
subjects previously treated and refractory to azacitidine and venetoclax therapy 
(see Table 2-1).   
In this study, Part 1 and Part 2 were initially designed to investigate AMG 176 as 
monotherapy and combinational therapy in subjects with multiple myeloma (MM).  As of 
December 2019, 48 subjects were enrolled in Part 1 where clinical responses were 
observed at dose levels > 240 mg/m².  However, AMG 176 associated elevations of 














Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 18 of 219 
CONFIDENTIAL  
 
 
CLOSED TO ENROLLMENT:  Multiple myeloma Part 1a enrolled 36 subjects for dose 
escalation.  Multiple myeloma Part 1b enrolled 12 subjects for dose escalation.  Acute 
myeloid leukemia Part 3a enrolled 17 subjects for dose escalation.  Part 3b enrolled 
11 subjects.  Acute myeloid leukemia Part 3c enrolled 4 subjects in Japan. 
OPEN TO ENROLLMENT:  Part 3d will enroll about 11 subjects in the United States.  
Part 4 will enroll approximately 60 subjects.  Part 5 will enroll approximately 68 subjects.  
The rationale for the number of subjects required is detailed in Section 9.2. 
Summary of Subject Eligibility Criteria 
Multiple Myeloma 
Subjects  18 years of age with relapsed or refractory MM. 
Subjects must have a pathologically documented, definitively diagnosed, MM relapse or 
refractory PD and have received at least 2 therapeutic treatments or regimens for MM.   
Subjects must have measurable disease per the International Myeloma Working Group 
(IMWG) response criteria.   
Acute Myeloid Leukemia 
Subjects  18 years of age with AML as defined by the World Health Organization 
(WHO) Classification (Section 11.14) persisting or recurring following 1 or more 
treatment courses except acute promyelocytic leukemia (APL).  The investigator must be 
of the opinion that no other treatment option will result in a durable response (DR).  In 
Part 5A cohorts 1 and 2, enrollment will be restricted to subjects with persisting or 
recurring AML ≤ 2 prior lines of therapy.   
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2.   
Treatments 
AMG 176 will be supplied as either a 10 mL liquid deliverable volume in a single use 
(20 R) glass vial or a 14.4 mL liquid deliverable volume in a single use (30 R) glass vial.  
Vials are to be stored at temperatures at or below 25ºC and protected from light.  
AMG 176 is formulated as a sterile solution for infusion at a concentration of 25 mg/mL 
in 10% w/w 2-hydroxypropyl beta-cyclodextrin, buffered with 100 mM glycine to pH 9.0.  
The AMG 176 drug product is diluted in normal saline prior to infusion.  AMG 176 is 
administered as an intravenous (IV) infusion on a 28-day cycle as per the schedules 
shown in Table 1-1.   


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 19 of 219 
CONFIDENTIAL  
 
 
Table 1-1.  AMG 176 Dosing Schedule  
 
AMG 176 dosing (IV infusion on a 28-day cycle) 
Part 1b, 3b, 3c, 3d, and 4 
(cohort 1 through 4) 
QW, day 1 of every week of the 28-day cycle 
Part 4 (cohorts 5a and 5b) 
BIW, days 1 and 2 each week for the first 3 weeks of 
each 28-day cycle 
Part 3d 
QW for 3 weeks only, after which subjects may crossover 
to Part 3b or Part 4 for continued treatment if approved 
by the investigator and Amgen medical monitor 
Part 5A (cohorts 1 and 2) 
QW or BIW 
Part 5B 
Regimen 1:  Day 1 - 3 (3 consecutive days) the first 
week, and BIW on weeks 2 and 3 each cycle in the first 
6 subjects.  If this schedule is deemed safe by the DLRT, 
the next 6 subjects will receive Regimen 2 
Regimen 2:  Day 1 - 5 (5 consecutive days) the first 
week, and BIW dosing week 2 for each cycle 
BIW = twice weekly; DLRT = dose-level review team; IV = intravenous; QW = once weekly 
 
Procedures 
After written informed consent has been obtained, all screening tests and procedures will 
be performed within 14 days of administration of the first dose of AMG 176 (day 1), or 
itraconazole (ie, day -17 to day -3) for Part 3d, unless otherwise noted.  Subjects will be 
seen in clinic where critical clinical safety and study evaluations will be performed 
including physical examination, vital signs, clinical laboratory tests, electrocardiograms 
(ECGs), PK, and 
r sample collections and disease assessments. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 
Statistical Considerations 
All subjects who are enrolled and receive at least 1 administration of the investigational 
product (AMG 176) will be included in the Full Analysis Set (FAS).  The analyses will be 
performed on FAS, unless otherwise specified.  The analyses of DLT will include only 
DLT-evaluable subjects.   
Descriptive statistics will be provided for selected demographics, safety, PK, PD and 
 data by dose, dose schedule, and time as appropriate.  Descriptive statistics 
on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may also be presented.   
The proportion of subjects with overall response per IMWG criteria for MM subjects or 
with complete remission per 2017 ELN criteria for AML subjects with corresponding 
2-sided exact 95% CI will be calculated using the Clopper-Pearson method 
(Clopper and Pearson, 1934).   


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 20 of 219 
CONFIDENTIAL  
 
 
For a full description of statistical analysis methods, please refer to Section 9.   
Statistical Hypotheses 
At least 1 dose level of AMG 176 administered as monotherapy will achieve acceptable 
safety and tolerability in subjects with relapsed or refractory MM with evidence of 
biologic impact as shown by either evidence of reduction in MCL1 activity in circulating 
monocytes/circulating blasts and/or evidence of anti-tumor activity.   
At least 1 dose level of AMG 176 administered as a monotherapy or in combination with 
azacitidine will achieve acceptable safety and tolerability in subjects with relapsed or 
refractory AML with evidence of biologic impact, as shown by either evidence of 
reduction in MCL1 activity in circulating monocytes/circulating blasts and/or evidence of 
anti-tumor activity.   
Dose Optimization Plan to inform Recommended Phase 2 Dose (RP2D) for the 
Combination of AMG 176 with Azacitidine 
The data to date support a monotherapy MTD of 360 mg/m² and a monotherapy 
recommended phase 2 dose (RP2D) of 240 mg/m² for AMG 176.  Given the limited 
monotherapy activity, further development has since proceeded utilizing combination 
therapy of AMG 176 with azacitidine.  Preclinical models have demonstrated synergistic 
anticancer activity with this combination.   
The RP2D for the combination of AMG 176 with azacitidine (here from referred to as the 
“combination RP2D”) will be estimated using the totality of data from across the 
first in human (FIH) study, including the PK, safety, efficacy, PD 
 for efficacy, 
and other results from the dose escalation and dose expansion.  
Dose-exposure-response analyses for safety and efficacy will be conducted to inform the 
combination RP2D.   
Two dose levels will be selected for the expansion phase based on the preliminary 
dose-exposure–response analyses and PK/PD modeling using available data from 
preclinical and dose escalation phase.  In order to minimize bias, assignments will be 
randomized to each dose level in Part 5A.  Pharmacokinetic exposure separation, 
minimal dose expected to achieve efficacy, highest dose with acceptable safety profile 
and other aspects will be considered for dose selection of the expansion phase.   
AMG 176 has exhibited a predictable PK/PD profile.  Based on the available data from 
the dose escalation part of Study 20150161, preliminary dose-exposure analyses 
indicated dose-related increases in exposure with mean terminal elimination half-life (t½) 
of approximately 4 to 23 hours in AML subjects.  Preliminary dose-exposure-response 
analyses in subjects with relapsed or refractory (R/R) MM and in subjects with R/R AML 
demonstrated no concerning safety signals, including troponin elevations, at AMG 176 
doses of 240 mg/m² or less (QW or BIW) when administered as monotherapy or in 
combination with azacitidine.  Preliminary efficacy is observed at a range of dose levels 
from 60 to 240 mg/m² AMG 176 monotherapy and in combination with azacitidine in 
AML subjects.   


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 21 of 219 
CONFIDENTIAL  
 
 
Further dose-exposure-response analyses and PK/PD modeling based on the totality of 
data (PK, safety, efficacy, PD 
 for efficacy), using all data from dose escalation 
and dose expansion, will be conducted to develop robust dose-exposure-response 
relationships to guide the selection of the combination RP2D (the dose that achieves 
maximum efficacy with acceptable toxicity in the target AML population). 
Sponsor Name: 
 Amgen, Inc. 
 




Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 23 of 219 
CONFIDENTIAL  
 
 
Figure 1-2.  Study Design and Treatment Schema – Multiple Myeloma Part 1a AMG 176 BIW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) 
 
BIW = twice weekly; IV = intravenous; MTD = maximum tolerated dose. 
a  Enrolled 36 subjects.  A standard 3+3 design will be used to identify the MTD or recommended dose. 
b  Ramp-up dosing in cycle 1 will be utilized whenever the target dose level is at 180 mg/m² or higher (cohort 7 or higher).  Ramp-up dosing consists of an initial dose at 
cycle 1 week 1 of 120 mg/m2 followed by an increase to the target dose level for subsequent doses. 
c  AMG 176 will be administered in monthly cycles of treatment.  Each cycle AMG 176 BIW is defined as an IV infusion once daily for two consecutive days followed by 
a 5-day break and repeated each week for 3 weeks followed by one week with no treatment. 
d  A safety follow-up visit will take place 30 days (+3 days) after the last dose of protocol-required therapies. 
e  Long-term follow-up assessments will occur every 3 months ( 14 days) after end of treatment (EOT) for 1 year. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 24 of 219 
CONFIDENTIAL  
 
 
Figure 1-3.  Study Design and Treatment Schema – Multiple Myeloma Part 1b AMG 176 QW Monotherapy Dose Escalation 
(CLOSED TO ENROLLMENT) 
  
IV = intravenous; MTD = maximum tolerated dose; QW = once weekly. 
a  Enrolled 12 subjects.  A standard 3+3 design will be used to identify the MTD or recommended dose. 
b  The starting dose level will be 180 mg/m2 QW.  AMG 176 will be administered in monthly cycles of treatment.  Each cycle AMG 176 QW is defined as an IV infusion 
once weekly followed by a 6-day break and repeated each week for 3 weeks followed by one week with no treatment. 
c  Ramp-up dosing in cycle 1 will be utilized whenever the target dose level is at 180 mg/m2 or higher.  Ramp-up dosing consists of an initial dose at cycle 1 week 1 of 
120 mg/m2 followed by an increase to the target dose level for subsequent doses. 
d  A safety follow-up visit will take place 30 days (+3 days) after the last dose of protocol-required therapies. 
e  Long-term follow-up assessments will occur every 3 months ( 14 days) after end of treatment (EOT) for 1 year. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 25 of 219 
CONFIDENTIAL  
 
 
Figure 1-4.  Study Design and Treatment Schema – Acute Myeloid Leukemia Part 3a AMG 176 BIW Monotherapy Dose 
Escalation (CLOSED TO ENROLLMENT) 
 
BIW = twice weekly; IV = intravenous 
a Enrolled 17 subjects.  A standard 3+3 design will be used to identify the maximum tolerated dose. 
b The starting dose level will be 60 mg/m2 BIW.  AMG 176 will be administered in monthly cycles of treatment.  Each cycle AMG 176 BIW is defined as an IV infusion 
once daily for two consecutive days followed by a 5-day break and repeated each week for 3 weeks followed by one week with no treatment. 
c Ramp-up dosing in cycle 1 will be utilized whenever the target dose level is at 180 mg/m2 or higher.  Ramp-up dosing consists of an initial dose at cycle 1 week 1 of 
120 mg/m2 followed by an increase to the target dose level for subsequent doses. 
d A safety follow-up visit will take place 30 days (+3 days) after the last dose of protocol-required therapies. 
e Long-term follow-up assessments will occur every 3 months ( 14 days) after end of treatment (EOT) for 1 year. 




Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 27 of 219 
CONFIDENTIAL  
 
 
Figure 1-6.  Study Design and Treatment Schema – Acute Myeloid Leukemia Part 3c AMG 176 QW Monotherapy Dose 
Escalation in Japan (COMPLETED) 
 
IV = intravenous; PD = pharmacodynamics; PK = pharmacokinetics; QW = once weekly 
a  Enrolled 4 subjects.  A standard 3+3 design without dose escalation will be used to evaluate the safety, tolerability, PK, and PD of AMG 176 administered QW in AML 
subjects in Japan. 
b  AMG 176 will be administered in monthly cycles of treatment.  Each cycle AMG 176 QW is defined as an IV infusion once weekly followed by a 6-day break and 
repeated each week for 4 consecutive weeks. 
c  A safety follow-up visit will take place 30 days (+3 days) after the last dose of protocol-required therapies. 
d  Long-term follow-up assessments will occur every 3 ( 14 days) months after end of treatment (EOT) for 1 year. 












Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 33 of 219 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Part 1a (Multiple Myeloma BIW) and Part 3a (AML BIW) 
 
Page 1 of 4 
See Table 1-9 or assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 34 of 219 
CONFIDENTIAL  
 
 
 
 
Page 2 of 4 
  See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 35 of 219 
CONFIDENTIAL  
 
 
 
 
Page 3 of 4 
  See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 36 of 219 
CONFIDENTIAL  
 
 
 
 
Page 4 of 4 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 37 of 219 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1b (Multiple Myeloma QW), Part 3b (AML QW; Cohorts 1-3 Only), and Part 3c (AML QW 
in Japan) 
 
Page 1 of 4 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 38 of 219 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1b (Multiple Myeloma QW), Part 3b (AML QW; Cohorts 1-3 Only), and Part 3c (AML QW 
in Japan) 
 
Page 2 of 4 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 39 of 219 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1b (Multiple Myeloma QW), Part 3b (AML QW; Cohorts 1-3 Only), and Part 3c (AML QW 
in Japan) 
 
Page 3 of 4 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 40 of 219 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Part 1b (Multiple Myeloma QW), Part 3b (AML QW; Cohorts 1-3 Only), and Part 3c (AML QW 
in Japan) 
 
Page 4 of 4 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 41 of 219 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Part 3d (AML in United States) DDI Assessment With Itraconazole 
 
See Table 1-9 for assessment notes and abbreviation definitions. 
Screen
Cycle
Cycle ≥ 2
Weeks
Week ≥ 5
Days
D-17 to D-3 D-3
D-2
D-1
D2
D3
D4
D9
D16 D17 D22
Hours (relative to start of dosing)
 pre-dose
0
EOI
3
4
5
7
8 12
24h after D1
48h after D1
72h after D1
 pre-dose
0
EOI
3
5
7
8 12
24h after D8
 pre-dose
0
 EOI
3
5
7
8
24h after D15
48h after D15
168h after D15
Informed consent
X
Clinical evaluation
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECHO/MUGA
X
X
X
Hospitalization
TLS prophylaxis 
X
X
Prior / Concomitant medication reporting
Adverse event reporting
X
Serious adverse event reporting
AMG 176 dosing 
X
X
X
Itraconazole dosing
X
X
X
X
X
X
X
Safety lab tests
X
X
X
X
X
X
TLS test monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac monitoring tests
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X
X
Hepatitis serology
X
AMG 176 PK 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bone marrow aspirate/biopsy
X
Bone marrow aspirate/biopsy
X
X
Peripheral blood count
X
X
X
X
X
X
X
For subjects 
that do not 
crossover
GENERAL AND SAFETY ASSESSMENT
EOT
SFU
D1
D8
D15
Treatment
Cycle 1
W1
W2
LTFU / EOS
W3
W4
For subjects that 
crossover:  Follow 
time points and 
assessments in 
Table 1-5 or     
Table 1-6, as 
applicable to 
crossover, starting 
after Week 3. 
(Note :  the AMG 
176 PK sample 
must be collected 
168 hours after 
the day 15 dose 
as part of Part 
3d).
Hospitalization
Hospitalization
DISEASE ASSESSMENTS
X
X
STUDY TREATMENT
LABORATORY ASSESSMENTS 
X
Local Labs
Central Labs


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 42 of 219 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Parts 4 (Cohorts 1-4 Only) and 5A (AML) AMG 176 QW in Combination With Azacitidine 
Note:  Timepoints shown in the schedule of activities are relative to start of dosing of the corresponding treatment:  AMG 176 or azacitidine.   
 
Page 1 of 3 
See Table 1-9 for assessment notes and abbreviation definitions. 
Screen
Cycle
Weeks
Days
D-14 to D0
D2
D3-7
D9
D16
D23
Hours (relative to start of dosing)
 pre-dose
0
5m
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
Informed consent
X
Clinical evaluation
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
12-lead ECG
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/MUGA
X
X
Hospitalization
TLS prophylaxis 
X
X
Prior / Conmeds reporting
AE / SAE reporting
AMG 176 dosing 
X
X
X
X
Azacitidine dosing
X
X
X
Local Labs
Safety lab tests
X
X
X
X
X
TLS test monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac monitoring tests
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
Hepatitis serology
X
LABORATORY ASSESSMENTS 
Hospitalization
Hospitalization
Prior & Concomitant Medications Reporting
AE & SAE Reporting
STUDY TREATMENT
1
2
Treatment
Cycle 1
3
4
D1
D8
D15
D22
GENERAL AND SAFETY ASSESSMENT


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 43 of 219 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Parts 4 (Cohorts 1-4 Only) and 5A (AML) AMG 176 QW in Combination With Azacitidine 
Note:  Timepoints shown in the schedule of activities are relative to start of dosing of the corresponding treatment:  AMG 176 or azacitidine.   
 
Page 2 of 3 
See Table 1-9 for assessment notes and abbreviation definitions. 




Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 45 of 219 
CONFIDENTIAL  
 
 
Table 1-6.  Schedule of Activities:  Parts 4 (Cohorts 5a and 5b Only) and 5A (AML) AMG 176 BIW in Combination With 
Azacitidine 
 
Page 1 of 2 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 46 of 219 
CONFIDENTIAL  
 
 
Table 1-6.  Schedule of Activities:  Parts 4 (Cohorts 5a and 5b Only) and 5A (AML) AMG 176 BIW in Combination With 
Azacitidine 
 
Page 2 of 2 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 47 of 219 
CONFIDENTIAL  
 
 
Table 1-7.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – Regimen 1 (Days 1 Through 3 In Week 1 And BIW 
In Weeks 2 And 3 Only)  
 
Page 1 of 3 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 48 of 219 
CONFIDENTIAL  
 
 
Table 1-7.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – Regimen 1 (Days 1 Through 3 In Week 1 And BIW 
In Weeks 2 And 3 Only) 
 
Page 2 of 3 
See Table 1-9Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 49 of 219 
CONFIDENTIAL  
 
 
Table 1-7.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – Regimen 1 (Days 1 Through 3 In Week 1 And BIW 
In Weeks 2 And 3 Only) 
 
Page 3 of 3 
See Table 1-9 for assessment notes and abbreviation definitions. 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 50 of 219 
CONFIDENTIAL  
 
 
Table 1-8.  Schedule of Activities:  Part 5B (AML) Conventional Dosing – Regimen 2 (Days 1 Through 5 In Week 1 and BIW 
In Week 2 Only)  
Page 1 of 3 
See Table 1-9 for assessment notes and abbreviation definitions. 
Screen
Weeks in Cycle
Days
D-14 to D0
D10
D17
D24
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 D5 doing
48h after D5 doing
 pre-dose
0
EOI
3
4
5
7
8
12
24h after D8/pre-dose
0
 EOI
3
4
5
7
8
12
24h after D9
 pre-dose
0
 EOI
8
 pre-dose
0
EOI
8
24h after D16
 pre-dose
0
 EOI
8
 pre-dose
0
EOI
8
24h after D23
Informed consent
X
Clinical evaluation
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X X
X X X
X
X
X X X
X
X
X X
X X X X X
X X
X X X X
X
X
X X X
X X
X
X
X X X
X X
X
ECHO/MUGA
X
X
X
Hospitalization
TLS prophylaxis 
X
X
X
X
Prior / Conmed reporting
AE / SAE reporting
Subsequent anti-cancer therapy & Survival
AMG 176 dosing 
X
X
X
X
Azacitidine dosing
X
X
X
X
Safety lab tests
X
X
X
X
X
X
X
X
X
TLS monitoring test 
X
X
X
X
X X X
X
X
X X X X X
X
X
X X X
X
X
X X
X
X
X
X
X
Cardiac monitoring tests
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X X
X
X
Pregnancy test
X
X
Hepatitis serology
X
AMG 176 PK
X
X X
X X
X
X X
X X
X X X
X X
X X
X
X X
X X
X
Azacitidine PK
X
X
X
X
X
X
X
X
X
X
Bone marrow aspirate/biopsy
X
Peripheral blood count 
X
X
X
X
X
Overall disease response
D16
D22
Treatment Cycle 1
W1
W2
W3
W4
D1
D2-5
Assessed and documented at every cycle and at time of PD
LABORATORY ASSESSMENTS 
Local Labs
Central Labs
DISEASE AND IMAGING ASSESSMENTS
D23
GENERAL AND SAFETY ASSESSMENT
Hospitalization days (Days 1 through 4)
Prior & Concomitant Medications Reporting
AE & SAE Reporting
STUDY TREATMENT
D6-7
D8
D9
D15






Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
Page 53 of 219 
CONFIDENTIAL  
 
 
Table 1-9.  Schedule of Activities Notes and Abbreviation Definitions 
Clinical evaluations:  Physical exam, ECOG status, and weight will be collected pre-dose on dosing days.  Medical and surgical history, height and 
neuropathy assessment (for MM subjects only) need only be collected at the screening visit.  Prior to dosing on day 1 of every cycle, BSA must be 
calculated. 
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 approximately 15 minutes apart (± 5 minutes), with each baseline ECG in 
triplicate 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) for 
a total of 9 ECGs 
Cycles 1 through 4:  Triplicate ECGs run consecutively (ie, all 3 ECGs should be started with ± 5 minutes of infusion and 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  
For Part 4 Cohorts 5a and 5b as well as Part 5A, 12-lead ECG assessments for C1D4 through D7 are optional based on investigator discretion. 
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 4 weeks of C1D1 as part of standard of care, 
then it does not have to be repeated during screening as long as the same modality is used throughout the study.  During LTFU and ECHO/MUGA 
is only required at the first LTFU visit. 
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 for subjects on the AMG 176 QW schedule (Parts 1b, 3b, 
and 4) or post second dose of AMG 176 for subjects on the BIW schedule (Parts 1a and 3a).  Hospitalization period can be increased per 
institutional standards or investigators discretion. 
TLS Prophylaxis:  See Section 6.1.4.1 for prophylaxis requirements including additional serum chemistry and hematology laboratory samples that 
must be collected within 24 hours prior to the first dose, and electrolyte values must be within normal range prior to AMG 176 dosing.  
Hospitalization for the purpose of TLS prophylaxis will not be captured as a Serious Adverse Event (SAE). 
Peripheral Neuropathy Assessment:  For MM subjects a peripheral neuropathy assessment will be performed at screening, on treatment if clinically 
indicated and then at the SFU visit.  A neurological examination does not need to be performed by a neurologist, but should be performed by a 
qualified professional with knowledge and experience performing a neurological exam.   
Patient Interview Substudy – Parts 3b, 4, and 5:  Approximately 10 AML subjects from Parts 3b, 4, and 5 at select sites in countries where English is 
the primary language will be asked to participate in a Patient Interview Substudy (one 60-minute interview).  The interview will take place as soon as 
possible after the completion of cycle 1, excluding days on which AMG 176 is administered and days on which subjects are hospitalized. 
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Table 1-9.  Schedule of Activities Notes and Abbreviation Definitions (continued) 
AMG 176 dosing:  AMG 176 will be administered IV BIW (day 1 and 2, Weeks 1, 2, and 3) or QW (day 1, Weeks 1, 2, 3, [and 4]) depending on the 
Part and cohort the subject is enrolled in.  A ramp-up dose of 120 mg/m2 will be required if the target dose is  180 mg/m2.  AMG 176 will be infused 
for 2 hours ( 5 minutes). 
For Part 3d:  After week 3 subjects may crossover to Part 3b or Part 4 for continued treatment if approved by the investigator and Amgen medical 
monitor.  Subjects from Part 3d who crossover to Part 3b will not crossover (for a second time) to Part 4.  
For Part 5B (conventional dosing):  Dosing will be AMG 176 on 3 consecutive days the first week, and BIW on weeks 2 and 3 each cycle in the first 
6 subjects (regimen 1).  If this schedule is deemed safe by the DLRT, the next 6 subjects will receive AMG 176 on 5 consecutive days the first week, 
and BIW dosing week 2 for each cycle (Regimen 2).   
Azacitidine:  Azacitidine will be co-administered with AMG 176 to subjects enrolled in Parts 4 and 5.  Azacitidine will be administered at a dose of 
75 mg/m2 IV or SC daily for the first 7 days of a 28-day cycle. 
Oral itraconazole capsules (200 mg) will be given once daily (QD) for 7 days, starting at 8 am ( 1 hour) on day -3 through day 4 (last dose of 
itraconazole will be on day 4).  Itraconazole dosing on day 1 should be at approximately the same time ( 5 minutes) as the start of infusion of 
AMG 176. 
Safety Labs:  Safety labs include chemistry, hematology, urinalysis, and coagulation analytes.  See Table 11-1 for the list of analytes.  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). 
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.  For the BIW schedule, the D1 24-hour post-dose and the D2 pre-dose TLS monitoring 
test can be drawn at the same time.   
For Part 4 Cohorts 5a and 5b as well as Part 5A, TLS monitoring test for C1D4 through D7 are optional based on investigator discretion. 
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. 
For Part 4 Cohorts 5a and 5b as well as Part 5A, cardiac monitoring tests for C1D4 through D7 are optional based on investigator discretion. 
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Table 1-9.  Schedule of Activities Notes and Abbreviation Definitions (continued) 
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. 
PK:  PK samples should be collected at the exact nominal time point as noted.  Timepoints shown in the schedule of activities are relative to start of 
dosing of the corresponding treatment:  AMG 176 or azacitidine.  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.   
AMG 176 PK:  Samples collected and analyzed for AMG 176 at the timepoints indicated for cycle 1.  Note:  In the event that one or more additional 
step-doses are administered, PK should be collected at the following time points for the first two doses at the target dose:  pre-dose, EOI, hour 3, 
hour 5, hour 7, hour 8, and hour 12 relative to the start of the target doses.  All AMG 176 timepoints are relative to start of infusion. 
Azacitidine PK:  Samples collected and analyzed for azacitidine at pre-dose, EOI (10-40 min for IV or 30 min for SC), and 4 and 8 h after the start of 
IV infusion or following the SC dose of azacitidine. 
For Part 4 Cohorts 5a and 5b as well as Part 5A, AMG 176 PK assessments for C1D4 through D7 are optional based on investigator discretion.   
Optional Pharmacogenetics - saliva:  For subjects who consent to the pharmacogenomics portion of the study, a saliva sample will be collected for 
extraction of DNA.  These collections will not be requested for subjects in Japan.  
Multiple myeloma Disease Assessments:  Refer to Section 8.2.2.1 
AML Disease Assessments:  Refer to Section 8.2.2.2 
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 adverse event [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 subjects medical records.   
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Table 1-9.  Schedule of Activities Notes and Abbreviation Definitions (continued) 
LTFU/EOS:  Long-term follow-up (LTFU) visits will occur every 3 months ( 14 days) 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.  During LTFU, all SAEs that the investigator becomes aware of, regardless of 
whether they are or are not suspected to be related to the investigational product, will be reported to Amgen.  All serious adverse events (regardless 
of causality) shall be reported to Amgen immediately and no later than 24 hours after the investigator first becomes aware of the event. 
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 subjects’ 
medical records.   
AE  adverse event; ALT  alanine aminotransferase; AML  acute myeloid leukemia; ANC  absolute neutrophil count; AST  aspartate 
aminotransferase; BIW  twice weekly; BNP  B-type natriuretic protein; BSA  body surface area; CBC  complete blood count; CR  complete 
response; CT  computed tomography; CXDX  cycle X day X; D  day; ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern 
Cooperative Oncology Group; EOI  end of infusion; EOS  end of study; EOT  end of treatment; FDG  fluorodeoxyglucose; 
 
 
; G-CSF  granulocyte-colony stimulating factor; GGT  gamma-glutamyl transferase; h  hour; HBcAb  hepatitis B core antibody; 
HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCVAb  hepatitis C virus antibody; Ig  immunoglobulin; INR  international 
normalized ratio; LDH  lactate dehydrogenase; LFT  liver function test; LTFU  long-term follow-up; MCH  mean cell hemoglobin; MCHC  mean 
cell hemoglobin concentration; MCV  mean cell volume; min  minute; MM  multiple myeloma; MRD  minimal residual disease; 
MUGA  multigated acquisition scan; NaHep  sodium heparin; PBMC  peripheral blood mononuclear cell; PD  pharmacodynamics; 
PET  positron emission tomography; PK  pharmacokinetics; PT  prothrombin time; PTT  partial thromboplastin time; Q4W  every 4 weeks; 
Q8W  every 8 weeks; QTc  QT interval corrected; RBC  red blood cell; SAE  serious adverse event; SC  subcutaneous; Screen  Screening; 
SFLC  serum-free light chain; SFU  safety follow-up; SOA  schedule of activities; SPEP  serum protein electrophoresis; TBA  total bile acid; 
TLS  tumor lysis syndrome; UPEP  urine protein electrophoresis; W  week 
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Product:  AMG 176 
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2. 
Introduction 
2.1 
Study Rationale 
Acute Myeloid Leukemia (AML) is a clonal disorder characterized by ineffective 
hematopoiesis and an accumulation of abnormal blasts in the bone marrow 
(Albitar et al, 2002; Doll and List, 1989).  The combination of azacitidine and venetoclax 
represents the current standard frontline therapy for newly diagnosed patients 
considered unfit for intensive chemotherapy due to either age or medical comorbidity 
(DiNardo et al, 2020).  While remission rates and median overall survival (OS) represent 
a significant improvement compared to prior therapy, the regimen is not curative.  
Primary resistance may occur, with a mean OS of less than 3 months observed for 
patients upon relapse (Fenaux et al, 2009; Prebet et al, 2011; Jabbour et al, 2010).  
Recent studies demonstrate that the myeloid cell leukemia sequence 1 (MCL1) protein, 
an intrinsic anti-apoptotic protein within the B-cell lymphoma/leukemia 2 (BCL2) family, 
may drive the resistance to BCL2 inhibition by venetoclax.   
The upregulation of MCL1 has been described in many human malignant subtypes, 
including AML and myelodysplastic syndromes (MDS) (Fischer et al, 2023; 
Caenepeel et al, 2018), highlighting MCL1 as a promising target for the next generation 
of therapy for these malignancies.  MCL1-dependency was observed in AML mouse 
models as well as in human AML derived cell lines (Glaser et al, 2012), and inhibition of 
MCL1 induced leukemic cell death in these models.  Preclinical investigations have also 
demonstrated that MCL1 inhibition synergizes with standard of care (SOC) therapy and 
increases antileukemic activity by sensitizing leukemic cells towards apoptosis 
(Kelly et al, 2014; Phillips et al, 2015; Caenepeel et al, 2018).  As evidence of this, 
combination of MCL1 inhibition with venetoclax overcomes BCL2 inhibitor resistance 
and is active in venetoclax-resistant cell lines and patient samples (Zhang et al, 2020).  
In the current study, AMG 176, an MCL1 inhibitor, is combined with azacitidine to 
overcome treatment resistance in subjects with relapsed or refractory AML.  In support 
of this expectation, preliminary results demonstrate clinical responses in subject 
previously treated and refractory to azacitidine and venetoclax therapy (see Table 2-1).   
Patients with AML are susceptible to invasive fungal infections and often require 
prophylaxis and treatment with azole antifungal agents such as voriconazole and 
posaconazole (Halpern et al, 2015; Lat and Thompson, 2011), which are known to inhibit 
cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp).  Since AMG 176 may be 
metabolized by CYP3A4 and is a P-gp substrate, co-administration with inhibitors of 


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CYP3A4/P-gp may lead to increases in AMG 176 exposure.  As a result, clinical trials 
with AMG 176 prohibited the use of azole antifungal therapy and other medications that 
are strong CYP3A4/P-gp inhibitors.   
To answer the question of whether a drug-drug interaction (DDI) exists between azole 
and AMG 176 therapy, an assessment is planned in a separate cohort of AML subjects 
(Part 3d) to evaluate the effect of itraconazole, a strong CYP3A4 and P-gp inhibitor, on 
the pharmacokinetics of AMG 176.  Itraconazole was selected for this assessment as an 
index inhibitor of CYP3A that will allow extrapolation of results to other azole antifungal 
therapies (Chen et al, 2016; Liu et al, 2016; US FDA, 2016).  Analysis to date of this 
itraconazole interaction cohort (Part 3d) has thus far shown no prohibitive interaction 
between azoles antifungals and AMG 176, allowing for clinical use of azole antifungal 
therapy in subjects receiving AMG 176 (see Section 4.3.1.2.3).   
In this study, Part 1 and Part 2 were initially designed to investigate AMG 176 as 
monotherapy and combinational therapy in subjects with multiple myeloma (MM).  As of 
December 2019, 48 subjects were enrolled in Part 1 where clinical responses were 
observed at dose levels > 240 mg/m².  However, AMG 176 associated elevations of 
troponin were observed at dose levels of 360 and 480 mg/m² in MM subjects.  In 
contrast, clinical responses in AML were observed at the lower dose levels, indicating 
that AML may be more susceptible to MCL1 inhibition and can be treated with lower 
doses compared to subjects with MM.  The combination of these observations led to 
further development in AML and a pause in MM development for now.  Part 1 will remain 
closed to enrollment and Part 2 was removed from the protocol during Amendment 10.  
To avoid the potential for troponin elevations, only doses ≤ 240 mg/m² will be further 
investigated.  Additionally, preclinical data demonstrates that MCL1 inhibition is more 
efficacious in combination with other antileukemic therapies.  Consequently, 
combinational therapy will be prioritized in this study (Parts 4 and 5) to optimize the 
clinical benefit to subjects, and monotherapy dose escalation will be performed only to 
inform the combinational study, and not to confirm the likely monotherapy maximum 
tolerated dose (MTD) of 240 mg/m².  As of November 2022, 33 subjects have been 
enrolled in monotherapy (Part 3b:  11 subjects) and combination therapy (Part 4:  
22 subjects) cohorts at dose levels of ≤ 240 mg/m²; no concerning safety events 
(including elevations of troponin) and no Dose-Limiting Toxicities (DLTs) were observed. 


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2.2 
Background 
2.2.1 
Disease 
2.2.1.1 
Multiple Myeloma Background 
Multiple myeloma is a plasma cell neoplasia characterized by clonal proliferation of 
malignant plasma cells in the bone marrow microenvironment, production of a 
monoclonal protein present in the blood or urine and associated organ dysfunction 
(Palumbo and Anderson 2011).   
Multiple myeloma is the second most common (10-15% of all) hematological cancer.  
It is responsible for 15-20% of deaths from hematological cancer and about 2% cancer 
deaths.  Recent improved understanding of the pathogenesis of myeloma has led to the 
development of new treatments.  Survival is improving, with median OS in the range of 
7-10 years after initial diagnosis.  Nevertheless, myeloma remains an incurable cancer 
and with subsequent relapses the disease becomes refractory to current treatments.  
Therefore, relapsed or refractory MM is still an unmet medical need 
(Smith and Yong 2013). 
Myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma 
cells that are derived from post–germinal-center B cells.  Multistep genetic and 
micro-environmental changes lead to the transformation of these cells into a malignant 
neoplasm.  Myeloma is thought to evolve most commonly from a monoclonal 
gammopathy of undetermined clinical significance (usually known as MGUS) that 
progresses to smoldering myeloma and, finally, to symptomatic myeloma.  Several 
genetic abnormalities that occur in tumor plasma cells play major roles in the 
pathogenesis of myeloma (Palumbo and Anderson, 2011).   
The uncontrolled growth of myeloma cells has many consequences, including skeletal 
destruction, bone marrow failure, increased plasma volume and viscosity, suppression of 
normal immunoglobulin (Ig) production, and renal insufficiency (Durie, 2011).   
Symptomatic (active) disease should be treated immediately, whereas asymptomatic 
(smoldering) myeloma requires only clinical observation, since early treatment with 
conventional chemotherapy has shown no benefit.  Investigational trials are currently 
evaluating the ability of novel therapies to delay the progression from asymptomatic to 
symptomatic myeloma.  The treatment strategy is mainly related to age.  Current data 
would support the initiation of induction therapy with thalidomide, lenalidomide, or 
bortezomib-based regimens plus hematopoietic stem-cell transplantation for patients 
under the age of 65 years who do not have substantial heart, lung, renal, or liver 


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dysfunction.  Autologous stem-cell transplantation with a reduced-intensity conditioning 
regimen should be considered for older patients or those with coexisting conditions.  
Conventional therapy combined with thalidomide, lenalidomide, or bortezomib should be 
administered in patients older than 65 years of age.  Less intensive approaches that limit 
toxic effects or prevent treatment interruption that would reduce the intended treatment 
effect should be considered in patients over 75 years of age or in younger patients with 
coexisting conditions.  Biologic age, which may differ from chronologic age, and the 
presence of coexisting conditions should determine treatment choice and drug dose 
(Palumbo and Anderson, 2011; NCT03301220).  There are ongoing studies evaluating 
the additive effects of newer agents in first line therapy, including monoclonal antibodies 
and next generation proteasome inhibitors (Mateos et al, 2018; NCT02541383; 
NCT01335399; NCT0185052; NCT02252172; NCT02579863).   
Treatment of relapsed or refractory MM presents a special therapeutic challenge, due to 
the heterogeneity of disease at relapse and the absence of clear biological based 
recommendations regarding the choice of salvage therapies at various time points of 
disease progression.  With increasing recognition of the inherent clonal heterogeneity 
and genomic instability of the plasma cells influencing both inherent and acquired 
therapeutic resistance, the identification of the optimal choice and sequence of therapies 
has become critical.  Several new agents and targets are currently under development 
and show considerable promise.  Besides carfilzomib (proteasome inhibitor) and 
pomalidomide (immunomodulatory drug [IMiD]) that were granted approval by the United 
States (US) Food and Drug Administration (FDA) in 2012 and 2013, respectively, for 
relapsed or refractory MM, the proteasome inhibitor ixazomib received approval in 2015.  
Other newer treatment approaches also received approval in 2015, including monoclonal 
antibodies targeting SLAMF7 (ie, elotuzumab) or CD38 (ie, daratuzumab) 
(O’Donnell and Raje, 2017).  Despite advances in the management of MM as described, 
relapse is inevitable in almost all patients.  Recurrence of myeloma is typically more 
aggressive with each relapse, leading to the development of treatment-refractory 
disease, which is associated with a shorter survival (Dimopoulos et al, 2014).  As the 
approved agents move to earlier lines of therapy and in combination regimens, more 
treatment options are still warranted.   


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2.2.1.2 
Acute Myeloid Leukemia Background 
Acute myeloid leukemia is characterized by accumulation of abnormal blasts in bone 
marrow.  These cells disrupt normal hematopoiesis, thus contributing to the bone 
marrow failure that is the most common underlying cause of death.  The abnormal blasts 
can escape into the peripheral blood and may infiltrate organs.  Diagnosis is based on 
demonstration that the marrow or blood has > 20% blasts of myeloid origin 
(Estey, 2016).   
Acute myeloid leukemia represents approximately 90% of all acute leukemias in adults, 
and accounts for about 25% of all cases of leukemia diagnosed in the Western 
hemisphere (Hayat et al, 2007; Döhner et al, 2017).  In the United States (US), AML 
represents the most common form of acute leukemia in adults and causes approximately 
1.2% of all cancer deaths with an annual incidence rate of 2.2 per 100 000, or 
approximately 20 000 new cases per year.  Age adjusted incidence ranges from 
1 per 100 000 in people < 20 years to > 10 per 100 000 in the elderly.  Current induction 
chemotherapy protocols combining cytarabine and an anthracycline administered as 
first-line treatment induce remissions in a majority (55% to 75%) of patients.  Standard 
consolidation therapy with high doses of cytarabine leads to improved survival in 
younger patients.  However, up to 70% of patients relapse, and only 20% to 30% of 
patients attain a long-term disease-free survival (Döhner et al, 2017).  Azacitidine 
combined with venetoclax has become the standard frontline therapy for newly 
diagnosed patients who are older or unfit for intensive chemotherapy.  The ongoing 
phase 3 randomized control trial (VIALEA) of azacitidine with or without venetoclax in 
newly diagnosed AML subjects recently confirmed a significant survival benefit for the 
combination and solidified its status as the SOC (DiNardo et al, 2020).  While the 
remission rates and median OS all represent a significant improvement compared to 
prior therapy, the regimen is not curative.  Primary resistance does occur, and relapses 
are not infrequent.  Patients who progress despite venetoclax therapy have extremely 
poor outcomes, with no defined SOC and a median survival of 2.9 months with treatment 
and 1.4 months without treatment (Maiti et al, 2021).  Consequently, there is a high 
unmet need for new therapies in this population.  Preliminary data from this study as of 
06 September 2022 has shown responses in heavily treated refractory subjects, 
including in those previously exposed to BCL2 inhibitor venetoclax.   


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2.2.1.3 
Combination Therapy in Multiple Myeloma and Acute Myeloid 
Leukemia 
Both indications targeted in this study have well described genomic instability and clonal 
heterogeneity (Bianchi and Ghobrial, 2014; Ding et al, 2012).  In relapsed MM, the 
combination of three novel agents have proven to be superior to doublets in at least 
5 different randomized clinical trials (Dimopoulos et al, 2016; Moreau et al, 2016; 
Palumbo et al, 2016; Lonial et al, 2015; Stewart et al, 2015).  Similarly, it is expected that 
combination strategies in AML will allow for superior results than monotherapy 
approaches despite targeting dominant mutations (Wouters, 2017).  Because of these 
observations and with the desire to allow for expedient development of effective 
therapies for these grievous diseases, the proposed study will include evaluation of 
AMG 176 in monotherapy and selected combination therapies.   
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 B-cell 
receptor associated kinases (BAK), B-cell lymphoma/leukemia 2 associated X-protein 
(BAX), or the BCL2 homology 3 (BH3)-only protein family members, such as Bcl-2-
interacting mediator of cell death (BIM) and p53 up-regulated modulator of apoptosis 
(PUMA), are critical effectors for the induction of apoptosis.  Upon the induction of 
apoptotic stimuli, pro-apoptotic BH-3 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, mitochondrial outer membrane permeabilization (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 


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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 MM (Peperzak et al, 2013).  Myeloid cell leukemia sequence 1 is 
highly expressed in a variety of human tumors, and over-expression of MCL1 has been 
implicated in resistance to chemotherapy and to BCL2/B-cell lymphoma extra large 
(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.   
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 half maximal 
inhibitory concentration (IC50) of 0.241 nM.  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.  In cellular assays, AMG 176 disrupts the 
interaction between MCL1 and BAK with IC50 of 30.8 nM.  In cell viability studies 
performed in a panel of tumor cell lines derived from MM, AML and non-Hodgkin’s 
lymphoma AMG 176 exhibited IC50 values ranging from 14 nM to greater than 20 M, 
with IC50 values of less than 1 M observed in 13 of the 23 tested cell lines.  
In-vivo, AMG 176 treatment resulted in a dose-dependent inhibition of the interaction 
between MCL1 and BAK.  In pharmacodynamic (PD) studies, treatment with a single 
dose of AMG 176 resulted in a dose-dependent induction of multiple markers of 
apoptosis including activation of BAK, and the cleavage of caspase 3 and PARP in an 
OPM2-Luc MM tumor xenograft model.  In an OPM2-Luc tumor xenograft efficacy 
model, AMG 176 significantly inhibited the growth of established tumors, with tumor 
regression observed at 2 doses 30 and 60 mg/kg administered orally once daily (QD).  


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Additional studies were performed examining AMG 176 efficacy in an OPM2-Luc tumor 
xenograft model following an intermittent dosing schedule.  AMG 176 significantly 
inhibited the growth of established tumors at doses of 30 mg/kg on a 2-day on/5-day off 
(QD × 2) schedule or a 5-day on/2-day off schedule (QD × 5).  At doses of 60 mg/kg, 
regression of established tumors was observed with a 2 day on/5-day off (QD × 2) and a 
5-day on/2-day off (QD × 5) schedule.  Once weekly (QW) oral administration of 
AMG 176 significantly inhibited the growth of established OPM-2 MM tumor xenografts 
at doses of 50 mg/kg and 100 mg/kg, with 97% tumor growth inhibition observed at 
50 mg/kg and 70% tumor regression observed at 100 mg/kg respectively.   
Although single agent activity was observed in the preclinical experiments described 
above, the mechanism of action of AMG 176 is expected to allow for additive or 
synergistic effects when combined with agents that lead the malignant cell towards 
apoptosis.  With this hypothesis, combination studies with well-established therapeutic 
agents for MM and AML were conducted.   
In a cell viability study performed using OPM-2 cell line, the addition of different 
concentrations of dexamethasone to AM-8621 (an analog of AMG 176) led to a 1- to 
2.5-fold change in the IC50 values.   
The combination of AMG 176 and carfilzomib was tested in an orthotopic OPM-2 model 
of MM in which tumor cells were engrafted in the bone marrow of mice.  Daily 
administration of AMG 176 (20 mg/kg) combined with twice-weekly treatment with 
carfilzomib (3 mg/kg), achieved significant inhibition of tumor burden (99% reduction in 
bioluminescence imaging [BLI]), exceeding the effect achieved with either single agent 
alone (85% and 82% reduction in BLI with AMG 176 and carfilzomib, respectively).   
The combination of AM-8621 and the hypomethylating agent decitabine was tested 
across a panel of 4 AML cell lines (EOL1, GDM1, MOLM13 and MV-4-11) in a 72-hour 
viability assay.  A synergistic interaction was detected in each of the 4 cell lines with this 
combination.  Additionally, the combination of AM-8621 and decitabine was tested in 
primary AML patient samples where improvements in both potency and efficacy were 
observed over either single agent alone.   
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 (Q2W) off schedule (Caenepeel et al, 2018).  The combination of AMG 176 and the 
hypomethylating agent decitabine was also tested in the MOLM13 orthotopic AML 


Product:  AMG 176 
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CONFIDENTIAL  
 
 
xenograft model.  Mice were treated with the combination of AMG 176 at 30 mg/kg 
(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, 2019).   
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 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 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 µM and 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 (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 
DDIs by inhibition (eg, inhibition of CYP3A4 substrates), CYP3A4 induction and 
transporter mediated DDIs.   
2.2.2.3 
AMG 176 Nonclinical 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).  AMG 176 nonclinical safety studies 
consisted of an exploratory 14-day dog intravenous (IV) toxicology study, Good 


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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 Investigator’s Brochure). 
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 (see Section 4.3.2).  While no preclinical safety data 
exist for QW dosing, the BIW 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 a phase 1, FIH, multicenter, open-label, 
dose-expansion study (Study 20150161) in subjects with relapsed or refractory (R/R) 
AML.  For efficacy data in AML subjects, see Table 2-1.   
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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Table 2-1.  Study 20150161 Best Overall Response – Acute Myeloid Leukemia  
 
Part 3a 
AMG 176 
60 mg/m2 
BIW 
monotherapy 
(N = 6) 
Part 3a 
AMG 176 
120 mg/m2 
BIW 
monotherapy 
(N = 5) 
Part 3b 
AMG 176 
60 mg/m2 
QW + 
azacitidine 
(N = 5) 
Part 3b 
AMG 176 
120 mg/m2 
QW 
monotherapy 
(N = 5) 
Part 4 
AMG 176 
120 mg/m2 
QW + 
azacitidine 
(N = 4) 
Part 3b 
AMG 176 
180 mg/m2 
QW 
monotherapy 
(N = 5) 
Part 4 
AMG 176 
180 mg/m2 
QW + 
azacitidine 
(N = 4) 
Part 3b 
AMG 176 
240 mg/m2 
QW 
monotherapy 
(N = 4) 
Part 4 
AMG 176 
240 mg/m2 
QW + 
azacitidine 
(N = 6) 
Best overall response – n () 
CR without minimal residual 
disease (CRMRD-) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Complete remission (CR) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
CR with incomplete hematologic 
recovery (CRi) 
1 (17) 
1 (20) 
0 (0.0) 
0 (0.0) 
1 (25)a 
0 (0.0) 
0 (0.0) 
1 (25) 
2 (33)a 
Morphologic leukemia-free state 
(MLFS) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (20) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Partial remission (PR) 
1 (17) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (25) 
0 (0.0) 
0 (0.0) 
Stable disease (SD)b 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (20) 
2 (50) 
2 (40) 
1 (25) 
0 (0.0) 
1 (17)a 
Progressive disease (PD) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Missing 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
BIW = twice weekly; CRi = complete response/remission with incomplete recovery of peripheral blood counts; QW = once weekly;  
For AML = Best overall response is defined as the first response category achieved in the following order:  CRMRD-, CR, CRi, MLFS, PR, SD, PD.  Response criteria for AML are European 
LeukemiaNet Response Criteria. 
a  Active subjects with days on Study 160 to 448. 
b  Only SD > 100 days is included in this table. 
Data snapshot date:  September 2022. 
 


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2.3 
Benefit/Risk Assessment 
Based on nonclinical toxicity studies in AMG 176, early evidence of clinical activity, and 
clinical safety experience in the current study, the overall benefit/risk profile supports the 
further clinical development of AMG 176 in combination therapy for subjects with R/R 
AML.  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.  As of 01 August 2022, this study enrolled 44 subjects with relapsed or refractory 
AML.  Reference should be made to the Investigator’s Brochure (IB) for further data on 
AMG 176.   
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.   
2.3.1 
Key Benefits 
As AMG 176 is in early development and clinical experience is limited, key benefits are 
still being evaluated.   
Nearly all subjects have had prior exposure to venetoclax and azacitidine, with majority 
confirmed as refractory.  This population has a median OS of less than 3 months 
(Maiti et al, 2021).  These clinical responses documented in a heavily pretreated 
population demonstrate the synergistic capability of AMG 176 to overcome treatment 
resistance (Table 2-1).  These results support the potential of more robust clinical 
responses and improved outcomes with the addition of AMG 176 to other AML 
therapies.  
2.3.2 
Key Risks 
Based on biological plausibility, nonclinical toxicity studies of AMG 176, and clinical 
safety experience, tumor lysis syndrome (TLS) and increased troponins have been 
determined to be identified risks.   
Refer to Section 6.2 for dose modification guidelines for AMG 176 and azacitidine.   
2.3.2.1 
Tumor Lysis Syndrome 
Administration of AMG 176 has been associated with TLS including 1 subject with a fatal 
outcome out of 109 safety-evaluable subjects.  The BCL2 inhibitor venetoclax also 
carries an associated risk of TLS, suggesting this may represent a feature of 
antiapoptotic therapy.  Subjects with a high tumor burden or compromised renal function 
(eg, ISS Stage II/III) may be at elevated risk for TLS, which may further increase in the 
setting of combinational therapy with azacitidine due to the anticipated increase in 


Product:  AMG 176 
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CONFIDENTIAL 
 
 
 
antileukemic 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 for specific recommendations regarding the mitigation and management 
of TLS.   
2.3.2.2 
Increased Troponin 
Increased troponin elevations may occur with MCL-1 inhibition (Guo et al, 2018).  
Clinical experience to date from the FIH study of AMG 176 (Study 20150161) in subjects 
with R/R MM and in subjects with R/R AML demonstrated troponin elevations primarily 
at higher dose levels of 360 mg/m² and 480 mg/m² when administered as monotherapy, 
but neither cardiac toxicity nor concerning elevations were observed at doses of 
AMG 176 of 240 mg/m² or less when administered as monotherapy or in combination 
with azacitidine.  Mitigation measures for this study include monitoring troponin cardiac 
enzymes and electrocardiograms (ECGs).   
A cardiac monitoring plan has been implemented to mitigate the risk of cardiac toxicity.  
Refer to Section 11.2 (Appendix 2), Section 8.2.5.3, and Section 6.2 for specific 
information regarding the cardiac monitoring plan and dose modification guidelines, 
respectively.   
2.3.2.3 
Other Risk 
In addition to the 2 identified risks, potential risks for AMG 176 based on nonclinical 
findings include: 
 
gastrointestinal toxicity 
 
bone marrow toxicity 
 
male reproductive toxicity 
 
drug-drug interactions 
 
hepatobiliary toxicity 
 
cardiovascular toxicity (for details, see Section 2.2.2.3). 
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 IB for further description of potential risks. 










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Protocol Number:  20150161  
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CONFIDENTIAL 
 
 
 


Product:  AMG 176 
Protocol Number:  20150161  
Date:  13 July 2023 
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CONFIDENTIAL 
 
 
 
AML = acute myeloid leukemia; BIW = twice weekly; DLRT = dose level review team; IV = intravenous; 
MM = multiple myeloma; MTCD = maximum tolerated combination dose; MTD = maximum tolerated dose; 
mTPI = modified toxicity probability interval; PD = pharmacodynamics; PK = pharmacokinetics; QW = once 
weekly; RP2D = recommended phase 2 dose; SC = subcutaneous; US = United States 
 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 1, multicenter, open-label dose-escalation study to define the MTD or 
recommended dose and maximum tolerated combination dose (MTCD) as well as the 
safety, tolerability, PK, PD, and efficacy of AMG 176 administered as monotherapy or in 
combination with SOC. 
A dose-level review team (DLRT) will be responsible for dosing recommendations, which 
may include escalation to the next nominal or intermediate dose, de-escalation to a 
lower nominal or intermediate dose; modifications of the ramp-up dosing, alternative 
dose frequencies, continuation, delay or termination of dosing; or repetition or expansion 
of a cohort; or determination of recommended dose.  For definition of the DLT-evaluation 
period and DLT-evaluable subject refer to Section 6.2.1.2.1. 
Cycles of AMG 176 treatment may continue until confirmed progressive disease (PD) 
(defined by 2017 European LeukemiaNet [ELN] criteria for AML subjects 
[Section 11.15]), the subject becomes intolerant to the study medication, signs and 
symptoms of clinical progression are evident as determined by the principal investigator, 
or the subject withdraws consent.  Evaluation of disease response will be performed 
every 28 days ( 7 days) until PD irrespective of cycle duration including dose delays or 
treatment discontinuation.  The disease assessment schedule is independent of 
treatment schedules.   
Ramp-up dosing in cycle 1 will be utilized whenever the AMG 176 target dose level is at 
180 mg/m² or higher to mitigate the risk of TLS (see Section 6.1.1).   


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A safety follow-up (SFU) visit must be performed 30 days (+3 days) after the last dose of 
protocol-required therapies.  Long-term follow-up assessments will occur every 3 months 
( 14 days) after end of treatment (EOT) for 1 year and include survival, subsequent 
anti-cancer therapy, and any cardiac associated serious adverse event or studies 
performed.   
The overall study design is described by a study schema in Section 1.2.  An overview of 
the study design is presented in Table 4-1.  The endpoints are defined in Section 3.   
 








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4.1.1 
AMG 176 Monotherapy (Part 3b) and Combination with Azacitidine 
(Parts 4 and 5) for AML 
Part 3b (AML) will include weekly doses of AMG 176 monotherapy at 120, 180, and 
240 mg/m2 to inform the combinational therapy cohorts in Parts 4 and 5.  Clinical trial 
results from Part 1a and Part 1b demonstrated that dose levels of AMG 176 of less than 
or equal to 240 mg/m2 (Part 1a BIW; Part 1b QW) were not associated with increased 
troponin in contrast to the 360 mg/m2 dose level where 2 of 8 subjects experienced a 
DLT (troponin elevation).  Additionally, clinical responses in AML were observed at 
doses  240 mg/m2.  To avoid the potential for cardiac toxicity with the MTD of 
360 mg/m2, only doses  240 mg/m2 will be further investigated on this study, with this 
dose representing the monotherapy RP2D.  Additionally, preclinical data demonstrates 
that MCL1 inhibition is more efficacious in combination with other antileukemic therapies.  
Consequently, combinational therapy will be prioritized in this study to optimize the 
clinical benefit to subjects (Parts 4 and 5). 
Part 4 will start with AMG 176 60 mg/m2 in combination with azacitidine and will begin 
after completion of the 120 mg/m2 AMG 176 monotherapy cohort in Part 3b.  The 
decision to initiate enrollment in Part 4 will be made by the DLRT after the review of all 
available safety and tolerability data from the 120 mg/m2 AMG 176 monotherapy cohort.  
Following Part 4 (combination dose exploration), a dose expansion phase (Part 5) will be 
conducted in approximately 68 subjects to confirm safety, PK, and PD at the MTCD and 
to obtain additional safety and efficacy data. 
Additionally, dose levels lower than 30 mg/m2 may also be explored if required or 
supported by emerging data.  Intermediate doses and alternative dose frequencies may 
also be used if required or supported by emerging data.  For each part, DLTs will be 
assessed during DLT evaluation period.  See Section 6.2.1.2.2 for defined DLTs for MM 
and AML.  Subjects who complete the DLT evaluation period (see Section 6.2.1.1) 
without experiencing a DLT may proceed to a higher dose level within Part 3b or 
crossover to Part 4 combinational therapy for the following treatment cycle once the 
target cohort has been deemed safe by the DLRT and after consultation with the 
sponsor.  Dose-limiting toxicities experienced by subjects who proceeded to a higher 
dose or combination treatment as described above will not be considered for dose level 
decisions.  However, the DLRT will take this information into account to inform dose 
escalation recommendations. 


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For AML Part 3b and Part 4, each dose cohort will initially enroll 3-4 subjects and up to 
10 subjects per cohort may be enrolled.  After reviewing all available safety and 
tolerability data, dose level decisions (eg, escalation/de-escalation/expansion) will be 
made by the DLRT using a modified Toxicity Probability Interval (mTPI) model 
(Ji et al, 2010) based on all subjects that have been enrolled at current dose.  Dose 
escalation is considered to be complete if one of the following rules is met: 
 
The highest planned dose level is evaluated, MTD/MTCD has not been defined 
and no DLTs occur at any dose level.  In this case the maximum administrated 
dose (MAD) may be used for phase 2. 
 
An MTD/MTCD is identified. 
Guidelines for dose level decisions can be found in Table 4-2.  Details regarding the 
mTPI model and dose finding are described in Section 11.16.  Please note one 
exception to the guidelines provided in Table 4-2, a single grade 3 treatment-related 
troponin elevation will result in dose de-escalation regardless of number of subjects 
treated at current dose. 
Table 4-2.  Guidelines for Dose-level Decisions for Part 3b and Part 4 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Number of DLTs 
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 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. 
The MTD/MTCD is defined as the highest dose with a probability of DLT lower than or 
close to a targeted toxicity probability of 0.2. 
For the first dose level and at each new higher dose level, the first enrolled subject will 
be treated, and then after a period of 72 hours, subsequent subjects will be treated, 
provided that there are no significant toxicities relating to the treatment of the first 
subject.  


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In addition to safety, efficacy of complete remission per ELN in Part 4 will be evaluated.  
At MTCD or optimal biological dose (OBD), 1 complete remission out of 6 subjects, or 
2 complete remissions out of 10 subjects are expected. 
Upon completion of Part 4, enrollment will commence in Part 5A to confirm the 
safety and tolerability of the two selected doses along with the dosing schedule 
(QW or BIW) and to further evaluate the preliminary efficacy of AMG 176 in 
combination with azacitidine.  In Part 5A, approximately 48 subjects will be 
enrolled, with 24 subjects randomized to the cohort of AMG 176 120 mg/m² in 
combination with azacitidine and 24 subjects randomized to the cohort of 
AMG 176 240 mg/m² in combination with azacitidine, where the same dosing 
schedule (QW or BIW) will be used for both cohorts.  Simon’s two-stage minimax 
design (Simon, 1989) will be used for conducting the trial in each cohort of 
Part 5A.  Details about Simon’s two-stage minimax design are provided in 
Section 9.4.1.1.  
In Part 5B, 20 subjects will be enrolled to test 2 regimens.  The enrollment of 
Part 5B will start after Part 5A is complete.  Regimen 1 consists of administering 
AMG 176 at 240 mg/m² QD for 3 days + 4 days off followed by BIW dosing on 
weeks 2 and 3.  If this schedule is deemed safe by the DLRT after 6 subjects have 
enrolled on Regimen 1 cohort, the next 6 subjects in Regimen 2 cohort will receive 
AMG 176 at 240 mg/m² QD for 5 consecutive days, and then BIW on week 2.  
Safety data will be monitored continually. 
4.1.2 
AMG 176 Tolerability in Subjects with AML in Japan (Part 3c) 
AML subjects will be confirmed according to a standard 3+3 design without dose 
escalation.  Three subjects with relapsed or refractory AML will be enrolled into Part 3c 
and treated with AMG 176 using the QW dosing schedule (see Part 1b for description).  
Three additional subjects will be enrolled if 1 of initial 3 subjects experience a DLT.  
A dose with > 33% subjects experiencing a DLT is defined as not tolerable.  The 
tolerable dose of investigational drug is defined as a dose at which fewer than one-third 
of subjects experience a DLT.  If 2 or more of 6 subjects experience a DLT, appropriate 
action will be discussed by DLRT. 
4.1.3 
Drug-drug interaction Assessments with Itraconazole in the United 
States (Part 3d) 
A separate cohort of about 11 subjects with AML will be enrolled for this DDI 
assessment using a fixed sequence design (Figure 1-7), where AMG 176 will be 


Product:  AMG 176 
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CONFIDENTIAL  
 
 
co-administered with itraconazole during week 1 followed by dosing of AMG 176 alone in 
subsequent weeks.  Since subjects are hospitalized during the first week of AMG 176 
dosing, itraconazole administration will be limited to the first week to ensure proper 
monitoring and oversight of subjects in the event of increased exposure to AMG 176.  
A 7-day sentinel dosing will be utilized between the first and second subject enrolled in 
this cohort.  All safety data available will be evaluated in the first subject prior to enrolling 
all subsequent subjects.  
Subjects will receive:  
 
Oral itraconazole capsules (200 mg) QD starting at 8 am on day -3 through day 4 
(total of 7 days) to achieve adequate CYP3A4 inhibition prior to, and following, 
AMG 176 administration.   
 
Intravenous AMG 176 (60 mg/m2) on day 1 at approximately the same time as 
itraconazole dosing ( 5 minutes).   
Serial PK sampling will be conducted at specified time points after the AMG 176 dose on 
day 1 to characterize the plasma concentrations of AMG 176 when given in combination 
with itraconazole.  Subjects will receive AMG 176 (60 mg/m2) alone on day 8 and 
day 15.  Serial PK sampling will be conducted at specified time points after the AMG 176 
dose on day 15 to characterize the plasma concentrations of AMG 176 without 
itraconazole.  AMG 176 pharmacokinetics will be compared from day 1 (with 
itraconazole) relative to day 15 (without itraconazole).  After day 15, subjects will be 
eligible to receive the highest cleared monotherapy or combination therapy dose if 
deemed safe by the investigator and Amgen medical monitor. 
4.2 
Number of Subjects 
Subjects with relapsed or refractory MM and subjects with relapsed or refractory AML 
are eligible for this study (see Section 5).  It is anticipated that approximately 
219 subjects will be enrolled in the different parts of this study.   
CLOSED TO ENROLLMENT:  Multiple myeloma Part 1a enrolled 36 subjects for dose 
escalation.  Multiple myeloma Part 1b enrolled 12 subjects for dose escalation.  Acute 
myeloid leukemia Part 3a enrolled 17 subjects for dose escalation.  Acute myeloid 
leukemia Part 3c enrolled 4 subjects in Japan.  Part 3b enrolled 11 subjects.   
OPEN TO ENROLLMENT:  Part 3d will enroll about 11 subjects in the US.  Part 4 will 
enroll approximately 60 subjects.  Part 5 will enroll approximately 68 subjects. 
The rationale for the number of subjects required is detailed in Section 9.2.   


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Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
During dose escalation, subjects who are not DLT-evaluable will be replaced (see 
Section 6.2.1.1).  Subjects in Part 3d who are unable to complete the 3-week period will 
be replaced.  Subjects will not be replaced for any other reason.   
4.2.2 
Number of Sites 
The study will be conducted at approximately 7 to 23 sites in North America, Australia, 
Asia, and Europe.   
4.3 
Justification for Investigational Product Dose 
AMG 176 is administered as an IV infusion once daily twice weekly (BIW) followed by 
5 days break in Part 1a, Part 3a, and cohorts 5a and 5b of Part 4.  AMG 176 is 
administered as an IV infusion for one day followed by 6 days break (QW); in Part 1b, 
3b, 3c, 3d, and 4 (cohorts 1-4).  This schedule was repeated for a total of 3 consecutive 
weeks followed by 1 week off in the earlier parts of the study, which are now closed to 
enrollment (ie, Parts 1a, 1b, and 3a).  AMG 176 was administered QW in Part 3c, which 
is now closed to enrollment, for a total of 4 consecutive weeks.  AMG 176 was 
administered QW in Parts 3b, 3d, and 4 (cohorts 1-4) for a total of 4 consecutive weeks 
and BIW in Part 4 (cohorts 5a and 5b) for the first 3 weeks of each 28-day cycle.  
Additionally, AMG 176 will be administered in Part 5 either QW for a total of 
4 consecutive weeks or BIW for the first 3 weeks of each 28-day cycle.  This 28-day 
duration is considered 1 cycle.  Ramp-up dosing of 120 mg/m2 will be utilized whenever 
the target dose level is at 180 mg/m2 or higher, applicable to all indications (AML or MM) 
and all dosing schedules (BIW or QW) to mitigate the risk of TLS (see Section 4.1). 
The AMG 176 doses proposed in this study are:  
Multiple Myeloma 
 
For MM Part 1a BIW potential dose levels are:  30, 40, 50, 60, 120, 180, 240, 
360, and 480 mg/m2 of AMG 176 (IV; BIW).   
 
For MM Part 1b QW potential dose levels are:  180, 240, 360, and 480 mg/m2 of 
AMG 176 (IV; QW).  The starting dose level will be 180 mg/m2 tested with BIW 
dosing in MM subjects but dosing will be only one day per week instead of day 1 
and day 2. 


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Acute Myeloid Leukemia 
 
For AML Part 3a of the study, potential dose levels are:  60, 120, and 180 mg/m2 
of AMG 176 (IV; BIW).  The starting dose level will be the latest dose tested in 
MM subjects and cleared as safe and tolerable by the DLRT up to a maximum 
starting dose of 60 mg/m2.  Part 3a doses will be given once daily twice weekly 
(BIW) followed by a 5-day break and repeated each week for 3 weeks followed 
by 1 week with no treatment.   
 
For AML Part 3b, potential dose levels are:  120, 180, and 240 mg/m2 of 
AMG 176 (IV; QW).  For AML Part 3c, the potential dose level is 120 mg/m2 
(IV; QW).  For AML Part 3d, the dose selected is 60 mg/m2 (IV; QW). 
 
For AML Part 4 of the study, potential dose levels are:  60, 120, 180, and 
240 mg/m2 of AMG 176 (IV; QW or BIW).  Investigations of QW and BIW dosing 
schedule may run in parallel.  Part 4 will start after 120 mg/m2 dose cohort(s) of 
Part 3b is cleared as safe and tolerable by the DLRT.  Subjects in Japan will be 
enrolled in Part 4 after safety and tolerability is confirmed in Part 3c by the DLRT.   
 
For AML Part 5A, 2 cohorts will be enrolled:  Cohorts 1 and 2 will evaluate 
2 different dose levels to determine the optimal biological dose (OBD) on either a 
QW or BIW dosing schedule.   
 
AML Part 5B, will evaluate AMG 176 first under Regimen 1 dosing 
(3 consecutive days on week 1, BIW on weeks 2 and 3) for 6 subjects.  If this 
schedule is deemed safe by the DLRT, the next 6 subjects will proceed under 
Regimen 2 dosing (days 1 - 5 on week 1, BIW on week 2).  If Regimen 2 is 
deemed safe by the DLRT, then the remaining enrollment to Part 5B will employ 
the Regimen 2 dosing schedule.   
4.3.1 
Starting and Maximum Planned Doses 
The proposed clinical starting dose of 30 mg/m2 was based on the HNSTD noted in GLP 
toxicology study in Beagle dogs and the STD10 in GLP toxicology study in rats, which 
were found to be 10 mg/kg and 60 mg/kg administered daily, respectively.  This 
corresponds, per ICH S9 Guidance, to a human daily equivalent dose of 33 mg/m2 and 
36 mg/m2.  AMG 176 human PK parameters were predicted from a combination of 
in vitro and in vivo nonclinical data.  It was assumed that AMG 176 PK parameters 
remained constant and did not depend on doses or time.  At the starting dose of 
30 mg/m2 BIW, the predicted exposure margins of maximum observed concentration 
(Cmax) and area under concentration-time curve (AUC) to the rat STD10 were 174-fold 
and 400-fold, respectively.  The predicted exposure margins of Cmax and AUC to the dog 
HNSTD were estimated at 64-fold and 180-fold, respectively, for BIW (see Table 4-1).  
While no preclinical data exist for QW dosing, it is anticipated that the Cmax for a 
QW dose regimen would be roughly equivalent to the respective dose level BIW (ie, the 
Cmax for a 60 mg/m2 dose QW would be similar to that following a 60 mg/m2 dose given 
BIW).  Meanwhile, the AUC is expected to be significantly less for QW dosing compared 
to BIW.  For this reason, the exposure margins for Cmax and AUC for the QW arm are 


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predicted to be about the same and greater, respectively, for the rat STD10 and the dog 
HNSTD. 
4.3.1.1 
Multiple Myeloma 
The highest planned dose in MM subjects was 480 mg/m2 for MM subjects BIW.  Safety 
and tolerability data from prior dose levels will guide the dose escalations and the 
planned top dose for AMG 176 in the dose escalation phase (see Section 4.1).   
The AMG 176 PK-tumor dynamic relationships were characterized by the tumor dynamic 
models with data collected from athymic nude mice bearing OPM-2 tumors after multiple 
doses of AMG 176 following BIW or QW regimens.  The tumor dynamic model described 
tumor growth, drug inhibitory effect and tumor volume change over the treatment period 
in control- and AMG 176-treated mice.  To project human efficacious dose, it was 
assumed that it required at least the same AMG 176 plasma concentration in human as 
that in mice for inhibiting tumor growth.  The predicted ED50 for monotherapy in humans 
was therefore 360 mg/m2 or 480 mg/m2, following BIW or QW dosing regimens, 
respectively. 
4.3.1.2 
Acute Myeloid Leukemia 
4.3.1.2.1 
Part 1a 
As described above in Section 4.3.1. 
4.3.1.2.2 
Part 3b and 3c 
For AML Part 3b and 3c, the starting dose is 120 mg/m2 QW, which is based on prior 
clinical experience that demonstrated significant clinical efficacy in subjects with AML 
(Section 2.3.1) and a lower risk of troponin elevation.  Increased troponin has been 
designated as an identified risk (Section 2.3.2); however, no troponin elevations were 
observed at total weekly doses of 120 mg/m2 or 180 mg/m2.  Together, these data 
suggest that a dose of 120 mg/m2 administered QW will be safe and efficacious in 
subjects with AML.  Dose levels of 180 mg/m2 and 240 mg/m2 of AMG 176 administered 
QW as monotherapy may also be investigated in Part 3b based on review of safety data 
by the DLRT.  For safety data at levels exceeding 240 mg/m2 of AMG 176, see 
Section 2.2.2.4.   
4.3.1.2.3 
Part 3d 
For AML Part 3d, the dose selected is 60 mg/m2 (IV, QW), which was selected based on 
considerations of the predicted magnitude of the DDI during co-administration with 
itraconazole and available safety and efficacy data. 


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Itraconazole is widely used as a strong index inhibitor of CYP3A4 in clinical DDI studies 
based on potency and specificity of CYP3A4 inhibition and is also a clinical inhibitor for 
P-gp (Chen et al, 2019; Liu et al, 2016; US FDA, 2016).  Patients with AML are 
susceptible to invasive fungal infections and often require prophylaxis and treatment with 
antifungal agents such as voriconazole and posaconazole (Halpern et al, 2015; Lat and 
Thompson, 2011), which are known to inhibit CYP3A4 and P-gp.  AMG 176 is 
metabolized, in part, by CYP3A4, and is a P-gp substrate; hence, co-administration with 
inhibitors of CYP3A4/P-gp may lead to increases in AMG 176 exposure.  As a result, 
clinical trials with AMG 176 previously prohibited the use of medications that are strong 
CYP3A4/P-gp inhibitors, including voriconazole and posaconazole.   
A DDI assessment is planned in a separate cohort of AML subjects (Part 3d) in the FIH 
study 20150161 to evaluate the effect of itraconazole, a strong CYP3A4 and P-gp 
inhibitor, on the pharmacokinetics of AMG 176.  In Part 3d, subjects receive oral 
itraconazole capsules (200 mg) QD starting at 8 am on day -3 through day 4 (total of 
7 days) to achieve adequate CYP3A4/P-gp inhibition prior to, and following, AMG 176 
administration.  AMG 176 is dosed QW on day 1 of week 1 through 3.  Data analysis is 
conducted to assess AMG 176 exposure changes with or without co-administration of 
itraconazole (exposures on week 1 vs week 3).   
As of November 2022, preliminary data were available for 5 subjects from Part 3d 
AMG 176 60 mg/m² in combination with itraconazole.  Preliminary analyses indicate no 
trend for increases in AMG 176 exposure with concomitant administration of 
itraconazole, although a trend towards decreases in AMG 176 exposure was observed:  
point estimates for Cmax and area under the concentration time curve from 0 to 168 hours 
(AUC0-168 hr) ratios for AMG 176 with and without itraconazole were 0.62 
(90% CI 0.15, 1.10) and 0.79 (90% CI 0.24, 1.33), respectively.  Based on the current 
understanding of the DDI mechanism between AMG 176 and itraconazole, a decrease in 
exposure is not expected; the trend for decrease is likely due to the large PK variability 
and 1 outlier subject.  Further analyses will be conducted as more subject data (up to 
11 subjects) become available.   
A less than 1.4-fold increase in exposure is expected for AMG 176 when 
co-administered with itraconazole indicating a weak to no DDI, based on the analyses of 
preliminary clinical data from Part 3d and physiologically-based pharmacokinetic (PBPK) 
modeling and simulation (Section 4.3.1.2.3.1).  Consequently, in Protocol 


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Amendment 15 the exclusion criterion for co-administration of AMG 176 with azole 
antifungal therapies that are strong CYP3A4/P-gp inhibitors was removed.   
4.3.1.2.3.1 
Predicted Magnitude of DDI 
A preliminary PBPK model was developed in the Simcyp Simulator (version 20) and was 
used to predict the magnitude of DDI with itraconazole, a strong CYP3A4 and P-gp 
inhibitor.  Briefly, a compound file for AMG 176 was developed and verified based on in 
vitro and available clinical data of AMG 176 monotherapy across multiple dosing 
regimens.  Simcyp library model files for itraconazole and the primary metabolite OH-
itraconazole were used as inhibitors of CYP3A4.  The preliminary PBPK model was 
used to simulate the effect of itraconazole (200 mg × 7 days from day -3 through day 4) 
on AMG 176 given concurrently as a 60, 120, 180, and 240 mg/m² QW IV infusion over 
2 hours on day 1 using population representative or virtual population simulation.  The 
predicted AUC ratio was 1.2 to 1.4.  Based on this preliminary PBPK modeling analysis, 
a weak to no DDI is predicted when AMG 176 is co-administered with itraconazole.  
4.3.1.2.3.2 
Safety 
Increased troponin is an identified risk for AMG 176 based on available safety data from 
the first trial that evaluated a range of doses from 30 to 480 mg/m2 given QW or twice 
weekly (BIW) to subjects with AML and MM.  Troponin elevations in AML and MM 
subjects studied to date were observed primarily at higher dose levels of 360 and 
480 mg/m2 (BIW); troponin elevations were not reported for dose levels of 120 mg/m2 
(QW and BIW), 180 mg/m2 (QW and BIW), and 240 mg/m2 (QW and BIW).  Based on 
existing data, the 60 mg/m2 dose selected for this DDI assessment provides an 
estimated 6-fold safety margin in the event of increased exposures with itraconazole with 
respect to doses associated with troponin elevations in AML and MM subjects studied to 
date. 
4.3.1.2.3.3 
Efficacy 
In AML subjects in the FIH study, 2 subjects achieved complete response with 
incomplete cell recovery (CRi) (1 subject each at 60 and 120 mg/m2 BIW) and 1 subject 
achieved a PR (at 60 mg/m2 BIW) (Section 2.3.1).  The 60 mg/m2 dose selected for this 
DDI assessment may provide therapeutic benefit for subjects based on the clinical 
responses observed to date. 
In summary, the AMG 176 dose selected (60 mg/m2 QW) for Part 3d has an estimated 
6-fold safety margin with respect to doses associated with troponin elevations.  This 
dose is expected to be safe and tolerated during co-administration with itraconazole in 


Product:  AMG 176 
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the event of an increase in AMG 176 plasma concentrations.  The AMG 176 dose 
selected is additionally expected to provide potential therapeutic benefit to subjects.  
For Part 3d, after week 3, subjects may crossover to Part 3b or Part 4 for continued 
treatment if approved by the investigator and Amgen medical monitor.   
4.3.2 
Justification for the AML Conventional Dosing Schedule 
(5 Consecutive Days) 
Amgen’s preclinical humanized mouse modeling supports a conventional AML dosing 
schedule of AMG 176 (5 consecutive days) as more efficacious compared with QW or 
BIW dosing.  The model did not demonstrate any increased or prolonged hematotoxicity 
with conventional AML dosing.  However, markedly greater tumor growth inhibition was 
observed.   
Preliminary population PK modeling of the conventional AML dosing regimen 
(240 mg/m² QD for 5 days on, followed by 2 days off) demonstrated no concerning 
PK accumulation (< 2-fold) after multiple QD dosing of AMG 176.  Compared to BIW 
(240 mg/m²) dosing, the conventional dosing regimen (240 mg/m² QD for 5 days on, 
followed by 2 days off) achieved Cmax and AUC0-168 hr within a 2-fold range (median Cmax 
increased 1.1-fold and median AUC0-168 hr increased 1.9-fold at the relevant target dose).   
Preliminary dose-exposure-response analyses were conducted for troponin elevations in 
R/R MM and R/R AML subjects for AMG 176 (QW or BIW) administered as 
monotherapy or in combination with azacitidine, including subjects with troponin 
elevation as primary or secondary event due to other safety events (such as sepsis) or 
progression of disease.  Based on data from the conventional troponin assay (ADVIA 
Centaur®, cut-off upper reference limit of 0.04 or 0.1 ng/ml), preliminary 
exposure-response analyses for potential AMG 176 induced cardiac troponin elevation 
indicated no clear exposure-response correlation.  Based on data from an exploratory 
high sensitivity troponin assay (Abbott Architect HS TnI), preliminary dose-response 
analyses indicated correlation of troponin elevation with increasing AMG 176 dose 
levels, but no concerning troponin elevation have been observed at dose levels less than 
or equal to 240 mg/m² QW or BIW.   
Considering no significant PK accumulation and < 2-fold increase in exposures for the 
conventional dosing regimen compared to the BIW dosing regimen at 240 mg/m² dose 
level, concerning troponin elevation is not expected for the conventional dosing 
regimens.   


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Consequently, preclinical data and PK modeling supports the clinical investigation of the 
conventional AML dosing schedules.  With preclinical animal studies showing greater 
efficacy with conventional AML dosing, Amgen explores here the safety of a more 
conventional AML dosing regimen (ie, 5 consecutive days of AMG 176 administration 
during week 1 of a cycle).   
4.3.3 
Justification of the Monotherapy Recommended Phase 2 Dose 
(RP2D) 
In the current study, Part 1 and Part 2 were initially designed to investigate tapotoclax as 
monotherapy and combinational therapy in subjects with multiple myeloma (MM).  As of 
December 2019, 48 subjects were enrolled in Part 1 where clinical responses were 
observed at dose levels > 240 mg/m².  At that time, tapotoclax-associated elevations of 
troponin were observed at dose levels of 360 mg/m² and 480 mg/m².  Consequently, to 
avoid the potential for troponin elevations, only doses less than equal to 240 mg/m² are 
currently under investigation.  Additionally, monotherapy efficacy of tapotoclax in AML 
has been limited, with an overall response rate (ORR = CR + incomplete hematologic 
recovery [CRi]) of 9.4% (3 out of 32 subjects) in monotherapy Parts 3a, 3b, and 3c (all 
responses were CRi).  In contrast, increased antileukemic activity has been observed in 
combination with azacitidine.  Consequently, combination therapy has been prioritized in 
the current study (Parts 4 and 5) to optimize the clinical benefit to subjects, and 
monotherapy investigations were completed to support the combination therapy studies. 
As of November 2022, in AML subjects, 2 out of 17 subjects in Part 3a (ORR = 11.8%), 
1 out of 11 subjects in Part 3b (ORR = 9.1%), 0 out of 4 subjects in Part 3c (ORR = 0%), 
and 3 out of 21 subjects in Part 4 (ORR = 14.3%) have achieved the best overall 
response of CR or CRi.  With the 21 AML subjects who received combination tapotoclax 
plus azacitidine in Part 4, 12 subjects had at least 1 evaluable disease response; 
2 subject (9.6%) had CR; 1 subject (4.8%) had CRi; 8 subjects (38.1%) had stable 
disease (SD); 1 subject (4.8%) had PD (9 subjects [42.9%] did not have an evaluable 
disease response) (see Table 2-1 for details).  Three out of 21 subjects (14.3%) 
achieved CRi or better in all cohorts in Part 4, and 2 out of 6 subjects (33%) achieved 
CR in tapotoclax 240 mg/m² QW plus azacitidine cohort, demonstrating a better 
response at the 240 mg/m² dose compared with lower doses when administered in 
combination with azacitidine. 


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Preliminary PK/PD modeling for tapotoclax (monotherapy or in combination with 
azacitidine) to date have shown subtherapeutic exposures with regard to the estimated 
minimum efficacious exposures for tapotoclax at doses below 240 mg/m². 
The observed dose-exposure (AUC0-168 hr)-efficacy relationship for tapotoclax in 
combination with azacitidine demonstrated better response with increased tapotoclax 
dose and exposure, indicating a preliminary dose-exposure-response relationship for 
efficacy in the combination therapy setting. 
As a result of these data, tapotoclax 240 mg/m² is the monotherapy recommended 
phase 2 dose (RP2D). 
4.3.4 
Dose Optimization Plan to Inform Combination Recommended 
Phase 2 Dose (RP2D) 
The recommended combinational phase 2 dose (RP2D) will be estimated using the 
totality of data from across the FIH study, including the PK, safety, efficacy, PD 
for efficacy, and other results from the dose escalation and dose expansion.  
Dose-exposure-response analyses for safety and efficacy will be conducted to inform the 
RP2D.   
Two dose levels will be selected for the expansion phase based on the preliminary 
dose–exposure–response analyses and PK/PD modeling using available data from 
preclinical and dose escalation phase.  In order to minimize bias, assignments will be 
randomized to each dose level in Part 5A.  Pharmacokinetic exposure separation, 
minimal dose expected to achieve efficacy, highest dose with acceptable safety profile 
and other aspects will be considered for dose selection of the expansion phase.   
AMG 176 has exhibited a predictable PK/PD profile.  Based on the available data from 
the dose escalation part of Study 20150161, preliminary dose-exposure analyses 
indicated dose-related increases in exposure with mean terminal elimination t½ of 
approximately 4 to 23 hours in AML subjects.  Preliminary dose-exposure-response 
analyses in subjects with relapsed or refractory (R/R) MM and in subjects with R/R AML 
demonstrated no concerning safety signals, including troponin elevations, at AMG 176 
doses of 240 mg/m² or less (QW or BIW) when administered as monotherapy or in 
combination with azacitidine.  Preliminary efficacy is observed at a range of dose levels 
from 60 to 240 mg/m² for AMG 176 monotherapy and in combination with azacitidine in 
AML subjects.   


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Further dose exposure response analyses and PK/PD modeling based on the totality of 
data (PK, safety, efficacy, PD 
 for efficacy), using all data from dose escalation 
and dose expansion, will be conducted to develop robust doseexposureresponse 
relationships to guide the selection of the combination RP2D, designated as the dose 
that achieves maximum efficacy with acceptable toxicity in the target AML population. 
4.4 
Justification for Non-investigational Product Dose 
4.4.1 
Azacitidine 
For Parts 4 and 5A, the dose of azacitidine for the first treatment cycle, for all subjects 
regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously (SC) 
or IV, daily for the first 7 days of a 28 day cycle (as per local prescribing information).  
For Part 5B, all subjects will receive 7 days of azacitidine IV or SC daily at 
75 mg/m² on days 1 - 5, 8 - 9 of each 28-day cycle.   Prophylactic treatment to mitigate 
nausea and vomiting will be administered.   
4.4.2 
Itraconazole 
Itraconazole is widely used as a strong index inhibitor of CYP3A4 in clinical DDI studies 
based on potency and specificity of CYP3A4 inhibition (Chen et al, 2019; Liu et al, 2016; 
US FDA, 2016).  For Part 3d, the itraconazole dose selected is oral capsules 200 mg QD 
starting on day -3 through day 4 (total of 7 days).  This dose level and duration is 
consistent with recommendations outlined by the Innovation and Quality of 
Pharmaceutical Development’s Clinical Pharmacology Leadership Group (IQ-CPLG) that 
were based on an extensive literature review of clinical DDI studies with itraconazole 
(Liu et al, 2016) and verified using mechanistic PBPK modeling approaches 
(Chen et al, 2019).  The current assessment will continue to require itraconazole dosing 
to cover 4 to 5 half-lives of AMG 176 in order to ensure adequate CYP3A4 inhibition 
during the elimination phase of AMG 176.  The estimated t½ of AMG 176 ranges from 
approximately 4 to 25 hours across the range of doses evaluated, with most subjects 
exhibiting a t½ of approximately 8 to 12 hours.  Hence, an additional 3 days of 
itraconazole dosing after the AMG 176 dose on day 1 is considered adequate. 
4.5 
End of Study 
4.5.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 


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The primary completion date is the date when data for the primary endpoint are last 
collected for the purposes of conducting the last primary analysis (see Section 9.4.1.2). 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject across 
all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up, 
additional antibody testing), as applicable. 
4.5.2 
Study Duration for Subjects 
It is anticipated that each subject will be on study for approximately 2 weeks for 
screening, 6 months for the treatment period plus a 30-day (+3 days) safety follow-up 
visit after the last dose of protocol-required therapies.  The estimated study duration for 
subjects from screening through the safety follow-up visit is 7.5 months but this may be 
longer or shorter depending on the subject’s disease, ability to tolerate AMG 176, and/or 
willingness to participate in the study.  In addition, long-term follow-up assessments will 
occur every 3 months ( 14 days) after EOT for up to 1 year.   
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).   
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
All subjects:  
101 Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
103 Must be willing and able to undergo a core bone marrow biopsy (MM and AML 
subjects) and bone marrow aspirate (MM and AML subjects) at screening.  Core 
bone marrow biopsy or bone marrow aspirate performed as prior SOC can be 
used to meet screening requirements if performed within 4 weeks from enrollment 


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and no curative anti-cancer therapy was administered during the time from biopsy 
to enrollment.   
105 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
106 Age ≥ 18 years old 
 
For subjects in Japan only:  if a subject is younger than 20 years at the time 
of signing the informed consent form, informed consent must be obtained 
from both the subject and his/her legal representative 
107 Life expectancy of > 3 months, in the opinion of the investigator 
109 Hepatic function, as follows; total bile acid (TBA) < 5 × upper limit of normal (ULN), 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  3 × ULN, 
total bilirubin  1.5 × ULN (except subjects with Gilbert’s syndrome). 
110 Cardiac function, as follows; left ventricular ejection fraction (LVEF) greater than or 
equal to 50%.  2-D transthoracic echocardiogram (ECHO) is the preferred method 
of evaluation.  Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not 
available. 
111 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. 
112 Female subjects of childbearing potential must have a negative serum or urine 
pregnancy test within 3 days of the first dose (see Section 11.5 for definition of 
females of childbearing potential). 
Multiple myeloma subjects only:  
102 Pathologically documented, definitively diagnosed, MM relapse or refractory PD 
and have received at least 2 therapeutic treatments or regimens for MM.  The 
investigator must be of the opinion that no other treatment option will result in a 
durable response. 
104 Measurable disease per the International Myeloma Working Group (IMWG) 
response criteria (assessed within 28 days prior to enrollment), as indicated by one 
or more of the following: 
 
Serum M-protein ≥ 0.5 g/dL 
 
Urine M-protein ≥ 200 mg/24 hours 
 
Subjects who do not meet 1 of the 2 prior criteria:  serum free light chain 
(SFLC) > 10 mg/dL (≥ 100 mg/L) and an abnormal SFLC ratio (< 0.26 or 
> 1.65) as per the IMWG response criteria 
108 Hematological function, as follows without transfusion or growth factor support: 
 
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
 
Platelet count ≥ 50X 109/L (in subjects where < 50% of bone marrow 
nucleated cells were plasma cells) or ≥ 30 × 109/L (in subjects where 
≥ 50% of bone marrow nucleated cells were plasma cells) without transfusion 
or growth factor support 
 
Subjects should not have received platelet transfusions for at least 1 week 
prior to screening 


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 
Hemoglobin ≥ 8 g/dL 
 
Screening ANC should be independent of granulocyte- and 
granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) 
support for at least 1 week and of pegylated G-CSF for ≥ 2 weeks 
Acute myeloid leukemia subjects only: 
113 AML as defined by the World Health Organization (WHO) Classification 
(Section 11.14) persisting or recurring following one or more treatment courses, 
and for subjects in Japan, determined by the investigator to be not eligible for 
approved anticancer drug therapy in Japan; EXCEPT acute promyelocytic 
leukemia (APL).  The investigator must be of the opinion that no other treatment 
option will result in a durable response.  In Part 5A cohorts 1 and 2, enrollment will 
be restricted to subjects with persisting or recurring AML after 1 to 2 lines of prior 
therapy.   
114 Greater than or equal to 5% blasts (or blast equivalents) in bone marrow. 
115 Circulating white blood cells (WBCs) < 25 000/L. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
All subjects: 
201 Previously received an allogeneic stem cell transplant within 6 months OR having 
received immunosuppressive therapy within the last 3 months OR having signs or 
symptoms of acute or chronic graft-versus-host disease. 
202 Autologous stem cell transplant less than 90 days prior to enrollment.  
209 Currently receiving treatment in another investigational device or drug study.  
Other investigational procedures while participating in this study will be allowed if 
approved by Amgen medical monitor.  
210 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 
211 Known sensitivity to any of the products or component to be administered during 
dosing. 


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212 Myocardial infarction within 6 months of enrollment, symptomatic congestive heart 
failure (New York Heart Association > class II).  
213 History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
6 months prior to enrollment. 
214 Active infection requiring IV anti-infective treatments within 1 week of enrollment 
215 Known or suspected human immunodeficiency virus (HIV) infection or subjects 
who are HIV seropositive.  Testing will be performed if required by local regulatory 
authorities. 
216 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 (HBsAb; Japan only):  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 
217 Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved 
to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 1, 
or to levels dictated in the eligibility criteria with the exception of grade 2 peripheral 
neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered 
irreversible (defined as having been present and stable for > 4 weeks may be 
allowed if they are not otherwise described in the exclusion criteria AND there is 
agreement to allow by both the investigator and sponsor). 
218 Treatment with medications known to cause QT interval corrected (QTc) interval 
prolongation within 1 week prior to enrollment unless approved by the Amgen 
Medical Team.  
219 Anti-tumor therapy:  chemotherapy, antibody therapy, molecular targeted therapy, 
or investigational agent within 5 times the t½ of the drug, or until the relevant 
biological effect has resolved (whichever is longer).  Exceptions:  hydroxyurea to 
control peripheral blood leukemic cell counts is allowed until prior to receiving the 
first dose of AMG 176.  Hydroxyurea is unapproved for AML in Japan. 
220 Prior systemic radiation therapy must have been completed at least 28 days prior 
to enrollment.  Prior focal radiotherapy completed at 14 days prior to enrollment.  
221 Major surgery within 28 days of enrollment. 
235 Women of reproductive potential who are unwilling to practice an acceptable 
method of highly effective birth control while on study through 3 months after 
receiving the last dose of study drug.  Men who are unwilling to practice sexual 
abstinence (refrain from heterosexual intercourse) or use a condom with 
spermicide during treatment and for an additional 4 months following the last dose 
of study drug if sexually active with a female of childbearing potential.  For 
acceptable methods of highly effective birth control, and definition of females of 
childbearing potential see Section 11.5. 


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223 Women planning to become pregnant or breastfeed while on study through 
3 months after receiving the last dose of study drug.  Subjects who suspend 
breastfeeding prior to starting treatment with study drug and do not intend to 
resume breastfeeding before 3 months after receiving the last dose of study drug 
can be enrolled 
236 Male subjects who are unwilling to abstain from donating sperm during treatment 
and for an additional 4 months following the last study drug administration 
224 History or evidence of any other clinically significant disorder, condition or disease 
that, in the opinion of the investigator or Amgen physician, if consulted, would pose 
a risk to subject safety or interfere with the study evaluation, procedures or 
completion. 
225 Use of any medications (except anti-tumor medications), including herbal 
medicines (eg, St. John’s wort), vitamins, or supplements consumed by the subject 
within 5 times the t½ of the drug, or until the relevant biological effect has resolved 
(whichever is longer), and continuing use if applicable, that was not 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. 
226 Use of known strong inhibitors of CYP3A4 within 5 times the t½ or until the relevant 
biological effect has resolved (whichever is longer), prior to enrollment unless 
reviewed and approved by the principal investigator and the Amgen medical 
monitor prior to enrollment.  Written documentation of this review is required for 
subject participation.  Exception:  use of azole antifungal therapies falling into this 
category based on the current data from Part 3d subjects.   
228 Use of known CYP3A4 sensitive substrates with a narrow therapeutic window 
within 5 times the t½ of the drug or its major active metabolite or until the relevant 
biological effect has resolved (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  
229 Use of known OATP1B1 and/or OATP1B3 or BCRP substrates with a narrow 
therapeutic window within 5 times the t½ of the drug or its major active metabolite 
or until the relevant biological effect has resolved (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. 
230 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, Patient 
Reported Outcomes) to the best of the subject and investigator’s knowledge. 
231 Subjects with elevated cardiac troponin above the manufacturer’s 99th percentile 
upper reference limit (URL) for ADVIA Centaur XP assay (0.04 ng/mL for females 
and 0.059 ng/mL for males) at screening confirmed by the central laboratory.  
232 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. 


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239 DDI assessment cohort with itraconazole only:  History of QT prolongation, 
torsades de pointes, ventricular tachycardia, and cardiac arrest 
240 History or evidence of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection unless agreed upon with medical monitor and meeting the 
following criteria: 
 
negative test for SARS-CoV-2 RNA by real time polymerase chain reaction 
(RT-PCR) within 72 hours prior to first dose of AMG 176; and 
 
no acute symptoms of coronavirus disease 2019 (COVID-19) within 10 days 
prior to first dose of AMG 176 (counted from day of positive test for 
asymptomatic subjects) 
241 Prior treatment with an MCL1 inhibitor. 
Multiple myeloma subjects only:  
203 Multiple myeloma with IgM subtype. 
204 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes). 
205 Existing plasma cell leukemia or rapidly proliferating extra medullary disease 
unless discussed and approved by Amgen medical monitor prior to enrollment.  
206 Waldenstrom’s macroglobulinemia. 
207 Amyloidosis. 
208 Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior 
to enrollment.  Topical or inhaled corticosteroids are permitted. 
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).   
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures.  For Part 3c only:  If a 
subject is younger than 20 years at the time of signing the informed consent, informed 
consent must be obtained both from the subject and his/her legal representative. 
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned manually or 
automatically.  This number will be used to identify the subject throughout the clinical 
study and must be used on all study documentation related to that subject.   
The unique study identification number will consist of 11 digits.  The first 3 digits will 
represent the last 3 digits of the protocol number (eg, 161).  The next 5 digits will 


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represent the country code and site number (eg, 66001) and will be identical for all 
subjects at the site.  The next 3 digits will be assigned in sequential order as subjects 
are screened (eg, 001, 002, 003).  For example, the first subject to enter screening at 
US site 66001 will receive the number 16166001001, and the second subject at the 
same site will be 16166001002.  The subject identification number must remain constant 
throughout the entire clinical study; it must not be changed after initial assignment, 
including if a subject is rescreened.   
All screening tests and procedures should be performed within 14 days of administration 
of the first dose of AMG 176 (day 1), or itraconazole (ie, day -17 to day -3) for Part 3d, 
unless otherwise indicated.  Subjects may be re-screened up to 2 additional times at the 
discretion of the investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside of the 14-day screening period.  Subjects who are deemed 
ineligible will be documented as screen failures (see Section 5.4).   
Subjects may be eligible to enroll once all screening tests and procedures are completed 
and results indicate that all eligibility criteria are met.  A site representative will complete 
and send the subject registration form and/or enrollment eligibility worksheet to the 
sponsor or designee.  The Amgen representative will acknowledge receipt and return 
confirmation of dose cohort (dose exploration part) or group (dose expansion part), 
respectively, to the site.   
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF).   
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 dosed with AMG 176.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, 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.   


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6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol.   
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment.   
6.1 
Treatment(s) Administered 
The Amgen Investigational Product used in this study is AMG 176.  The 
non-investigational products used in this study (azacitidine) may be considered 
investigational in some countries.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 176.   
6.1.1 
Investigational Product:  AMG 176 
All investigational products will be administered at the research facility by a qualified staff 
member.  A physician must be available at the time of administration of Investigational 
Product.   
Description 
AMG 176 is an anhydrous crystalline material that is a white to light brown powder, 
which is formulated as a sterile concentrate for solution for infusion.  The solution is 
administered IV after dilution into an IV bag containing normal saline (0.9% sodium 
chloride).   
Dosage Form 
The AMG 176 investigational product is formulated as a sterile concentrate for solution 
for infusion at a concentration of 25 mg/mL in 10% w/w 2-hydroxypropyl 
beta-cyclodextrin, and buffered with 100 mM glycine to pH 9.0.  AMG 176 is supplied as 
a sterile, preservative-free solution for IV infusion.   


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Drug Supply and Storage 
AMG 176 will be supplied as either a 10 mL liquid deliverable volume in a single use 
(20R) glass vial or a 14.4 mL liquid deliverable volume in a single use (30R) glass vial.   
The primary container closure system for the 10 mL presentation consists of a 20R 
borosilicate glass vial with a 20 mm elastomeric stopper, and an aluminum seal with 
flip-off dust cover.  A single use vial containing 14.4 mL fill of 25 mg/mL AMG 176 has 
also been developed for use in the clinic.  Additional details are provided in the IPIM.   
It is recommended that AMG 176 be stored at or below 25°C, protected from light, and 
according to the storage and expiration information (where required) provided on the 
label that is affixed to the package containing the investigational product. 
Dosage, Administration, and Schedule 
AMG 176 will be administered on a 28-day cycle.  The dosing schemes include BIW 
administration for 3 weeks of 4 in a cycle (6 doses per cycle, see below), QW 
administration every week of the cycle (4 doses per cycle, see below), or a conventional 
AML dosing scheme administering azacitidine in combination with AMG 176 (7 doses 
per cycle).  Prior to dosing on day 1 of every cycle, body surface area (BSA) must be 
calculated.  Each cycle of AMG 176 BIW is defined as an IV infusion once daily for 2 
consecutive days followed by a 5-day break and repeated each week for 3 weeks 
(Part 1a, 3a, 4 [cohorts 5a and 5b]) followed by 1 week with no treatment.  Intravenous 
BIW begins at study day 1.  Each cycle of AMG 176 QW is defined as an IV infusion QW 
followed by a 6-day break and repeated each week either for 3 weeks followed by 1 
week with no treatment (Part 1b), or for 4 consecutive weeks (Parts 3b, 3c, and 
4 [cohorts 1-4]).  Dosing begins at study day 1.  Part 5 dosing will be based on MTCD 
determined in Part 4. 
Ramp-up dosing will be utilized whenever the target dose level is at 180 mg/m2 or higher 
to mitigate the risk of TLS.  Ramp-up dosing consists of an initial dose at cycle 1 week 1 
of 120 mg/m2 followed by an increase to the target dose level for subsequent doses.  
Decisions regarding the AMG 176 ramp-up dosing period regimen, ramp-up period 
starting dose, dosing increments, will be made by DLRT and communicated to the 
IRB/IEC, as appropriate (see Section 11.3). 
Tumor lysis syndrome prophylaxis must be initiated in all subjects prior to all ramp-up 
dosing of AMG 176 and prior to all subsequent dose escalations (ie, first dose on the 
targeted cohort dose level).  Hospitalization and monitoring should begin the night before 


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AMG 176 administration and must continue until at least the 24-hour post-dose 
(QW schedule) or until 48 hours post the first dose in the BIW dosing schedule.  Refer to 
Section 6.1.4.1 for additional details on prophylaxis and management of TLS. 
The AMG 176 dose, start date/time, stop date/time and lot number is to be recorded for 
each subject in the electronic CRF (eCRF).  
The AMG 176 infusion time will be 120 ( 5) minutes.   
If a subject develops a reaction during or after the AMG 176 infusion, immediate 
treatment should be initiated according to best clinical practice.  Increase monitoring of 
vital signs as medically indicated until the subject is deemed medically stable in the 
opinion of the investigator.  All medication and symptoms should be documented in the 
eCRF. 
Intra-subject Dose Escalation 
For each part, DLTs will be assessed during the DLT evaluation period.  Subjects who 
complete the DLT-observation period without experiencing a DLT may proceed to a 
higher dose level or different dosing schedule cohort once the target cohort has been 
deemed safe by the DLRT and after consultation with the sponsor.  Dose-limiting 
toxicities experienced by subjects who proceeded to a higher dose or different schedule 
will not be considered for dose level decisions.  However, the DLRT will take this 
information into account to inform dose escalation recommendations.   
6.1.2 
Non-investigational Products:  Azacitidine and Itraconazole 
In some countries, the non-investigational products used in this study (azacitidine and 
itraconazole) may be considered investigational based on regional requirements. 
Refer to regional prescribing information for full details regarding azacitidine and 
itraconazole, respectively. 
6.1.2.1 
Azacitidine (Parts 4 and 5) 
Description 
Azacitidine is a pyrimidine nucleoside analog of cytidine.  The empirical formula is 
C8H12N4O5.  The molecular weight is 244 g/mol.   
The mechanism of action is through hypomethylation of DNA and direct cytotoxicity.  
Hypomethylation may restore normal function to genes that are critical for differentiation 
and proliferation.  The concentration of azacitidine required for maximum inhibition of 
DNA methylation in vitro does not cause major suppression of DNA synthesis.   


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Formulation 
Azacitidine is a white to off-white solid.  Azacitidine was found to be insoluble in acetone, 
ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene 
glycol, and polyethylene glycol; sparingly soluble in water, water-saturated octanol, 
5% dextrose in water, N-methyl-2-pyrrolidone, normal saline, and 5% Tween 80 in water; 
and soluble in dimethylsulfoxide (DMSO).   
The finished product is supplied in a sterile form for reconstitution as a suspension for 
SC injection or reconstitution as a solution with further dilution for IV infusion.   
Storage 
Store unreconstituted vials at 25°C; excursions permitted to 15°C to 30°C (5°F to 86°F).   
Accountability 
Sites will be required to record and document subject compliance regarding azacitidine 
dosing.  The quantity administered, route, start date/time, stop date/time, and lot number 
of azacitidine are to be recorded on each subject's CRF(s).  Stop date/time is required to 
be recorded on each subject’s CRF(s) only for IV administrations.   
Azacitidine will not be supplied by Amgen for this study unless required by local 
regulation or in response to a regional supply shortage.  In Japan, azacitidine will be 
supplied by Amgen for this study.   
Packaging 
Azacitidine is supplied as a lyophilized powder in 100 mg single use vials packaged in 
cartons of 1 or 2 vial(s).  Vials contain 100 mg of azacitidine and 100 mg of mannitol as 
a sterile lyophilized powder.   
Dosage, Administration, and Schedule 
For Parts 4 and 5A, azacitidine will be administered at a dose of 75 mg/m2 either IV or 
SC, as recommended in the prescribing information, daily for the first 7 days of a 28day 
cycle.  The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 
2 cycles and if no toxicity other than manageable nausea and vomiting has occurred.  
For Part 5B, all subjects will receive 7 days of azacitidine IV or SC daily at 
75 mg/m² on days 1 - 5, 8 - 9 of each 28-day cycle.    
On days where azacitidine is co-administered with AMG 176, azacitidine will be given 
before AMG 176.  A minimum of a 30-minute gap between the administration of 
azacitidine and AMG 176 is recommended.   


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6.1.2.2 
Itraconazole (Part 3d) 
Description 
Itraconazole is a synthetic triazole antifungal agent.  Itraconazole is a 1:1:1:1 racemic 
mixture of 4 diastereomers (2 enantiomeric pairs), each possessing 3 chiral centers.  
Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight 
of 705.64.   
The mechanism of action is through inhibition of the cytochrome P450-dependent 
synthesis of ergosterol, which is a vital component of fungal cell membranes.   
Formulation 
Itraconazole is a white to slightly yellowish powder.  It is insoluble in water, very slightly 
soluble in alcohols, and freely soluble in dichloromethane.  It has a pKa of 3.70 (based 
on extrapolation of values obtained from methanolic solutions) and a log 
(n-octanol/water) partition coefficient of 5.66 at pH 8.1.   
Itraconazole capsules contain 100 mg of itraconazole coated on sugar spheres 
(composed of sucrose, maize starch, and purified water).  Inactive ingredients are hard 
gelatin capsule, hypromellose, polyethylene glycol 20 000, titanium dioxide, FD&C Blue 
No. 1, FD&C Blue No. 2, D&C Red No. 22, and D&C Red No. 28.   
Storage 
Store at 15C to 25C.  Protect from light and moisture.   
Accountability 
Oral itraconazole capsules should be taken with a full meal.  Sites will be required to 
record and document subject compliance regarding itraconazole dosing.   
Itraconazole will not be supplied by Amgen for this study unless required by local 
regulation.   
Packaging 
Itraconazole is supplied as a commercially available oral capsule containing 100 mg of 
itraconazole, with a blue opaque cap and pink transparent body.  The capsules are 
supplied in unit-dose blister packs of 3 × 10 capsules, bottles of 30 capsules, and in the 
PulsePak containing 7 blister packs × 4 capsules each.   


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Dosage, Administration, and Schedule 
Subjects will receive oral itraconazole capsules (200 mg) QD starting at approximately 
8 am on day -3 through day 4 (total of 7 days) to achieve adequate CYP3A4 inhibition 
prior to, and following, AMG 176 administration.   
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.   
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 ramp-up dosing (see Section 6.1.1) will be used and TLS prophylaxis 
must be initiated in all subjects prior to all ramp-up dosing of AMG 176 and prior to all 
subsequent dose escalations (ie, first dose on the targeted cohort dose level).  In 
Part 5B, subjects will receive ramp-up dosing on days 1 and 2 of week 1 in cycle 1 
followed by the target dose starting on day 3.  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 subjects will be hospitalized to monitor for TLS and all TLS monitoring assessments 
will be performed as outlined in the Schedule of Assessments (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 


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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, 
may be used per principal investigator discretion and the institutional guidelines.  
Dosing per institutional guidelines. 
 
NOTE:  Allopurinol is unapproved for TLS prophylaxis in Japan. 
 
Hospitalization and monitoring, should begin the night before AMG 176 
administration and must continue until at least 24 hours post-dose (QW 
schedule) or until 48 hours post the first dose in the BIW dosing schedule 
 
NOTE:  Subjects in Part 3c will be hospitalized for a minimum of 29 days 
beginning from the night before AMG 176 administration in the first cycle. 
 
IV hydration must be started the night before AMG 176 administration and to be 
continued until at least 24 hours post–dose (QW schedule) during hospitalization 
as clinically tolerated (refer to Section 11.8.1 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 ramp-up 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 


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electrolytes abnormalities occurring post AMG 176 administration.  These labs must 
be reviewed in real time by the investigator.  
Day 2 dosing of AMG 176 (BIW schedule) should not be administered until the 
24 hours post dose laboratory values are reviewed 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 
institutional guidelines to ensure emergency dialysis is available and the 
appropriate staff is aware and prepared. 
6.1.5 
Other Treatment 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(s), combination product, or device(s) 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 or non-investigational product(s) provisioned and/or 
repackaged/modified by Amgen.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational products supplied by Amgen are to be reported according to the 
instructions provided in the IPIM.   
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 


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 
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.  In subjects with 
AML hydroxyurea is allowed to control blasts as described in Section 6.7.2. 
 
NOTE:  Hydroxyurea is unapproved for AML in Japan. 
 
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 
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 times the t½ 
of the drug, or until the relevant biological effect has resolved (whichever is 
longer); or products containing grapefruit, Seville oranges, or St. John’s wort 
within 7 days, prior to enrollment.  Exception:  use of azole antifungal therapies. 
 
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. 


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 
Use of oral contraceptives (either combined or progesterone only), estrogenic 
vaginal ring/percutaneous contraceptive patches, or implants of 
levonorgestrel/Injectable progesterone for the purpose of pregnancy prevention 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.  However, oral contraceptives may be used for the treatment of 
menorrhagia or other abnormal menstrual bleeding at the discretion of the 
investigator. 
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. 
6.1.8 
Concomitant Medications with Itraconazole (Part 3d only) 
Itraconazole has the potential to interact with many concomitant drugs.  Please refer to 
the current itraconazole US Prescribing Information (USPI) for additional information 
including: 
 
Medications which are contraindicated and prohibited during and after the last 
dose of itraconazole administration 
 
Medications which are not recommended during and after the last dose of 
itraconazole administration 
 
The following medications are contraindicated with itraconzale and should not be 
administered during concomitant administration with itraconazole:  cisapride, oral 
midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, 
levacetylmethadol (levomethadyl), and ergot alkaloids such as 
dihydroergotamine, ergometrine (ergonovine), ergotamine, and 
methylergometrine (methylergonovine).  This is not an exhaustive list; please 
refer to itraconazole USPI for additional details. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Dose Level Determination 
The DLRT will be responsible for dosing recommendations, which may include 
escalation to the next nominal or intermediate dose, de-escalation to a lower nominal or 
intermediate dose; modifications of the ramp-up dosing, alternative dose frequencies, 
continuation, delay or termination of dosing; or repetition or expansion of a cohort; or 
determination of recommended dose.  Refer to Section 11.3 for additional details 
regarding the DLRT. 
6.2.1.1 
Dose-Limiting Toxicity Evaluation Period 
The minimum DLT evaluation period is defined as 4 weeks of treatment in cycle 1.   


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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 4) and completed the DLT evaluation period.   
Subjects who did not complete 75% of the planned doses of AMG 176 (and 100% of the 
planned doses of azacitidine in Part 4) 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 MTD/MTCD 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 MTD determination 
and replaced at the discretion of the Medical Monitor.   
6.2.1.2 
Definition of Dosage 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 CTCAE version 4.0 (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 4.0.  The relationship of an 
adverse event to investigational product will be determined by the investigator.  An event 
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.   


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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 Parts 1 BIW and QW Dose Escalation 
unless clearly attributable to causes other than AMG 176 treatment.   
If a DLT of TLS is observed during the ramp-up period, it will be attributed to the 
ramp-up period and a modification may be made to the ramp-up period regimen for 
subsequent groups.  Any other DLTs observed during the ramp-up and/or designated 
group dosing period may require a modification of the designated cohort dose (and/or 
ramp-up 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/PD information will be reviewed.  In addition to DLTs, all ≥ grade 3 toxicities not 
meeting DLT criteria will be reviewed and may be considered in DLRT decisions.  
Modeling of available potential safety risk data (eg, for thrombocytopenia) to predict 
safety risk for dose escalation decisions may also be considered.  


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Table 6-1.  DLT Criteria 
 
Multiple Myeloma Subjects 
Acute Myeloid Leukemia Subjects 
All Subjects 
DLT 
Criteria 
 
Non-hematologic adverse events: 
- 
grade 3 nausea, vomiting, or 
diarrhea persisting more than 
3 days despite optimal medical 
support.  ≥ grade 4 nausea, 
vomiting, or diarrhea of any 
duration would be considered 
as a DLT 
- 
grade 3 fatigue lasting > 7 days 
- 
≥ grade 3 acute kidney injury 
(creatinine > 3 × baseline or 
> 4.0 mg/dL) lasting > 3 days 
- 
any treatment-related death 
 
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 
 
any clinical TLS per Cairo-Bishop 
criteria (see Section 11.8.3) 
despite the use of prophylaxis 
 
DILI meeting Hy’s Law criteria 
(ie, AST or ALT ≥ 3 × ULN and 
serum bilirubin > 2 × 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 
Page 1 of 3 
Footnotes defined on last page of the table 


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Table 6-1.  DLT Criteria (continued) 
 
Multiple Myeloma Subjects 
Acute Myeloid Leukemia Subjects 
All Subjects 
DLT Criteria 
 
hematologic adverse events: 
- 
grade 3 or 4 neutropenia with fever 
> 38.5°C 
- 
grade 4 neutropenia lasting > 7 days 
- 
grade 3 thrombocytopenia with ≥ grade 2 
hemorrhage  
- 
grade 4 thrombocytopenia lasting 
> 7 days 
- 
grade 3 anemia with symptoms or 
requiring intervention (eg, transfusion) 
- 
grade 4 anemia 
- 
≥ grade 4 hematologic adverse events 
 
any grade 5 adverse event that is not clearly 
due to disease progression 
 
hematological adverse events: 
- 
grade 4 neutropenia or 
thrombocytopenia lasting 
≥ 42 days from start of cycle 
in absence of evidence of 
active AML 
 
any treatment-related death 
 
Symptoms of clinically significant 
cardiac dysfunction, ECG 
changes, or diagnostic evidence 
of decreased cardiac function or 
cardiac injury irrespective of any 
cardiac troponin-I level (central or 
locally obtained) 
Page 2 of 3 
Footnotes defined on last page of the table 


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Table 6-1.  DLT Criteria (continued) 
 
Multiple Myeloma Subjects 
Acute Myeloid Leukemia Subjects 
All Subjects 
Exceptions 
The following adverse events are not DLTs 
unless the specific criteria above are met: 
 
Fatigue 
 
Nausea 
 
Diarrhea 
 
Vomiting 
 
Neutropenia 
 
anemia  
 
thrombocytopenia 
 
lymphopenia 
 
increased serum creatinine or 
electrolyte abnormalities 
Non-hematological adverse events: 
 
grade 3 or 4 elevation of serum lipase in 
absence of clinical pancreatitis that last 
< 72 hours 
 
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 
N/A 
Page 3 of 3 
AML = acute myeloid leukemia; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DILI = drug-induced liver injury; DLT = dose-limiting toxicity; 
ECG = electrocardiogram; N/A = not applicable; TLS = tumor lysis syndrome; ULN = upper limit of normal; URL  upper reference limit 
a  Further treatment with AMG 176 may be considered for grade 1 elevations of troponin-I (ie, isolated elevation of troponin > 99th percentile URL of 0.04 ng/mL for 
females and 0.059 ng/mL for males) 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 confirmation, 
grading, and withholding decisions.  The following criteria is developed based on 
CTCAE 4.0 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 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 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
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). 
Dosage Adjustments 
Upon completion of the ramp-up 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. 
o 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 site investigator and Amgen’s Medical Monitor.  
o Subjects must be informed of the risk of continuing on therapy.  Each 
subject is only allowed a single dose reduction.  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 site investigator and Amgen’s 
medical monitor. 
 
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 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. 


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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  
 
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 
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 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. 
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 × ULN or total bilirubin greater 
than 1.5 × 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 
manufacturer’s prognostic cut-off) OR any change in the clinical status, above lab 
analytes (central or locally obtained), echocardiogram, 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.   
o Low elevations from 0.04 ng/mL for females or 0.059 ng/mL for males to 
 0.1 ng/mL do not require withholding or dose reductions, though troponins 
should be monitored with subsequent doses.   


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o Elevations  0.1 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 
 
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. 
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 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 site investigator and 
Amgen’s medical monitor.  
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 arrythmias possibly associated with AMG 176 
 
Symptoms of clinically significant cardiac dysfunction, 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 


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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 Anemia 
Anemia is one of the MM- and AML-related organ/tissue dysfunction and is generally 
related to bone marrow infiltration or renal dysfunction.  In AML, patients often present 
with a normocytic, normochromic anemia which worsens with chemotherapy.  Subjects 
should be monitored for changes in hemoglobin as described in the schedule of 
assessments (see Section 1.3).  Increased monitoring should be implemented in 
subjects whose hemoglobin < 8 g/dL.  Subjects should have anemia corrected in 
accordance with the local practice and institutional guidelines.  Hemoglobin parameters 
of grade 3 but not considered as clinically relevant (ie, without symptoms of anemia and 
not leading to a clinical intervention including withdrawal of investigational product 
treatment, transfusion, or significant additional concomitant therapy) will not require 
discontinuation of AMG 176.  A sudden decrease in hemoglobin levels requires the 
investigation of hemolysis.  Treatment should be discontinued for persistent (ie, ongoing 
> 3 weeks after the end of a treatment cycle) grade 3 or 4 anemia in the absence of 
detectable MM or AML which may reflect a prolonged marrow toxic effect of AMG 176.   
6.2.2.2.2 
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 and 
antifungal per institutional guidelines.   
These subjects should be monitored for early signs of breakthrough infections after the 
initiation of antibacterial therapy to prompt additional evaluation and possible therapy 


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modification.  Subjects experiencing diarrhea should be closely monitored for their 
electrolyte levels. 
6.2.2.2.3 
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 assessments (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 
arrythmia related to AMG 176 administration, AMG 176 should be permanently 
discontinued.   
6.2.2.2.4 
Management of Renal Toxicities 
Renal dysfunction is one of the MM-related organ/tissue dysfunction.  Renal function 
must be monitored closely during treatment with AMG 176.  Serum chemistry values, 
including blood urea nitrogen (BUN), serum creatinine, and urine for urinalysis and 
microscopic exam (microscopic exam only needed for positive dipstick), must be 
obtained and reviewed prior to each dose of AMG 176 per the schedule of assessments 
(see Section 1.3).  AMG 176 must be held for subjects with CrCl or estimated glomerular 
filtration rate < 30 mL/min/1.73 m2 or any other grade 3 or 4 renal toxicity any time during 
study treatment participation.  Management should be tailored to the appropriate 
treatment for the underlying renal disorder according to the local SOC and institutional 
guidelines.  AMG 176 can be restarted when the toxicity has improved to at least a 
grade 2.   
6.2.2.2.5 
Management of Gastrointestinal Toxicities 
Gastrointestinal toxicity (vomiting and diarrhea) have been observed with the use of 
AMG 176.  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.   


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6.2.2.2.6 
Prophylaxis and Management of Tumor Lysis Syndrome 
Refer to Section 11.8 for guidance.   
6.2.2.2.7 
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 
troponin-I assay will be performed for all screening, grading, and withholding decisions.  


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6.2.2.2.8 
SARS-CoV-2 and COVID-19 Guidance 
Grade 
Interruption/Delay 
Specific 
Management 
Restart Guidance 
Permanent 
Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Asympto
matic 
Interruption required 
until at least 10 days 
since positive 
SARS-CoV-2 test. 
UNLESS subject 
previously fully 
vaccinated against 
SARS-CoV-2.  If 
subject previously 
vaccinated and tests 
positive, then discuss 
with medical monitor. 
Follow local 
guidelines and 
SOC for COVID-19 
treatment and 
isolation 
Contact Amgen 
medical monitor 
within 1 business 
day to ensure 
appropriate 
documentation and 
management of 
study activities 
 
Restart possible upon agreement between investigator and Amgen 
medical monitor provided: 
 
There are no new findings on physical exam related to 
SARS-CoV-2, AND 
 
Subject tests negative for SARS-CoV-2 by RT-PCR, 
OR 
 
If subject continues to test positive for SARS-CoV-2 more than 
10 days after initial positive test, or if subject initially tests positive 
in the setting of prior COVID vaccination, resume investigational 
product only after discussion with subject and reassessment of 
individual risk/benefit 
 
Consider chest imaging, ECG, ECHO, and cardiology assessment 
prior to restart 
 
Consider hospitalization for restart of IP based on length of treatment 
interruption, risk of CRS at restart, and amount of time since subject 
was last treated 
 
Dose modification:  resume at the same dose or reduce to next lower 
dose, if clinically indicated 
 
Premedication and assessments:  follow guidance in SOA tables 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
IP therapy, if: 
Subject required 
treatment interruption 
greater than 28 days and 
upon discussion with 
Amgen medical monitor 
the decision is made to 
permanently discontinue 
treatment 
OR 
Initial benefit/risk 
assessment for individual 
subject is not maintained 
any longer 
Page 1 of 2 
Abbreviations defined on last page of table. 


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Grade 
Interruption/Delay 
Specific 
Management 
Restart Guidance 
Permanent 
Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Symptom
atic 
Interruption required 
until at least 10 days 
since complete 
resolution of acute 
symptoms 
Follow local 
guidelines and SOC 
for COVID-19 
treatment and 
isolation 
Contact Amgen 
medical monitor 
within 1 business day 
to ensure appropriate 
documentation and 
management of study 
activities 
 
Restart possible upon agreement between investigator and Amgen 
medical monitor provided: 
 
There are no new findings on physical exam and chest imaging, 
related to SARS-CoV-2 
 
Subject tests negative for SARS-CoV-2 by RT-PCR,  
 
OR 
 
If subject continues to test positive for SARS-CoV-2 more than 
10 days after initial positive test, resume IP only after discussion 
with subject and reassessment of individual risk/benefit 
 
Consider chest imaging, ECG, ECHO, and cardiology assessment 
prior to restart  
 
Consider hospitalization for restart of IP based on length of treatment 
interruption, risk of CRS at restart, and amount of time since patient 
was last treated  
 
Dose modification:  resume at the same dose or reduce to next lower 
dose if clinically indicated 
 
Premedication and assessments:  follow guidance in SOA tables 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
IP therapy if: 
Subject required 
treatment interruption 
greater than 28 days due 
to severe or 
life-threatening COVID-19 
OR 
Initial benefit/risk 
assessment for individual 
subject is not maintained 
any longer 
Page 2 of 2 
COVID-19 = coronavirus disease 2019; CRS = cytokine release syndrome; ECG = electrocardiogram; ECHO = echocardiogram; RT-PCR = real-time polymerase chain 
reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOA = Schedule of Activities; SOC = standard of care 
 


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6.2.2.3 
Non-Investigational Products:  Azacitidine and Itraconazole 
The reason for dose change of non-investigational products 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.   
6.2.2.3.1 
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 × 109/L and/or ANC  1 × 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 × [baseline 
count - nadir count]). 
 
Subjects without reduced baseline blood counts (ie, WBC  3.0 × 109/L and 
ANC  1.5 × 109/L, and platelets  75.0 × 109/L) prior to the first treatment. 
For subjects with baseline (start of treatment) WBC  3.0 × 109/L, ANC  1.5 × 109/L, 
and platelets  75.0 × 109/L, adjust the dose as follows, based on nadir counts for any 
given cycle: 
Table 6-2.  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 × 109/L, ANC  1.5 ×109/L, or 
platelets  75.0 × 109/L, dose adjustments should be based on nadir counts and bone 
marrow biopsy cellularity at the time of the nadir as noted below, 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 6-3.  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 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.   
6.2.2.3.2 
Itraconazole 
Discontinue administration of itraconazole if there are signs or symptoms of congestive 
heart failure or acute cardiac injury.  Refer to the itraconazole capsule USPI for 
additional information regarding itraconazole-specific adverse reactions and instructions 
for dose modifications or withdrawal.   
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.   
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and/or other protocol-required therapies during 
the study are provided in the IPIM.   


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6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
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 
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 (Parts 4 
and 5 only) directly from the investigator or designee, under supervision.  The date and 
time of each dose administered in the clinic will be recorded in the source documents 
and recorded in the CRF.   
For subjects enrolled in Part 3d, itraconazole dosing will be documented in the source 
documents and CRF.  For days when subjects will self-administer itraconazole, they will 
be given a dosing diary to record the self-administered itraconazole doses.  The diary 
should be reviewed at the next clinic visit and documented in the source documents and 
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 
Section 6.2.2.1 and Section 6.2.2.2.7.   
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 
The investigator or designee will collect relevant prior therapy which includes previous 
chemotherapy or radiotherapy, anticancer therapies (eg, stem cell transplant).   


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For prior therapies, collect therapy name, regimen, start and stop dates, reason for 
stopping therapy, best response, and date of progression.   
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments, including RBC and platelet transfusions as deemed necessary to provide 
adequate supportive care except for those listed in Section 11.8.1 and Section 6.1.7.   
Concomitant therapies (including vaccines) are to be collected from screening start 
through 30 days (+3 days) after the last dose of protocol-required 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 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.  
Hydroxyurea is unapproved for AML in Japan.   
6.7.2.1 
Bone Disease Therapy (Multiple Myeloma Subjects Only) 
Bisphosphonate or denosumab therapy is strongly recommended for all MM subjects 
with evidence of lytic destruction of bone or with osteopenia (Gralow et al, 2013; 
Terpos et al, 2013).  Commercially available IV bisphosphonates (pamidronate and 
zoledronic acid) or denosumab are preferred when available, and should be used 
according to the manufacturer’s recommendations, as described in the prescribing 
information, for subjects with osteolytic or osteopenic myelomatous bone disease.  Oral 
bisphosphonates may be used as alternatives if IV bisphosphonates or denosumab are 
not available at the study site.  It is preferred that investigators use the same route of 
bisphosphonate therapy for all subjects at their sites.   


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Investigators should not start bisphosphonate therapy during the study, unless it has 
been agreed with the sponsor that there is no sign of disease progression.  Subjects with 
evidence of lytic destruction of bone or with osteopenia who are not using a 
bisphosphonate at the time of enrollment should start a bisphosphonate within the first 
2 cycles of study drug.   
6.7.2.2 
Antifungal Prophylaxis 
Use of micafungin (or other echinocandins), posaconazole (or other azole antifungals), 
and amphotericin B for antifungal prophylaxis is allowed for neutropenic subjects with 
AML.   
6.7.2.3 
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.   
6.7.2.4 
Vaccines 
Every effort should be made to fully vaccinate subjects at least 14 days prior to first dose 
of AMG 176.  The use of vaccines except live vaccines will be allowed during therapy 
per regional and institutional SOC.  SARS-CoV-2 vaccinations should be avoided during 
screening (within 14 days from the first dose of AMG 176) and should be also avoided in 
the first treatment cycle for better assessment of safety parameters.  Throughout study 
participation, SARS-CoV-2 vaccination should be avoided within 3 days after the 
administration of AMG 176 due to the potential of overlapping adverse events.   
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution.   
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 7.1 and Section 7.2.1.   


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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 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 
Section 1.3) 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 or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 11.3.   
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following:   
 
decision by sponsor (other than subject request, safety concern, or lost to 
follow-up) 
 
lost to follow-up 
 
death 
 
subject request 
 
safety concern (eg, due to an adverse event) 
 
ineligibility determined 
 
protocol deviation 
 
non-compliance (eg, procedural or dosing as defined in Section 6.5) 
 
confirmed disease progression per International Myeloma Working Group 
Uniform Response Criteria (IMWG-URC) in MM subjects (Section 11.9)  
 
confirmed disease progression per 2017 ELN criteria (Section 11.15) in AML 
subjects 
 
AML:  Hematological or extramedullary relapse subsequent to complete 
response (CR)/CRh*/CRi/morphologic leukemia-free state on protocol treatment.  


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Exception:  a blast equivalent count > 5% at the pre-dose assessment (after the 
infusion-free interval) would not lead to permanent treatment discontinuation 
even if the count had been < 5% directly after the previous treatment cycle. 
 
requirement for alternative therapy 
 
pregnancy 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) 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 


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possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record.   
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.   
 
For subjects who are lost to follow-up, the investigator can search publicly 
available records (where permitted) to ascertain survival status.  This ensures 
that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible.   
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3).   
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment.   
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct.   
8.1 
General Study Periods 
A signed and dated IRB-approved informed consent must be obtained before any study 
specific procedures are performed.  Procedures that are part of routine care are not 
considered study-specific procedures and may be used at screening to determine 
eligibility.  All subjects will be screened for eligibility before enrollment.  Only eligible 
subjects will be enrolled into the study.   
Demographic data 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 
 and 
PK.   
Cycle 1 and 2 visits should be done on days specified as possible.  All subsequent visits 
beginning on cycle 3 will have a  1-day window unless otherwise specified.   
8.1.1 
Screening, Enrollment and/or Randomization 
After obtaining informed consent, all screening procedures and tests establishing 
eligibility will be performed within a period of 14 days prior to enrollment unless 
otherwise noted in the schedule of assessments.  Core bone marrow biopsy or bone 
marrow aspirate performed as SOC can be used to meet screening requirements if 


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performed within 4 weeks from enrollment and no curative anti-cancer therapy was 
administered during the time from biopsy to enrollment.  The procedures to be 
completed during the screening period are described in the Schedule of Assessments 
(see Section 1.3).   
All blood and urine samples collected for screening assessments will be submitted and 
analyzed by the local/central laboratory as applicable (see Section 8.2.5).  Screening 
laboratory assessments used to determine subject eligibility may be repeated once (up 
to a total of 2 times during the 14-day screening period), if necessary.  The investigator 
must provide appropriate rationale prior to repeating any other screening procedures or 
tests during the screening period.  Testing for HIV is not required unless mandated by 
local regulatory authorities.   
After the subject has signed the informed consent, the current medication list should be 
sent to Amgen’s medical monitor for review and approval.  Written documentation of this 
review and Amgen acknowledgment is required for subject participation.  In addition, any 
new medication other than what is indicated for TLS prophylaxis, should be reviewed 
and approved by the principal investigator and the Amgen medical monitor prior to start 
of the treatment.   
Rescreening 
Subjects may be re-screened up to 2 additional times at the discretion of the 
Investigator.  The subject must sign a new informed consent form if the re-screening 
attempt occurs outside of the 14-day screening period.  For subjects undergoing 
re-screening, a bone marrow biopsy and imaging procedures are not needed if 
performed within the last 4 weeks from enrollment.   
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Assessments (see Section 1.3).  The date of the first 
dose of AMG 176 is defined as day 1.  AMG 176 is to be administered after all 
protocol-specific pre-dose assessments have been performed during each visit that it is 
required.  Subjects will receive treatment until disease progression (see Section 8.2.2.1 
and Section 8.2.2.2), unacceptable toxicity, withdrawal of consent, or death (whichever 
occurs first); this is also applicable to subjects enrolled in Part 3d after they crossover to 
Part 3b or Part 4.   


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8.1.3 
End of Treatment 
The 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.  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 days (+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 assessments will occur every 3 months ( 14 days) 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 long-term follow-up visit will require an echocardiogram (see Section 8.2.3.4.2).   
8.1.6 
End of Study 
The end of study visit for an individual subject will be the final long-term follow-up visit.   
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points.   
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed.   
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on 
 
and pharmacokinetics of the protocol-required therapies.   


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8.2.1.3 
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.   
8.2.1.4 
Physical Examination 
A complete physical examination will be performed by the investigator or designee 
according to local practices at screening and time points specified in the Schedule of 
Assessments (Section 1.3).  Physical examination findings should be recorded on the 
appropriate case report form (CRF) (eg, medical history, event).   
8.2.1.5 
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).   
8.2.1.6 
Eastern Cooperative Oncology Group Performance Status  
Eastern Cooperative Oncology Group Performance Status (Section 11.10) assessments 
will occur at time points specified in the Schedule of Assessments (see Section 1.3).   
8.2.2 
Efficacy Assessments 
8.2.2.1 
Multiple Myeloma Tumor Assessment and Disease Assessment 
Disease assessment will be performed at screening and every 28 days (± 7 days) until 
confirmed PD (Section 8.2.2.1.7) irrespective of cycle duration including dose delays and 
treatment discontinuation as per the schedule of assessments (Section 1.3).  For 
subjects who do not progress during treatment, disease assessments will continue to be 
measured every 28 days (± 7 days) until PD.   
Disease response and progression assessments include:  serum protein electrophoresis 
(SPEP), urine protein electrophoresis (UPEP), SFLC, serum and urine immunofixation 
(SIFE, UIFE, respectively) (Section 8.2.2.1.1) bone marrow aspirate sample evaluation 


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(Section 8.2.2.1.2), serum calcium, skeletal survey evaluation (Section 8.2.2.1.6), and 
plasmacytoma evaluation (Section 8.2.2.1.5).   
8.2.2.1.1 
Serum Protein Electrophoresis, Urine Protein Electrophoresis, 
Serum Free Light Chain, Serum Immunofixation, and Urine 
Immunofixation 
Serum protein electrophoresis and 24-hour UPEP is required for all subjects at 
screening.  Thereafter, SPEP is to be done at each time point for all subjects as 
indicated in the schedule of assessments.  Serum free light chain assay and ratio will be 
performed at each time point as specified in the schedule of assessments.   
Urine protein electrophoresis with 24-hour urine collection is required at each time point 
only if screening UPEP shows measurable paraprotein in the urine and for confirmation 
of very good partial response (VGPR) or complete remission as per IMWG-URC.  If 
screening UPEP is negative, spot urine is required at each time point.  If positive for 
paraprotein, a 24-hour urine collection with UPEP must be done at the next assessment 
and at each subsequent assessment unless the UPEP shows an absence of 
paraprotein.  Immunofixation is required at next assessment only if SPEP or UPEP 
results are zero/undetectable.   
8.2.2.1.2 
Bone Marrow Sample Evaluation  
Bone marrow aspirate samples will be collected from all subjects during screening to 
quantify percent myeloma involvement and for 
, both to be performed at the study 
center.  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.   
An additional bone marrow aspirate sample will only be required to confirm a complete 
response.   
An aliquot of the bone marrow aspirate collected at screening will be sent to the central 
laboratory for minimal residual disease (MRD) clone type status determination by 
next-generation sequencing (NGS).  Additional bone marrow aspirates will be collected 
for MRD disease assessments for subjects who achieve complete response and 
12 months following a complete response if this response persists.   


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8.2.2.1.3 
Quantitative Immunoglobulin  
Quantitative Ig will be performed at screening and quantitative IgA and IgD at every 
disease assessment in subjects with IgA or IgD myeloma, respectively.  For subjects 
with other myeloma subtypes, quantitative Ig will be repeated only if clinically indicated.  
For example, if frequent infection despite MM disease control or deemed clinically 
indicated by the investigator.   
8.2.2.1.4 
Beta-2 Microglobulin 
Beta-2 microglobulin will be performed at screening.  In addition, it will be performed at 
each time point for all subjects as indicated in the schedule of assessments as part of 
risk stratification.   
8.2.2.1.5 
Plasmacytoma in Multiple Myeloma Subjects 
Plasmacytoma survey will be performed at the time points as specified in the schedule of 
assessments (see Section 1.3).  For subjects without a history of extramedullary 
disease, assessment by physical examination at screening is acceptable.  
Plasmacytoma evaluation is to be repeated during treatment only to confirm a response 
of partial response or better, to confirm PD, or if clinically indicated.  If clinically indicated 
due to history of extramedullary disease, the same technique (may include ultrasound, 
X-ray, computed tomography [CT] scan, magnetic resonance imaging [MRI], positron 
emission tomography [PET], or other SOC method) must be employed for each 
measurement.   
8.2.2.1.6 
Skeletal Survey in Multiple Myeloma Subjects 
Bone lesion assessment is required at screening on all MM subjects.  A bone lesion 
survey by standard radiography (X-ray) will include lateral radiograph of the skull, 
anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, 
ribs, femora, and humeri.  Low-dose whole body CT, fluorodeoxyglucose-PET (FDG 
PET)/CT, or MRI may be used in place of standard radiography.  Bone lesion 
assessment at screening (all subjects) may be done within 30 days prior to enrollment, if 
performed as a part of SOC.  It should be repeated if worsening clinical symptoms 
suggest PD or as clinically indicated.  These imaging studies will be read locally.   
8.2.2.1.7 
Disease Response Assessment in Multiple Myeloma 
Subjects will be evaluated for disease response and progression according to the IMWG 
response criteria in Section 11.9.  Disease status categories include stringent complete 
response, complete response, VGPR, partial response, minimal response, stable 
disease, and PD.   






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in Section 11.15 for additional detail.  Complete remission/CRi must be established from 
bone-marrow samples 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.   
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3).   
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic blood pressure (SBP), 
diastolic blood pressure (DBP), respiratory rate, heart rate and temperature.  Subject 
must be in rested and calm state for at least 5 minutes before BP assessments are 
conducted.  The position selected for a subject should be the same that is used 
throughout the study and documented on the vital sign eCRF.  Record all measurements 
on the vital signs eCRF.   
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs/temperature eCRF.  Vital signs 
will be recorded at screening and time points specified in the Schedule of Assessments 
(see Section 1.3).   
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.   
8.2.3.2 
Electrocardiograms (ECGs) 
The subject should rest for at least 5 minutes before ECG assessment is conducted.  
Electrocardiograms should be performed in a standardized method, in triplicate (at 
designated time points), and run consecutively (approximately 1 minute apart), prior to 
blood draws or other invasive procedures.  Each ECG must include the following 
measurements:  QRS, QT, QTc, RR, and PR intervals.   
Electrocardiograms will be performed as follows (at time points indicated in Section 1.3):   
 
Screening:  Single ECG 
 
Baseline (pre-dose cycle 1 day 1):  Three baseline ECGs will be collected 
approximately 15 minutes apart (± 5 minutes), with each baseline ECG in 


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triplicate 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) for a total of 
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 
The principal investigator or designated site physician will review all ECGs.   
Once signed, the original ECG tracing will be retained with the subject’s source 
documents and transferred electronically to a central ECG vendor for reconciliation and 
storage per Amgen instructions.  At the request of Amgen, a copy of the original ECG 
will be made available to Amgen.   
Note:  ECGs will be transferred electronically to an ECG central vendor for reconciliation 
and storage per Amgen instructions.   
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.   
8.2.3.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained.   
8.2.3.4 
Other Safety 
8.2.3.4.1 
Peripheral Neuropathy Assessment in Multiple Myeloma Subjects 
The peripheral neuropathy assessment should be done at screening and safety 
follow-up (Section 1.3).  These assessments must be reported on the corresponding 
eCRF page (see Section 11.13 for peripheral neuropathy assessment tool).   
8.2.3.4.2 
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 MRI at baseline, EOT, 
and the first long-term follow-up visit is recommended.  If cardiac imaging was performed 


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within 4 weeks of C1D1, one does not need to be performed again at screening as long 
as the same modality is used throughout the study.   
8.2.4 
Adverse Events and Serious Adverse Events  
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Disease-related Events 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
medicinal product(s)/study treatment/protocol-required therapies through the safety 
follow-up visit are reported using the Event CRF.  Additionally, the investigator is 
required to report a fatal disease-related event on the Event CRF.   
Events assessed by the investigator to be related to the investigational medicinal 
product(s)/study treatment/protocol-required therapies, and determined to be serious, 
require reporting of the event on the Event CRF.   
8.2.4.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and is described in 
Section 11.4.   
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the safety follow-up visit are reported using the Event CRF.   
8.2.4.1.3 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through safety follow-up visit are reported using the Events CRF.  Exception:  
cardiac-associated serious adverse events will be collected from signing of the informed 
consent through the end of long-term follow-up.   
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee immediately and no later than 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 immediately and no later than 24 hours of it being 
available.   


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The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events.   
8.2.4.1.4 
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 8.2.4.1.3) is complete, then these serious adverse events will be reported to 
Amgen immediately and no later than 24 hours following the investigator’s awareness of 
the event on the Events CRF.  In addition, the investigator will also need to collect/report 
fatal serious adverse events (regardless of causality) to Amgen immediately and no later 
than 24 hours following investigator’s awareness of the event.   
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 
immediately and no later than 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.   
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4.   




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8.2.4.5 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.   
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.   
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary.   
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements.   
8.2.4.6 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes.   
8.2.4.7 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 3 months after 
the last dose of investigational product.   
If a pregnancy is reported, the investigator is to inform Amgen immediately and no later 
than 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.   


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8.2.5 
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.  
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).   
8.2.5.1 
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. 
8.2.5.2 
Tumor Lysis Syndrome Laboratory Monitoring 
Tumor lysis syndrome prophylaxis must be initiated prior to all ramp-up 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 (QW 
schedule) or until 48 hours post the first dose in the BIW dosing schedule.  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.   


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8.2.5.3 
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.   
8.2.5.4 
Pregnancy Testing 
Females of childbearing potential will have a local laboratory pregnancy test (urine or 
serum) performed at screening, prior to each treatment cycle (pre-dose), end of 
treatment, and at the safety follow-up visit.   
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.   
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations.   
8.2.6 
Pharmacokinetic Assessments 
For pharmacokinetic assessment blood samples for quantitative determination of 
AMG 176 and azacitidine, will be collected at time points specified in the Schedule of 
Assessments (see Section 1.3).  Sample collection, processing, storage, and shipping 
instructions are provided in a separate laboratory manual.  Please NOTE:  
Pharmacokinetic and 
 samples are required to be shipped the day of the draw.  
Backup samples are to be shipped separately and can be batched weekly for shipment.   
Note:  Pharmacokinetic samples must not be drawn from the IV site where 
investigational product has been administered.  Pharmacokinetic samples must be 
drawn from a site which is distal (eg, opposite arm) from the site where the 
investigational product has been administered to avoid contamination of the PK samples 
and to better estimate PK parameters.  Additionally, all sites should document the site of 
drug infusion and the site of PK sample collection relative to the site of drug infusion.   
8.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study (saliva 
sample), DNA analyses may be extracted and performed.  These optional 
pharmacogenetic analyses focus on inherited genetic variations to evaluate their 
possible correlation to the disease and/or responsiveness to the therapies used in this 
study.  The goals of the optional studies include the use of genetic markers to help in the 


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investigation of cancer and/or to identify subjects who may have positive or negative 
response to AMG 176.  An additional saliva sample will be collected for all subjects on 
study in Parts 1a, 1b, 3a, 3b, and 4.  A saliva sample will not be collected for Part 3c and 
subjects in Japan in Part 4.   
The final disposition of samples will be described in Section 11.6.   
 
 
, 


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8.2.9 
Optional Substudies 
 
 
 
 
   


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
At least one dose level of AMG 176 administered as monotherapy will achieve 
acceptable safety and tolerability in subjects with relapsed or refractory MM with 
evidence of biologic impact as shown by either evidence of reduction in MCL1 activity in 
circulating monocytes/circulating blasts and/or evidence of anti-tumor activity.   
At least 1 dose level of AMG 176 administered as a monotherapy or in combination with 
azacitidine will achieve acceptable safety and tolerability in subjects with relapsed or 
refractory AML with evidence of biologic impact, as shown by either evidence of 
reduction in MCL1 activity in circulating monocytes/circulating blasts and/or evidence of 
anti-tumor activity.   
9.2 
Sample Size Determination 
It is anticipated that approximately 219 subjects will be enrolled in the different parts of 
this study.  Multiple myeloma Part 1a enrolled 36 subjects for dose escalation.  Multiple 
myeloma Part 1b enrolled 12 subjects for dose escalation.  Acute myeloid leukemia 
Part 3a enrolled 17 subjects for dose escalation.  Part 3b enrolled 11 subjects.  Acute 


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myeloid leukemia Part 3c enrolled 4 subjects in Japan.  Part 3d will enroll about 
11 subjects in the US.  Part 4 will enroll approximately 60 subjects.  Part 5 will enroll 
approximately 68 subjects.   
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 MTD or MTCD and 
to evaluate DDI.  With 3 subjects in a cohort, there is a 27 to 70 probability of 
observing at least one DLT if the true DLT rate is 10 to 33 and with 6 or 9 subjects in 
a cohort there is a 47 to 91 probability and 61 to 97 probability, respectively.   
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
The analysis of all endpoints (see Section 3), unless noted otherwise, will be conducted 
on the Full Analysis Set (FAS), and by cohort.  The FAS is defined as all subjects that 
are enrolled and receive at least 1 dose of AMG 176.  The analysis of DLT will be 
restricted to DLT evaluable subjects (see Section 6.2.1.2.1).  The PK Analysis Set will 
contain all subjects who have received at least 1 dose of the investigational product and 
have at least 1 PK sample collected.  These subjects will be evaluated for PK analysis 
unless the number of data points required for analysis is not enough, or significant 
protocol deviations have affected the data, or if key dosing or sampling information is 
missing. 
9.3.2 
Covariates 
The relationship of covariates to efficacy endpoints will be explored if appropriate.  
 may be incorporated in additional 
 
  The analyses of 
 performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints.   
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 4.5.1.   


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9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analyses 
No formal interim efficacy analysis is planned.  Interim safety analyses will be performed 
to support the evaluation of safety as summarized in Table 9-1.   
Table 9-1.  Summary of Interim Analyses 
Part 
Interim Analysis 
Method 
Multiple myeloma Part 1a AMG 176 
BIW Monotherapy 
Safety/Dosing 
Decisions - DLRT 
Standard 3+3 Design 
(see Section 4.1.1) 
Multiple myeloma Part 1b AMG 176 
QW Monotherapy 
Safety/Dosing 
Decisions - DLRT  
Standard 3+3 Design 
(see Section 4.1.1) 
Acute myeloid leukemia Part 3a 
AMG 176 BIW Monotherapy 
Safety/Dosing 
Decisions - DLRT  
Standard 3+3 Design 
(see Section 4.1.1)  
Acute myeloid leukemia Part 3b 
AMG 176 QW Monotherapy 
Safety/Dosing 
Decisions - DLRT  
mTPI Design 
(see Section 4.1.1)  
Acute myeloid leukemia Part 3c 
AMG 176 QW Monotherapy (Japan 
Cohort) 
Safety/Dosing 
Decisions - DLRT  
Standard 3+3 Design 
(see Section 4.1.2)  
Acute myeloid leukemia Part 4 
AMG 176 QW and BIW in 
combination with azacitidine 
Safety/Dosing 
Decisions - DLRT  
mTPI Design 
(see Section 4.1.1)  
Acute myeloid leukemia Part 5A 
AMG 176 (QW or BIW) in 
combination with azacitidine 
Safety/Dosing 
Decisions 
Simon’s Two-stage 
Minimax Design 
(see Section 4.1.1) 
BIW = twice weekly; DLRT = dose-level review team; mTPI = modified Toxicity Probability Interval; 
QW = once weekly 
Safety data will be reviewed on an ongoing basis.  The DLRT (see Section 11.3) will 
review all available cumulative data by cohort prior to making dose escalation 
recommendations.  Adverse events and DLTs observed in all subjects will be evaluated 
continually and considered in all enrollment and dosing decisions.   
In Part 5A, Simon’s two-stage minimax design (Simon, 1989) will be used to 
provide interim futility criteria to minimize the number of subjects exposed to a 
potentially ineffective treatment.  The null hypothesis is that the true response 
rate of CR or CRi is 0.1 and the alternative hypothesis is that the true response 
rate of CR or CRi is 0.32.  In each cohort, the trial is carried out in two stages.  In 
stage I, a total number of 18 subjects is accrued.  If there are 3 (16.7%) or fewer 
responses (CR or CRi) among these 18 subjects, the study may be early stopped 
based on the totality of the data.  Otherwise, additional 6 subjects will be accrued 
in stage II, resulting in a total number sample size of 24.  If there are 6 (25%) or 


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more responses (CR or CRi) among these 24 subjects, we will reject the null 
hypothesis and claim that the treatment is promising.  The design controls the 
two-sided type I error rate at 0.05 and yields the power of 0.8. 
 and preliminary efficacy data will be reviewed on an ongoing basis as 
part of an evaluation of evidence of biologic impact.  In particular, the number of overall 
responses (per IMWG for MM subjects or 2017 ELN criteria for AML subjects) and the 
level of AMG 176 inactivation of MCL1 by the activation of BAX and caspase 3 in 
circulating monocytes and /or the decrease of circulating monocytes will be regularly 
reviewed.   
Additional interim analyses will be performed when the target number of subjects 
enrolled in each part has had the opportunity to complete 6 months of treatment.   
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 AMG 176.   
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, PD and 
 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.  


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9.4.2.2 
Efficacy Analyses 
9.4.2.2.1 
Multiple Myeloma (Part 1a, and Part 1b) 
Endpoint 
Statistical Analysis Methods 
Primary 
There are no primary efficacy endpoints in MM 
Secondary 
Summaries of BAX and caspase 3 levels in the circulating monocytes will be 
provided.  Summaries will be described over time using the absolute level and 
also using changes from baseline levels.  Plots of the relationship between 
AMG 176 concentrations and BAX/caspase 3 levels and/or monocyte counts 
will be provided. 
The proportion of subjects with overall response to treatment per the IMWG 
for MM subjects with corresponding 2-sided exact 95% CI will be calculated 
using the Clopper-Pearson method (Clopper and Pearson, 1934) and 
tabulated for subjects treated at the MTD 
Kaplan-Meier curve will be presented for PFS, time to response (partial 
response or better) and DOR with estimates for rates and 2-sided 95% CI at 
selected weeks. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
9.4.2.2.2 
Acute Myeloid Leukemia (Part 3a, Part 3b, Part 3c, Part 3d, Part 4, 
and Part 5) 
Endpoint 
Statistical Analysis Methods 
Primary 
There are no primary efficacy endpoints in AML 
Secondary 
The proportion of subjects with overall response using 2017 ELN criteria for 
AML subjects with corresponding 2-sided exact 95% CI will be calculated 
using the Clopper-Pearson method (Clopper and Pearson, 1934) and 
tabulated for subjects treated at the MTCD. 
Kaplan-Meier curve will be presented for EFS, time to response, and DOR 
with estimates for rates and 2-sided 95% CI at selected weeks. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Primary 
The analysis of the probability of DLT will include data from DLT 
evaluable- subjects (see Section 6.2.1.2.1 for definition of DLT-evaluable).  
The primary analysis for each part will only include DLTs that occur within the 
protocol defined DLT evaluation interval. 
 
9.4.2.3.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code all events categorized as adverse events or disease-related events.   


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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 withdrawal from investigational product or other protocol 
required therapies, and treatment emergent adverse events will also be provided.  
Subject incidence of disease-related events, fatal disease-related events, and 
device-related events, if applicable, will be tabulated by system organ class and 
preferred term.  Similar summaries will also be provided to events of interest.  
Subject-level data may be provided instead of tables if the subject incidence is low.   
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.  Shifts in vital sign 
values between baseline and the worst on-study value will be tabulated by cohorts.   
9.4.2.3.5 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects’ maximum change from baseline in QT interval corrected by 
Fridericia’s formula will be categorized and the number and percentage of subjects in 
each group will be summarized.  Subjects’ maximum post baseline values will also be 
categorized and the number and percentage of subjects in each group will be 
summarized.  All on-study ECG data will be reviewed and select parameters of interest 
may be plotted.   
9.4.2.3.6 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to AMG 176.  The 
number of cycles initiated, completed, discontinued will be summarized.  In addition, the 
duration, total dose, and dose intensity of AMG 176 will be summarized.   
9.4.2.3.7 
Exposure to Non-investigational Product 
Descriptive statistics will be produced to describe the exposure to azacitidine.  The 
number of cycles initiated, completed, discontinued, the duration of therapy and total 
dose will be summarized.  Subject-level data may be provided instead of the summary if 
the subject incidence is low or single dose is given.   


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9.4.2.3.8 
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.  In addition, the 
number and proportion of subjects receiving anti-cancer therapies during long-term 
follow-up will be summarized.   
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.   
The PK parameters for AMG 176 including, but not limited to Cmax, minimum observed 
concentration (Cmin), AUC, CL, and, if feasible, t½ will be estimated using standard 
non-compartmental PK methods and summarized by dose groups using means, 
standard deviations, medians, minimums, and maximums for intensive and peak/trough 
determinations.  AMG 176 concentrations at each time point along with PK parameter 
values may be reviewed for each subject.  Individual AMG 176 concentration/time 
profiles will be plotted by dose groups.  Summary statistics will be computed for each 
sampling time and parameter as appropriate.  For subjects in Part 3d (DDI assessment 
with itraconazole), AMG 176 PK parameters (Cmax, AUC) will be compared from day 1 
(with itraconazole) to day 15 (without itraconazole) to evaluate the effect of itraconazole 
on the PK of AMG 176.  Geometric mean ratios for Cmax and AUC values and associated 
90 CI (Test/Reference) will be estimated.  The “Test” treatment will be AMG 176 
co-administered with itraconazole on day 1, while the “Reference” treatment will be 
AMG 176 administered without itraconazole on day 15.  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.  Additional analyses to explore 
relationship between exposure and safety and exposure and efficacy may also be 
performed.  Pharmacokinetic parameters such as Cmax, AUC, and t½, if feasible, will be 
estimated and summarized for azacitidine. 
9.4.2.4.2 
Prior Anti-cancer Therapy Summary 
Prior anti-cancer therapies for current malignancy will be summarized.   


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10. 
References 
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leukemia in adults:  2017 ELN recommendations from an international expert panel, on 
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2006;20(12):2220.  Leukemia.  2007;21(5):1134. 
Durie BG.  International Myeloma Foundation.  Multiple Myeloma Cancer of the Bone 
Marrow.  Concise Review of the disease and treatment Options.  2011/2012. 
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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. 
Fischer MA, Song Y, Arrate MP, et al.  Selective inhibition of MCL1 overcomes 
venetoclax-resistance in a murine model of myelodysplastic syndromes.  
Haematologica.  2023;108(2):522-531. 
Glaser SP, Lee EF, Trounson E, et al.  Anti-apoptotic MCL1 is essential for the 
development and sustained growth of acute myeloid leukemia.  Genes Dev.  
2012;26(2):120-125. 
Gralow JR, Biermann JS, Farooki A, et al.  NCCN Task Force Report:  Bone Health In 
Cancer Care.  J Natl Compr Canc Netw.  2013;11(Suppl 3):S1-S50. 
Guo L, Eldrige S, Furniss M, et al.  Role of Mcl-1 in regulation of cell death in human 
induced pluripotent stem cell-derived cardiomyocytes in vitro.  Toxicol Appl Pharmacol.  
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Halpern AB, Lyman GH, Walsh TJ, et al.  Primary antifungal prophylaxis during 
curative-intent therapy for acute myeloid leukemia.  Blood.  2015;126(26): 2790-2797. 
Hayat MJ, Howlader N, Reichman ME, et al.  Cancer statistics, trends, and multiple 
primary cancer analyses from the surveillance, epidemiology, and end results (SEER) 
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International Conference on Harmonisation.  Guidance on S9 Nonclinical Evaluation for 
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Itraconazole Prescribing Information:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020083s040s041s044lbl.pdf  
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syndrome after failure of decitabine therapy.  Cancer.  2010;116(16):3830-3834. 


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Ji Y, Liou P, Bekele BN.  A modified toxicity probability interval method for dose-finding 
trials.  Clinical Trials.  2010;7:653-663. 
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human lymphomas even when they bear mutations in p53.  Genes Dev.  
2014;28(1):58-70. 
Kozopas KM, Yang T, Buchan HL, et al.  MCL1, a gene expressed in programmed 
myeloid cell differentiation, has sequence similarity to BCL2.  Proc Natl Acad Sci U S A.  
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Kumar S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
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Lat A, Thompson GR.  Update on the optimal use of voriconazole for invasive fungal 
infections.  Infection and Drug Resistance.  2011;4:43-53. 
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replacement for ketoconazole in drug–drug interaction studies.  J Clin Pharm.  
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Lonial S, Dimopoulos M, Palumbo A, et al.  Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma.  N Engl J Med.  2015;373:621-631. 
Maiti A, Rausch CR, Cortes JE, et al.  Outcomes of Relapsed or refractory acute myeloid 
leukemia after frontline hypomethylating agent and venetoclax regimens.  
Haematologica.  2021;106(3):894-898. 
Mateos MV, Dimopoulos JC, Suzuki K, et al.  Daratumumab plus Bortezomib, 
Melphalan, and Prednisone for Untreated Myeloma.  N Engl J Med.  2018;378:58-528. 
Moreau P, Masszi N, Grzasko NJ, et al.  Oral Ixazomib, Lenalidomide, and 
Dexamethasone for Multiple Myeloma.  N Engl J Med.  2016;374:1621-1634. 
National Comprehensive Cancer Network.  Clinical Practice Guidelines in Oncology, 
AML, 2013.  http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. 
O'Donnell EK, Raje NS.  New monoclonal antibodies on the horizon for multiple 
myeloma.  Ther Adv Hematol.  2017;8:41-53. 
Palumbo A, Chanan-Khan A, Weisel K, et al.  Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma.  N Engl J Med.  2016;375:754-766. 
Palumbo A, Anderson K.  Multiple Myeloma.  N Engl J Med.  2011;364:1046-1060. 
Peperzak V, Vikström I, Walker J, et al.  MCL1 is essential for the survival of plasma 
cells.  Nat Immunol.  2013;14(3):290-297. 
Phillips DC, Xiao Y, Lam LT, et al.  Loss in MCL-1 function sensitizes non-Hodgkin's 
lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199).  
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after azacitidine treatment failure.  J Clin Oncol.  2011;29(24):3322-3327. 
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in relapsed chronic lymphocytic leukemia.  N Engl J Med.  2016;374:311-322.   
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Dexamethasone for Relapsed Multiple Myeloma.  N Engl J Med.  2015;372:142-152. 
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11. 
Appendices 
 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
AST 
aspartate aminotransferase (SGOT) 
ASXL1 
additional sex combs like-1 
AUC 
area under the concentration-time curve 
AUC0-168 hr 
area under the concentration-time curve from 0 to 168 hours 
BAK 
B-cell receptor associated kinases 
BAX 
B-cell lymphoma/leukemia 2 associated X protein 
BCL2 
B-cell lymphoma/leukemia 2 
BCL2-L1 
BCL2 like 1 
BCR-ABL1 
breakpoint cluster region protein-Abelson murine leukemia viral 
oncogene homolog 1 
BCL-XL 
B-cell lymphoma extra large 
BCRP 
breast cancer resistance protein 
BIL 
Bilirubin 
BIM 
Bcl-2-interacting mediator of cell death 
BIW 
twice weekly 
BLI 
bioluminescence imaging 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBFB-MYH11 
core-binding factor subunit beta-myosin, heavy chain 11 
CEBPA 
CCAAT enhancer binding protein alpha 
CK-MB 
creatine kinase-muscle/brain 
CL 
Clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CrCl 
creatinine clearance 


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Abbreviation or Term 
Definition/Explanation 
CRi 
incomplete hematologic recovery; complete response/remission with 
incomplete recovery of peripheral blood counts 
CRF 
case report form  
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
D 
Day 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLRM 
dose-level review meeting 
DLRT 
dose-level review team 
DLT 
dose-limiting toxicity 
DMSO 
dimethylsulfoxide 
DOCR 
duration of complete remission 
DOR 
duration of response 
DBP 
diastolic blood pressure 
DR 
durable response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ED50 
pharmacologically active dose causing 50% tumor size reduction 
EDC 
electronic data capture 
EFS 
event free survival 
ELN 
European LeukemiaNet 
End of Study/EOS 
defined as the date when the last subject across all sites is assessed 
or receives an intervention for evaluation in the study (ie, last subject 
last visit), following any additional parts in the study (eg, long-term 
follow-up), as applicable.  
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject. 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), 
for the purposes of conducting the last primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.  
End of Treatment/EOT 
defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
EOI 
end of infusion 
eSAE 
electronic serious adverse event 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FIH 
first in human 
 
 
FLC 
serum light chain 
FLT3 
fms-like tyrosine kinase 3 
FLT3 ITD 
fms-like tyrosine kinase 3 internal tandem duplication 
FSH 
follicle stimulation hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor; 
GGT 
gamma-glutamyl transferase 
G-CSF 
granulocyte colony stimulating factor 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage colony stimulating factor 
h, hr 
Hour 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
heart rate/HR 
number of cardiac cycles per unit of time 
HiDAC 
high dose cytarabine 
HIV 
human immunodeficiency virus 
HNSTD 
highest-non-severely-toxic dose 
HRT 
hormone replacement therapy 
HSCT 
hematopoietic stem cell transplant 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 


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Abbreviation or Term 
Definition/Explanation 
IMWG 
International Myeloma Working Group  
IMWG-URC 
International Myeloma Working Group - Uniform Response Criteria 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IQ-CPLG 
Innovation and Quality of Pharmaceutical Development’s Clinical 
Pharmacology Leadership Group 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISS 
International Staging System 
ITD 
internal tandem duplication 
IV 
intravenous or roman numeral 4 
Ki 
inhibitory constant 
LAIP 
leukemia-associated immunophenotype 
LDH 
lactate dehydrogenase 
LKM1 
Liver Kidney Microsomal antibody 1 
LVEF 
left ventricular ejection fraction  
MAD 
maximum administrated dose 
MCL1 
myeloid cell leukemia sequence 1 
MDS 
myelodysplastic syndromes 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
medium fluorescent intensity 
MLFS 
morphologic leukemia free state 
MM 
multiple myeloma 
MOMP 
mitochondrial outer membrane permeabilization 
MRD 
minimal residual disease 
MRD[-] 
minimal residual disease negativity 
MRI 
magnetic resonance imaging 
MTCD 
maximum tolerated combination dose 
MTD 
maximum tolerated dose 
mTPI 
modified Toxicity Probability Interval 
MUGA 
multigated acquisition scan 
N, n 
Number 
NCCN 
National Clinical Cancer Network 
NGS 
next-generation sequencing 


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Abbreviation or Term 
Definition/Explanation 
NK 
natural killer 
NPM1 
nucleophism 1 
NT-pro-BNP 
N-terminal prohormone of brain natriuretic peptide 
OATP 
organic anion polypeptide transporters 
OBD 
optimal biological dose 
OR 
overall response 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PBPK 
physiologically based pharmacokinetic 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PML-RARA 
promyelocytic leukemia-reintoic acid receptor alpha 
PR 
partial response 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG or partial response 
PT 
prothrombin time 
PUMA 
p53 up-regulated modulator of apoptosis 
Q8W 
every 8 weeks 
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 
QT  
QT interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle as measured 
by ECG 
QTc  
QT interval corrected for heart rate using accepted methodology 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QW 
once weekly 
R/R 
relapsed or refractory 
RP2D 
recommended phase 2 dose 
RBC 
red blood cell 
RCV 
reference change value 
RT-PCR 
real-time polymerase chain reaction 
RUNX1 
runt-related transcription factor 1 


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Abbreviation or Term 
Definition/Explanation 
RUNX1-RUNX1T1 
runt-related transcription factor 1-RUNX1 translocation partner 1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBE-β-CD 
sulfobutylether-β-cyclodextrin 
SBP 
systolic blood pressure 
SC 
subcutaneous(ly) 
sCR 
stringent complete response 
Screen 
Screening 
SD 
standard deviation 
SFLC 
serum free light chain 
SFU 
safety follow-up 
SIFE 
serum immunofixation 
SOC 
standard of care 
SPEP 
serum protein electrophoresis 
STD10 
severely toxic dose in 10% of the animals 
t½ 
half-life 
TBA 
total bile acid 
TBL 
total bilirubin 
TDI 
time-dependent inhibition 
tmax 
time of maximum observed serum concentration 
TLS 
tumor lysis syndrome 
TP53 
tumor protein p53 
UIFE 
urine immunofixation 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
UPM 
unit probability mass 
US 
United States 
USPI 
US Prescribing Information 
VGPR 
very good partial response 
WBC 
white blood cell 
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.  All locally obtained test results are to be recorded in the eCRF.  
Pharmacokinetic,
 samples will be sent to the 
central laboratory for processing.  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). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.1 to Section 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 (continued) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AML = acute myeloid leukemia; 
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; eCRF= electronic case report form
; 
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; SARS-CoV-2 = severe 
acute respiratory syndrome coronavirus 2; SFLC = serum-free light chain; SPEP = serum protein 
electrophoresis; UPEP = urine protein electrophoresis; WBC = white blood cell 
a Peripheral blood counts for AML disease assessments will include ANC, platelets, hemoglobin, and blasts. 
b For local laboratory tests, all available analytes listed in the table should be recorded in the eCRF.   
 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose-Level Review Team 
Dose-Level Review Meetings (DLRM) 
The DLRT will hold meetings to review data, monitor safety, and make decisions on 
dose-escalation or dose de-escalation or changes.  The DLRT will be composed of the 
investigators or designees (for Part 3c, the Japan site investigators only), and the 
following Amgen representatives:  early development lead, medical monitor, global 
safety officer or designee, clinical study manager, biostatistician; additional members 
may be added as needed (eg, clinical pharmacologist).  The following members are 
responsible for DLRT recommendations:  investigators, Amgen medical monitor, and 
global safety officer or designee.  All available study data, including data collected after 
the initial DLT evaluation period, and including demographics, investigational product 
administration, medical history, concomitant medications, adverse events, ECGs, vital 
signs, laboratory data, and PK/PD information will be reviewed.  In addition to DLTs, all 
≥ grade 3 toxicities not meeting DLT criteria will be reviewed and may be considered in 
DLRT decisions.  Data to be reviewed will be queried.  The DLRT may review the 
available PK, PD and PK/PD information from all previous cohorts with known 
non-clinical data and safety information.  The planned dose will be adapted accordingly, 
if needed.  Modeling of available potential safety risk data (eg, for anemia) to predict 
safety risk for dose escalation recommendations may also be considered. 
A quorum, defined as > 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), must be in attendance for the dose-level 
review meeting (DLRM).  The decision to proceed to the next dose level or an interim 
dose level will be made by the sponsor in conjunction with the investigators after careful 
consideration of all available safety, laboratory, and PK information.  Safety data from all 
enrolled subjects in preceding cohorts and dose levels will also be considered.  
Additionally, further enrollment into a cohort can be stopped at any time to evaluate 
safety. 


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Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, 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. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the US 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/her site.  Updates to the sample informed 


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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 will then be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
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 
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 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.  


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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 
re-screening 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 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 


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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. 
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 International Committee of Medical Journal Editors (ICMJE) 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 


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to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
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.  


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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
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). 
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 


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transfer records, depending on the study.  Also, current medical records must be 
available. 
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 prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 














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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 


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Table 11-2.  Expected Disease-related Events by System Organ Class (SOC) for 
Multiple Myeloma 
System Organ Class 
Disease-Related Adverse Events 
Blood and lymphatic system disorders 
Anemia, neutropenia, leukopenia, 
thrombocytopenia.  
Cardiovascular disorders 
Shortness of breath (from renal failure), 
Oedema peripheral (renal failure) 
Eye disorders 
Blurred vision (hyperviscosity) 
Gastrointestinal disorders 
Nausea, constipation (hypercalcemia), 
abdominal pain (hypercalcemia) 
General disorders and administration site 
reaction 
Fatigue, malaise, pain, chest pain, mass, 
excessive thirst, 
Immune system disorders 
Infection in an immunocompromised host 
Investigations 
Hemoglobin decreased, platelet count 
decreased, white blood cell count decreased, 
total protein increase, creatinine increase, 
abnormal serum electrophoresis, 
immunoglobulin level increased or decreased, 
weight decreased. 
Metabolism and nutrition disorders 
Anorexia, hypoalbuminemia, hypercalcemia, 
dehydration 
Musculoskeletal and connective tissue 
disorders 
Skeletal pain, pathological fractures, 
osteoporosis, osteopenia, bone pain, pain in 
extremity, back pain, muscle weakness 
Neoplasms benign, malignant and 
unspecified 
Plasmacytoma  
Nervous system disorders 
Lethargy, confusion (from hypercalcemia), 
peripheral neuropathy, dizziness 
(hyperviscosity), headache (hyperviscosity) 
Renal and urinary disorders 
Renal failure, nephrotic syndrome, oliguria 
Vascular disorders 
venous thromboembolism 
Other 
Arthroplasty, osteotomy, bone fixation 


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Table 11-3.  Expected Disease-related Events by System Organ Class (SOC) for 
Acute Myeloid Leukemia 
System Organ Class 
Disease-Related Adverse Events 
Blood and lymphatic system disorders 
Febrile neutropenia, anemia, neutropenia, 
thrombocytopenia, leukopenia, leukocytosis, 
disseminated intravascular coagulation  
Cardiovascular disorders 
Palpitations, tachycardia 
Ear and labyrinth disorders 
Ear pain, tinnitus 
Eye disorders 
Blurred vision 
Gastrointestinal disorders 
Abdominal distension, abdominal pain, 
constipation, diarrhea, gingival pain, nausea 
General disorders and administration site 
reaction 
Fatigue, pyrexia, malaise, pain, chest pain 
Infections and infestations 
Infectiona, sepsis 
Investigations 
Alanine aminotransferase increased, aspartate 
aminotransferase increased, alkaline 
phosphatase increased, white blood cell 
decreased, hemoglobin decreased, platelet 
count decreased 
Metabolism and nutrition disorders 
Decreased appetite, hypokalemia, 
hyponatremia, hypocalcemia, hyperuricemia 
Musculoskeletal and connective tissue 
disorders 
Skeletal pain, muscular pain, arthralgia, 
generalized muscle weakness, neck pain 
Nervous system disorders 
Cranial nerve disorder, dizziness, headache, 
lethargy, meningismus, syncope 
Respiratory, thoracic, and mediastinal 
disorders 
Cough, dyspnea, epistaxis, pleuritic pain 
Other 
Hemorrhageb 
a Represents preferred terms under Infections and infestations SOC 
b Represents haemorrhage HLGT preferred terms contained within multiple SOCs.  Coded:  MedDRA 17.0 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female subjects of childbearing 
potential are outlined in Section 5.2.   
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant during 
treatment and for 3 months after the last dose of protocol-required therapies or father a 
child during treatment and for 4 months after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception for an increased length of time.  The 
investigator must discuss these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 


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Contraception Methods for Female Subjects 
Highly Effective Methods of Contraception 
 
Non-hormonal (ie, copper) intrauterine device (IUD) 
 
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) 
Potential DDI between the study drug(s) and hormone-based contraceptives are not 
established.  The hormonal contraceptive methods listed below therefore may have 
decreased effectiveness, and consequently may not prove as reliable with regard to 
prevention of pregnancy on study.   
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
 
Hormone-releasing intrauterine device  
 
Intrauterine hormonal-releasing system 
Study subjects should utilize any or all appropriate measures to prevent pregnancy while 
on study.   
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 with spermicide during treatment and for an additional 4 months 
after the last dose of protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, IUD, intrauterine hormonal-releasing system (IUS), 
female barrier method (diaphragm, cap, sponge [a female condom is not an option 
because there is a risk of tearing when both partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 


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Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 
immediately and no later than 24 hours of learning of a subject’s pregnancy.  
(Note:  Sites are not required to provide any information on the Pregnancy 
Notification Form that violates the country or regions local privacy laws). 
 
After obtaining the female subject’s signed 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 investigational product of the study drug.  This 
information will be forwarded to Amgen Global Patient Safety.  Generally, infant 
follow-up will be conducted up to 12 months after the birth of the child (if 
applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate 
will be reported as an adverse event or serious adverse event.  Note that an 
elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must 
be reported to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as 
a serious adverse event (eg, female subject experiences a spontaneous 
abortion, stillbirth, or neonatal death or there is a fetal or neonatal congenital 
anomaly) the investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which 
is considered reasonably related to the study treatment by the investigator, will 
be reported to Amgen Global Patient Safety as described in Section 11.4.  While 
the investigator is not obligated to actively seek this information in former study 


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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 the last dose of investigational product 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 immediately and no later than 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). 
 
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. 
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 immediately and no later than 
24 hours of the investigator’s awareness of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the 
study as described in exclusion criterion 233. 
 
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 the last dose of 
investigational product after discontinuing protocol-required therapies. 


Product:  AMG 176 
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Page 192 of 219 
CONFIDENTIAL  
 
 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 
 
 
  
 
 
Confidential Clinical Trials 
Pregnancy Notification Form 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
 
1. Case Administrative Information 
Protocol/Study Number:  20150161 
 
 
Study Design: 
Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2. Contact Information 
Investigator Name   
_ 
Site #   
 
 
Phone (  
)  
_ 
Fax (_     _)  
 
 
Email   
 
Institution   
 
Address    
 
 
3.  Subject Information 
Subject ID #   
_ 
Subject Gender: 
Female 
Male 
Subject age (at onset):       (in years) 
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
conception 
Frequency 
Route 
Start Date 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
 
5.  Pregnancy Information 
Pregnant female’s last menstrual period (LMP) 
mm   
/ dd______/ yyyy  
  
Unknown 
N/A 
 Estimated date of delivery   mm  
/ dd  
_/ yyyy  
 
If N/A, date of termination (actual or planned) mm   
 
/ dd   _/ yyyy  
 
 
Has the pregnant female already delivered? 
Yes 
No  
Unknown 
N/A 
If yes, provide date of delivery:  mm    
 
/ dd   
 
/ yyyy  
 
Was the infant healthy? 
Yes 
No 
Unknown 
N/A 
If any Adverse Event was experienced by the infant, provide brief details:  
 
 
 
 
 
 
Form Completed by: 
 
Print Name:    
 
 
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
 
 
FORM-115199                                                                                       Version 1.0                                                                         Effective Date: 24-Sept-2018 


Product:  AMG 176 
Protocol Number:  20150161 
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Page 193 of 219 
CONFIDENTIAL  
 
 
 
 
  
 
 
Confidential Clinical Trials 
 
Lactation Notification Form 
 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
1. Case Administrative Information 
Protocol/Study Number:  20150161 
 
 
Study Design: 
Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2.  Contact Information 
Investigator Name   
 
 
 
Site #   
 
 
Phone (  
)  
 
 
Fax (  
)  
 
 
Email   
 
Institution   
 
Address    
 
 
 3.  Subject Information 
Subject ID #   
 
 
 
 
 
Subject age (at onset):       (in years)
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
5.  Breast Feeding Information 
 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? 
Yes 
No 
 
If No, provide stop date:  mm   
 /dd   
/yyyy  
 
Infant date of birth: mm  
/dd  
/yyyy  
  
Infant gender: 
Female 
Male 
 
Is the infant healthy? 
Yes 
No 
Unknown 
N/A 
 
 
If any Adverse Event was experienced by the mother or the infant, provide brief details:  
 
 
 
 
 
 
 
  Form Completed by: 
 
Print Name:    
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
FORM-115201                                                                                      Version 1.0                                                                           Effective Date: 24-Sept-2018 


Product:  AMG 176 
Protocol Number:  20150161 
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Page 194 of 219 
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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood and tumor samples collected according to the Schedule of Activities 
(Section 1.3) can be analyzed for any of the tests outlined in the protocol and for any 
tests necessary to minimize risks to study subjects.  This includes testing to ensure 
analytical methods produce reliable and valid data throughout the course of the study.  
This can also include, but is not limited to, investigation of unexpected results, incurred 
sample reanalysis, and analyses for method transfer and comparability.   
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand MM 
and AML, the dose response and/or prediction of response to AMG 176, and 
characterize aspects of the molecule (eg, mechanism of action/target, 
s).  
Results from this analysis are to be documented and maintained but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of 
 are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent.   
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood 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 


Product:  AMG 176 
Protocol Number:  20150161 
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Page 195 of 219 
CONFIDENTIAL  
 
 
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.   


Product:  AMG 176 
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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009.   
Criteria for Withholding and/or Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver 
 (TBL, INR and transaminases) has not been 
identified.   
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to:   
 
hepatobiliary tract disease 
 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
alpha-one antitrypsin deficiency 
 
alcoholic hepatitis 
 
autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
nonalcoholic fatty liver disease including steatohepatitis 
 
non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix.   


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix).   
Table 11-4.  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 
> 3 × ULN  
at any time 
> 2 × ULN 
 
 
OR 
INR 
-- 
> 1.5 × (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 × ULN at any time 
> 5 × ULN but < 8 × ULN for ≥ 2 weeks 
> 5 × ULN but < 8 × ULN and unable to 
adhere to enhanced monitoring schedule 
> 3 × 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 
> 3 × ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8 × 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 medical monitor.   
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 11-4) 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, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4.   
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-4 or who experience AST or ALT elevations > 3 × 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 > 2 × 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 


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CONFIDENTIAL  
 
 
 
a more detailed history of:  
 prior and/or concurrent diseases or illness 
 exposure to environmental and/or industrial chemical agents  
 symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
concomitant use of medications (including non-prescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
 
viral serologies 
 
creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
appropriate liver imaging if clinically indicated 
 
appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies.   
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.   


Product:  AMG 176 
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Page 200 of 219 
CONFIDENTIAL  
 
 
11.8 
Appendix 8.  Additional Guidance for Tumor Lysis Syndrome 
11.8.1 
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS) 
All subjects will receive TLS prophylaxis as described in Section 6.1.4.1.  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.   
Allopurinol is unapproved for TLS prophylaxis in Japan.   
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 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).  
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 
electrocardiogram (ECG).   
Vital signs should be taken at time of all blood draws or any intervention.   
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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Abnormality 
Management Recommendations 
Hyperkalemia (including rapidly rising potassium) 
 Potassium ≥ 0.5 mmol/L 
increase from prior 
value (even if potassium 
within normal limits) 
 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 within normal limits, 
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 × 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 × 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 arrhytmias.  Do not 
administer in same IV line as sodium bicarbonate.  
 Recheck potassium, phosphorus, uric acid, calcium and 
creatinine every hour STAT. 
Page 1 of 2 


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CONFIDENTIAL  
 
 
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. 
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 2 of 2 
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.   


Product:  AMG 176 
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11.8.2 
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
Two or more of the following criteria occurring within 3 days before or 7 days after 
therapy: 
Element 
Value 
 
Change from Baseline 
Uric Acid 
≥ 476 µmol/L (8 mg/dL) 
OR 
25% increase from baseline 
Potassium 
≥ 6.0 mmol/L (6 mg/dL) 
OR 
25% increase from baseline 
Inorganic phosphorus 
≥ 1.45 mmol/L (4.5 mg/dL) 
OR 
25% increase from baseline 
Calcium 
≤ 1.75 mmol/L (7.0 mg/dL) 
OR 
25% decrease from baseline 
11.8.3 
Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
One or more of the following, in a subject meeting criteria for laboratory TLS: 
 
Grade 
Complication 
0 
1 
2 
3 
4 
5 
Creatininea, b 
Normal 
≤ 1.5 × ULN 
> 1.5 – 
3.0 × ULN 
> 3.0 – 
6.0 × ULN 
> 6.0 × ULN 
Death 
Cardiac 
Arrhythmiaa 
None 
Intervention 
not indicated 
Nonurgent 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically or 
controlled with 
device (eg, 
defibrillator) 
Life-threaten
ing (eg, 
arrhythmia 
associated 
with CHF, 
hypotension, 
syncope, 
shock) 
Death 
Seizurea 
None 
N/A 
One brief, 
generalized 
seizure(s) 
well 
controlled by 
anticonvulsan
ts or 
infrequent 
focal motor 
seizures not 
interfering 
ADL 
Seizure in 
which 
consciousness 
is altered; 
poorly 
controlled 
seizure 
disorder; with 
breakthrough 
generalized 
seizures 
despite medical 
intervention 
Seizure of 
any kind 
which are 
prolonged 
repetitive or 
difficult to 
control (eg, 
status 
epilepticus, 
intractable 
epilepsy) 
Death 
ADL = activities of daily living; CHF = congestive heart failure; N/A = not applicable; 
ULN = upper limit of normal 
a  Not directly or probably attributable to therapeutic agent. 
b  If no institutional ULN is specified, age/sex ULN creatine may be defined as follows:  Cairo-Bishop Clinical 
Tumor Lysis Syndrome Definition and Grading. 
Note:  Laboratory tumor lysis syndrome and at least one clinical complication. 
References: 
1. 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. 
2. Cairo MS, Bishop M.  Tumour lysis syndrome:  new therapeutic strategies and classification.  Br J 
Haematol.  2004;127(1):3-11. 


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11.9 
Appendix 9.  International Myeloma Working Group Uniform 
Response Criteria for Multiple Myeloma (IMWG-URC) 
Response 
Subcategorya Multiple Myeloma Response Criteria 
sCRb 
 
CR as defined below and 
 
Normal SFLC ratio and  
 
Absence of clonal cells in bone marrowc by immunohistochemistry or 
immunofluorescencec 
CRb 
 
Negative immunofixation on the serum and urine and  
 
Disappearance of any soft tissue plasmacytomas and 
 
 5 plasma cells in bone marrowc  
VGPRb 
 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis  
or  
 
 90 reduction in serum M-protein with urine M-protein 
level 100 mg/24 hours 
 
If the serum and urine M-protein are not measurable, a decrease of  90 
in the difference between the involved and uninvolved FLC levels required 
in place of the M-protein criteria.  However, documentation of VGPR 
requires collection and analysis of 24-hour urine sample for UPEP and 
immunofixation and confirmed to be negative. 
 
If present at Baseline, a  50 reduction in the size of soft tissue 
plasmacytomas is also required. 
PRb 
 
 50 reduction of serum M-protein and reduction in 24 hour urinary 
M-protein by  90 or to  200 mg/24 h 
 
If the serum and urine M-protein are unmeasurable, a  50 decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria. 
 
If serum and urine M-protein are not measurable, and serum free light 
assay is also not measurable,  50 reduction in plasma cells is required in 
place of M-protein, provided baseline bone marrow cell percentage was 
 30 
 
If present at Baseline, a  50 reduction in the size of soft tissue 
plasmacytomas is also required  
MR 
 
25-49 reduction in the level of serum M-protein and a 50–89 
reduction in 24-hour urinary M-protein, which still exceeds 200 mg per 
24 hours 
 
If the serum and urine M-protein are not measurable, a decrease of 
25-49 in the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria. 
 
If present at Baseline, a 25–49 reduction in the size of soft tissue 
plasmacytomas is also required 
Stable disease  
Not meeting criteria for CR, VGPR, PR, or PD 
Page 1 of 2 
Footnotes defined on next page 


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Response 
Subcategorya Multiple Myeloma Response Criteria 
PDb 
Any one or more of the following: 
 
Increase of  25 from lowest response value in: 
➢ Serum M-component and/or (the absolute increase must be  0.5 g/dL)  
o 
Urine M-component and/or (the absolute increase must be 
 200 mg/24 h) 
o 
Only in patients without measurable serum and urine M-protein levels; 
the difference between involved and uninvolved FLC levels.  The 
absolute increase must be  10 mg/dL 
➢ Bone marrow plasma cell percentages (absolute percentage must be 
 10) 
 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomase, f, g 
 
Development of hypercalcemia (corrected serum calcium  11.5 mg/dL or 
2.65 mmol/L) that can be attributed solely to the plasma cell proliferative 
disorder 
Page 2 of 2 
Source:  Durie et al, 2006; Rajkumar et al, 2011 (modified for protocol purposes). 
CR  complete response; sCR  stringent complete response; FLC  serum light chain; MR  minor 
response; PD  progressive disease; PR  partial response; SFLC  serum-free light chain; SPEP  serum 
protein electrophoresis; UPEP  urine protein electrophoresis; VGPR  very good partial response 
Note:  Patients with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required 
to meet response criteria in both UPEP and SPEP in order to qualify for a MR or better.  Conversely, it 
should be noted criteria for PD only needs to be met, and confirmed, in 1 parameter.  For patients without 
measurable protein on UPEP at Baseline, UPEP will need to be repeated to confirm a response. 
a  Patients with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to 
meet response criteria in both UPEP and SPEP in order to qualify for a MR or better.  Conversely, it 
should be noted that criteria for PD only needs to be met, and confirmed, in one parameter. 
b  All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time 
before the institution of any new therapy, as well as no known evidence of progressive or new bone 
lesions if radiographic studies were performed.  Radiographic studies are not required to satisfy these 
response requirements.  Bone marrow, plasmacytoma, and skeletal survey assessments are not required 
to be confirmed by repeat testing.  SD requires a duration of  6 weeks. 
C  Presence/absence of clonal cells is based upon the / ratio.  An abnormal / ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  
An abnormal ratio reflecting presence of an abnormal clone is / of  4:1 or  1:2. 
d  Determination of PD while on study requires 2 consecutive assessments made at any time before 
classification of PD and/or the institution of new therapy.  Serum M-component increases of  1 g/dL from 
nadir are sufficient to define progression if nadir M-component is  5 g/dL.   
e  Plasmacytomas:  A definite increase in the size is defined as a  50 increase as measured serially by the 
sum of the products of the cross-diameters of the measurable lesion.  A plasmacytoma is considered 
measurable if the longest diameter is at least 1 cm and the product of the cross diameters is at least 
1 cm2.  Plasmacytomas of lesser size will be considered non-measurable.   
f  The requirement for bi-directional measurements applies only to plasmacytomas. 
g  The plasmacytoma specifications for PD are based on interpretation of the IMWG-URC and practical 
considerations for study execution. 
 


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11.10 
Appendix 10.  ECOG Performance Status and NYHA Classification 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all 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. 
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. 
 


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11.11 
Appendix 11.  Medications That may Cause QTc Prolongation 
List of medications known to cause QTc interval prolongation is available at the following 
link:  https://crediblemeds.org/. 
If subject 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 subject 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 (AML).  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 
Amitriptyline* 
 24 hours, wide interpatient 
variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol 
(active metabolite t½  7 - 10 hours) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30  7 hours 
 
 
Clarithromycin 
Non-linear PK3-4 hour (250 mg Q12) 
5-7 hour (500 mg Q12) 
36 
 
Chloroquine 
6-60 days; mean 20 days 
 
 
Desipramine* 
 24 hours, wide interpatient 
variability 
 
 
Disopyramide 
6.7 hour (4-10) 
36 
 
Dofetilide 
10 hours 
48 
 
Dolasetron 
8.1 hours 
 
 
Domperidone 
7-8 hours 
48 
 
Doxepin* 
 24 hours, wide interpatient 
variability 
 
 
Droperidol 
2.2 hours 
10 
 
Page 1 of 3 
Footnotes defined on last page of the table. 
 


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


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Compounds 
Compound Half-life 
Possible Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult;  
3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active 
metabolite) t½  21-30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours (only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
 34 hours in healthy;  
 19 hours in Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hours 
24 
 
Thioridazine 
20-40 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 
2.8-3.7 hours (higher in female) 
18 
 
Page 3 of 3 
HCTZ  hydrochlorothiazide; IV  intravenous; IM  intramuscular; LAAM  levo-alpha-acetylmethadol; 
NAPA  N-acetylprocainamide; PK  pharmacokinetics; QD once daily. 
* 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 patients 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. 
 


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11.12 
Appendix 12.  Definition of Relapsed or Refractory Progressive 
Disease and Line of Therapies 
Relapsed disease is defined as progression occurs in the absence of therapy.  
Refractory disease is defined as disease that is nonresponsive while on primary or 
salvage therapy, or progresses within 60 days of last therapy. 
Progressive Disease (PD) for Subjects with MM requires any one or more of the 
following: 
 
Increase of  25 from lowest response value in any of the following 
 
Serum M-component and/or (the absolute increase must be  0.5 g/dl)  
 
Urine M-component and/or (the absolute increase must be  200 mg/24 h) 
 
Only in subjects without measurable serum and urine M-protein levels:  the 
difference between involved and uninvolved serum light chain (FLC) levels (the 
absolute increase must be  10 mg/dl) 
 
Bone marrow plasma cell percentage:  the absolute  must be  10 
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
 
Development of hypercalcemia (corrected serum calcium  11.5 mg/dL or 
2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
A line of therapy is defined as one or more cycles of a planned treatment program.  
This may consist of one or more planned cycles of single-agent therapy or combination 
therapy, as well as a sequence of treatments administered in a planned manner.  For 
example, a planned treatment approach of induction therapy followed by autologous 
stem cell transplantation, followed by maintenance is considered one line of therapy.  
A new line of therapy starts when a planned course of therapy is modified to include 
other treatment agents (alone or in combination) as a result of disease progression, 
relapse, or toxicity.  A new line of therapy also starts when a planned period of 
observation off therapy is interrupted by a need for additional treatment for the disease 
(Rajkumar 2011).  
Progressive Disease in Subjects with AML is defined as: 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute 
blast counts in the blood: 
 
 50 increase in bone marrow blasts over baseline (a minimum 15 point increase 
is required in cases with  30 blasts at baseline; or persistent marrow blast 
percentage of  70 over at least 3 months; without at least a 100 improvement in 
absolute neutrophil count (ANC) to an absolute level ( 0.5 x 109/L [500/L], and/or 
platelet count to  50 x 109/L [50,000/L] nontransfused); or 


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 
 50 increase in peripheral blasts (WBC x  blasts) to  25 x 109/L ( 25,000/L) 
(in the absence of differentiation syndrome)†; or 
 
New extramedullary disease 
Relapse After Complete Remission for Subjects with AML is defined as: 
 
Bone marrow blasts  5; or  
 
reappearance of blasts in the blood; or  
 
development of extramedullary disease 
These response criteria were published in 2010, "Diagnosis and management of AML in 
adults:  Recommendations from an international expert panel, on behalf of the European 
LeukemiaNet" (Döhner et al, 2010). 
The criteria for PD were suggested in the 2017 ELN recommendations 
(Döhner et al, 2017). 


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11.13 
Appendix 13.  Peripheral Neuropathy Assessment 
TNSr Items 
0 
1 
2 
3 
4 
Symptom extension 
(tingling, 
numbness, 
neuropathic pain)a 
None 
Symptoms 
limited to 
fingers or 
toes  
Symptoms 
extend to 
ankle or wrist 
Symptoms 
extend to knee 
or elbow 
Symptoms 
above knees 
or elbows or 
functionally 
Disability  
Pin sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to wrist/ankle 
Reduced up to 
elbow/knee 
Reduced up 
to above 
elbow/knee 
Vibration sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to wrist/ankle 
Reduced up to 
elbow/knee 
Reduced up 
to above 
elbow/knee 
Strengthb 
Normal 
Mild 
weakness 
Moderate 
weakness 
Severe 
Weakness 
Paralysis 
Tendon reflexes 
Normal 
Ankle reflex 
reduced 
Ankle reflex 
absent 
Ankle reflex 
absent/others 
reduced 
All reflexes 
absent 
a  The worse score of the 3 subcomponents (tingling/paresthesia, numbness, and neuropathic pain proximal 
extension) was used as the subjective symptom extension score. 
b  The muscle with the worse score is used as the strength score (toe, ankle, wrist and finger extensors and 
flexors, quadriceps, hamstrings, biceps, and triceps).  TNSr and pain items were adapted with permission 
[Smith, 2010]. 
 


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11.14 
Appendix 14.  World Health Organization Classification for Acute 
Myeloid Leukemia 
Definition AML:  20 myeloblasts in blood or in bone marrow.   
Abnormal promyelocytes in acute promyelocytic leukemia, promonocytes in AML with 
monocytic differentiation and megakaryoblasts in acute megakaryocytic leukemia are 
considered blast equivalents.  Subjects with APL are not eligible for this study.  First, 
AML should be classified as AML with recurrent cytogenetic abnormalities.  If this is not 
applicable the leukemia is classified as AML with multilineage dysplasia or therapy 
related and if this subtype is also not applicable as AML not otherwise categorized.  
Acute Myeloid Leukemia and Related Precursor Neoplasms, and Acute Leukemias of 
Ambiguous Lineage (Arber et al, 2016):   
AML and related neoplasms  
AML with recurrent genetic abnormalities 
 
AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);  
CBFB-MYH11 
Acute promyelocytic leukemia with PML-RARA* 
AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A† 
AML with t(6;9)(p23;q34.1); DEK-NUP214 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); 
GATA2,MECOM(EVI1) 
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);  
RBM15-MKL1‡ 
Provisional entity:  AML with BCR-ABL1 
AML with mutated NPM1§ 
AML with biallelic mutations of CEBPA§ 
Provisional entity:  AML with mutated RUNX1 
AML with myelodysplasia-related 
changes|| 
  
Therapy-related myeloid neoplasms{ 
 
AML, NOS 
AML with minimal differentiation 
AML without maturation 
AML with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/monocytic leukemia  
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis 
Page 1 of 2 
Footnotes defined on last page of table 


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Myeloid sarcoma 
 
Myeloid proliferations related to Down 
syndrome 
Transient abnormal myelopoiesis 
Myeloid leukemia associated with Down syndrome  
Blastic plasmacytoid dendritic cell 
neoplasm 
 
 
Acute leukemias of ambiguous lineage 
Acute undifferentiated leukemia 
MPAL with t(9;22)(q34.1;q11.2); BCR-ABL1** 
MPAL with t(v;11q23.3); KMT2A rearranged 
MPAL, B/myeloid, NOS 
MPAL, T/myeloid, NOS 
Page 2 of 2 
For a diagnosis of AML, a marrow blast count of  20 is required, except for AML with the recurrent 
genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16).  Adapted from Arber et al, 2016. 
MDS  myelodysplastic syndromes; MPAL  mixed phenotype acute leukemia; NK  natural killer 
* Other recurring translocations involving RARA should be reported accordingly:  for example, AML with 
t(11;17)(q23;q12); ZBTB16-RARA; AML with t(11;17)(q13;q12);NUMA1-RARA; AML with t(5;17)(q35;q12); 
NPM1-RARA; or AML with STAT5B-RARA (the latter having a normal chromosome 17 on conventional 
cytogenetic analysis). 
† Other translocations involving KMT2A (MLL) should be reported accordingly:  for example, AML with 
t(6;11)(q27;q23.3); MLLT4-KMT2A; AML with t(11;19)(q23.3;p13.3); KMT2A-MLLT1; AML with 
t(11;19)(q23.3;p13.1); KMT2A-ELL; AML with t(10;11)(p12;q23.3); MLLT10-KMT2A. 
‡ Rare leukemia most commonly occurring in infants. 
§ Diagnosis is made irrespective of the presence or absence of multilineage dysplasia. 
|| At least 20 ( 20) blood or marrow blasts AND any of the following:  previous history of MDS or 
MDS/MPN; myelodysplasia-related cytogenetic abnormality (see list below); multilineage dysplasia; AND 
absence of both prior cytotoxic therapy for unrelated disease and aforementioned recurring genetic 
abnormalities.  Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes 
are:  Complex karyotype (defined as 3 or more chromosomal abnormalities in the absence of 1 of the 
WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), 
t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCRABL1); Unbalanced abnormalities:  27 or del(7q); 25 
or del(5q); i(17q) or t(17p); 213 or del(13q); del(11q); del(12p) or t(12p); idic(X)(q13); Balanced 
abnormalities:  t(11;16)(q23.3;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3;q21.2); t(2;11)(p21;q23.3); 
t(5;12)(q32;p13.2); t(5;7)(q32;q11.2); t(5;17)(q32;p13.2); t(5;10)(q32;q21.2); t(3;5)(q25.3;q35.1). 
{ Cases should be classified with the related genetic abnormality given in the diagnosis. 
 The former subgroup of acute erythroid leukemia, erythroid/myeloid type ( 50 bone marrow erythroid 
precursors and  20 myeloblasts among nonerythroid cells) was removed; myeloblasts are now always 
counted as percentage of total marrow cells.  The remaining subcategory AML, NOS, pure erythroid 
leukemia requires the presence of  80 immature erythroid precursors with  30 proerythroblasts. 
** BCR-ABL1 leukemia may present as MPAL; treatment should include a tyrosine kinase inhibitor. 
 






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11.16 
Appendix 16.  Modified Toxicity Probability Interval Design 
A modified Toxicity Probability Interval (mTPI) design will be used to guide dose 
exploration.  The MTD is defined as the highest 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 MTD if the toxicity probabilities belong to the proper dosing interval [0.15, 0.25] 
which corresponds to staying at the current dose (S).  The underdosing interval is 
defined as (0, 0.15) in which the doses are deemed lower than the MTD and 
corresponds to a dose escalation (E).  The overdosing interval is (0.25, 1) in which the 
doses are deemed higher than the MTD 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 (0.5, 0.5) 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 for Part 3b (n  11 subjects) and 
Part 4 (n  approximately 60 subjects) are treated or all doses are determined to be 
intolerable.   
Operating Characteristics 
The operating characteristics of the mTPI were evaluated via simulations.  The cohort 
size was fixed to 6 subjects.  A total of 3 dose levels were considered for AML Part 3b 
and 4 dose levels were considered for AML Part 4.   
For Part 3b, the design was evaluated for 3 possible dose-response scenarios:  Low, 
Middle, and High MTD.  For Part 4, the design was evaluated for 4 possible 
dose-response scenarios:  Low, Middle, and High MTD.  Table 11-5 and Table 11-7 
show the dose level and true probability of DLT for each scenario used in the simulated 
studies estimating the MTD.  Table 11-6 and Table 11-8 report the operating 
characteristics from 1 000 simulated studies.   


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Table 11-5.  True Probability of DLT by Scenario for Simulated Studies Estimating 
MTD for Part 3b 
MTD scenario 
Dose Level 1 
Dose Level 2 
Dose Level 3 
Low 
0.20 
0.30 
0.40 
Middle 
0.15 
0.22 
0.28 
High 
0.10 
0.17 
0.23 
MTD  maximum tolerated dose 
Table 11-6.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using the mTPI Design for Part 3b 
MTD scenario 
Low 
Middle 
High 
Number of subjects 
Median (IQR) 
20 (6, 20) 
20 (20, 20) 
20 (20,20) 
Number of DLTs 
Median (IQR) 
4 (3, 5) 
3 (2, 4) 
3 (2, 4) 
Proportion of DLT () 
Median (IQR) 
30.0 (20.0, 33.3) 
20.0 (15.0, 30.0) 
15.0 (10.0, 20.0) 
Percentage of studies selecting MTD  
Dose Level 1 
38.1 
31.0 
23.8 
Dose Level 2 
19.8 
28.8 
31.6 
Dose Level 3 
4.0 
16.5 
27.4 
DLT  dose-limiting toxicity; IQR  Interquartile range; MTD  maximum tolerated dose 
Table 11-7.  True Probability of DLT by Scenario for Simulated Studies Estimating 
MTD for Part 4 
MTD scenario 
Dose Level 1 
Dose Level 2 
Dose Level 3 
Dose Level 4 
Low 
0.20 
0.30 
0.40 
0.45 
Middle 
0.10 
0.15 
0.20 
0.25 
High 
0.05 
0.10 
0.15 
0.2 
MTD  maximum tolerated dose 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  13 July 2023 
Page 219 of 219 
CONFIDENTIAL  
 
 
Table 11-8.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using the mTPI Design for Part 4 
MTD scenario 
Low 
Middle 
High 
Number of subjects 
Median (IQR) 
36 (6, 50) 
50 (48, 50) 
50 (50, 50) 
Number of DLTs 
Median (IQR) 
8 (2, 11) 
7 (5, 9)  
6 (4, 8) 
Proportion of DLT () 
Median (IQR) 
29.2 (22.2, 33.3) 
16.7 (14.0, 21.4) 
12.0 (1.0, 16.0) 
Percentage of studies selecting MTD  
Dose Level 1 
42.7 
21.4 
11.2 
Dose Level 2 
9.29 
28.2 
21.6 
Dose Level 3 
0.47 
25.8 
31.2 
Dose Level 4 
0.03 
10.0 
24.1 
DLT  dose-limiting toxicity; IQR  Interquartile range; MTD  maximum tolerated dose 




Product:  AMG 176 
Protocol Number:  20150161 
Date:  18 February 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 11 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed 
or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 176 2015061 
 
Amendment Date: 
05 February 2021 
Superseding Amendment Date: 
18 February 2021 
 
Rationale: 
This protocol is being amended to include the following updates: 
 
A drug-drug interaction (DDI) assessment in a separate cohort for acute myeloid 
leukemia (AML) subjects in the United States (US.) was added.  
 
Up to 8 subjects will receive AMG 176 once weekly (QW) intravenously (IV) in 
combination with oral itraconazole (200 mg) starting on day -3 through day 4 
(total of 7 days) in cycle 1 only. 
 
A fixed sequence design where AMG 176 will be co-administered with 
itraconazole during week 1, followed by dosing of AMG 176 alone in subsequent 
weeks, will be used to evaluate the effect of itraconazole (strong cytochrome 
P450 (CYP)3A4 inhibitor and P-glycoprotein (P-gp) inhibitor) on the 
pharmacokinetics (PK) of AMG 176 
Patients with AML are susceptible to invasive fungal infections and often require 
prophylaxis and treatment with antifungal agents such as voriconazole and 
posaconazole, which are known to inhibit CYP3A4 and P-gp.  AMG 176 is 
metabolized, in part, by CYP3A4, and is a P-gp substrate; hence, co-administration 
with inhibitors of CYP3A4/P-gp may lead to increases in AMG 176 exposure.  As a 
result, clinical trials with AMG 176 prohibit the use of medications that are strong 
CYP3A4/P-gp inhibitors, including voriconazole and posaconazole. 
 
Removed exclusion criterion 227 (related to the use of CYP1A2, CYP2C9, and 
CYP2D6 sensitive substrates with a narrow therapeutic window), based on the 
following: 
An updated DDI assessment predicting a less than 2-fold increase in exposure of 
these substrates during co-administration with AMG 176.  AMG 176 inhibited 
CYP1A2, CYP2C9 and CYP2D6, in human liver microsomes, with Ki (inhibition 
concentrations that are half of maximal) estimates of 4.4, 2.6, and 6.2 M, 
respectively.  The Simcyp Simulator (version 17), a commercially available 
physiologically based pharmacokinetic (PBPK) software platform was used to predict 
the magnitude of a DDI with sensitive CYP substrates during co-administration with 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  18 February 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
AMG 176 at doses of 60, 120, and 180 mg/m2 given on a QW schedule.  These 
simulations incorporated the unbound fraction of AMG 176 in both human plasma 
and human liver microsomes.  A compound file for AMG 176 was developed and 
verified based on in vitro and available clinical data.  Simcyp library model files were 
used for sensitive substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), and 
CYP2D6 (dextromethorphan).  The PBPK model was used to simulate the effect of 
AMG 176 given as an intravenous infusion over 2 hours QW (60, 120, and 180 
mg/m2) on sensitive substrates given concurrently with the 3rd weekly dose of AMG 
176.  The predicted area under the concentration-time curve (AUC) ratio ranged from 
1.4 to 1.9 for caffeine, 1.2 to 1.4 for S-warfarin, and 1.3 to 1.7 for dextromethorphan 
for the AMG 176 doses evaluated.  Based on these simulations, a weak DDI 
(1.25 to  2-fold increase in substrate exposure) is predicted when AMG 176 is 
co-administered with sensitive substrates of CYP1A2, CYP2C9, and CYP2D6.  
Medications that are sensitive substrates of these enzymes can be allowed with 
caution during co-administration with AMG 176. 
 
Editorial changes (including typographical, grammatical, and formatting) have been 
made throughout the document. 
On 18 February 2021, the protocol amendment 11 was superseded to include the 
following: 
 
To update the language for non-investigational product to clarify that Azacitidine will 
not be supplied by Amgen for this study unless required by local regulation or in 
response to a regional supply shortage. 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 September 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 12 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed 
or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia 
 
Amgen Protocol Number AMG 176 20150161 
 
Amendment Date: 
16 September 2021 
 
Rationale: 
The rationale for this protocol amendment is to include the following updates: 
 
In Parts 3b and 4 of the study, an additional AMG 176 dose level (240 mg/m2) at the 
once per week dosing schedule (QW) has been added as part of dose exploration 
(monotherapy and in combination with azacitidine).  It has been added to complete 
the evaluation of all the dose levels previously identified in the study as safe and 
without evidence of troponin elevations.  Additionally, an additional cohort has been 
added to Part 4 to explore 2-consecutive days per week dosing schedule (QD2) at 
240 mg/m2. 
 
Part 5 (AMG 176  azacitidine combination therapy) has been added to the study as 
a dose expansion once the maximum tolerated combination dose (MTCD) is 
determined in Part 4. 
 
Updated to include guidance relating to coronavirus disease 2019 (COVID-19): 
 
Eligibility criteria was updated to exclude subjects that have severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
 
Guidance for COVID-19 vaccinations was added (Sections 6.7.2 and 6.7.2.4) 
 
Section 6.2.2.2.8 was added to include management for subjects with 
asymptomatic and symptomatic SARS-CoV-2 infection and COVID-19 disease 
 
A new subsection has been added (Section 8.2.4.2 – Relationship to Study Drug) to 
provide guidance for investigators assessing the relationship of an adverse event to 
the use of study drug. 
 
Minor corrections and clarifications have been made throughout the protocol to 
correct identified errors: 
 
Part 3c has been updated to “completed” throughout protocol, includes final 
enrollment numbers. 
 
Table 1-2 was corrected by removing shading from the safety follow-up visit 
column in the AML subjects: bone marrow/aspirate/biopsy row. 
 
Section 6.1.2.2 was updated to align with the formatting of Section 6.1.2.1. 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 September 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Section 6.1.8 title was updated to indicate it is only applicable to Part 3d of the 
study. 
 
Section 8.1.3 was updated to remove the 1-day window for the end of treatment 
(EOT) visit as it should occur as soon as possible after last dose and does not 
need a window. 
 
Section 8.2.2.2.1 was updated to provide a 3-day window for collection of bone 
marrow smears up to 3 days prior to day 1 of cycles 2 and 3. 
 
Section 8.2.9 was updated to clarify that interviews should take place as soon as 
possible after completion of cycle 1. 
 
Several sections of the protocol have been updated to include required alignments 
with current Amgen protocol template (Sections 6.1.6, 8.2.4.1.4, 11.2, 11.3, and 
11.4): 
 
Section 6.1.6 Product Complaints:  Additional details have been added to clarify 
the types of product complaints. 
 
Section 8.2.4.1.4 Serious Adverse Events After the Protocol-required Reporting 
Period and Section 11.4 Reporting of Serious Adverse Event:  The safety 
monitoring language has been revised to minimally require reporting of serious 
adverse events (SAEs) related to the investigational product (rather than all 
SAEs) to be collected and reported to Amgen within 24 hours of investigator’s 
awareness after the protocol required reporting period has ended, during the 
Long Term Follow-up and End of Study periods.  
 
Section 11.2 Clinical Laboratory Tests: Updates related for reporting additional 
analyte test results and inclusion of coronavirus 2 (SARS-CoV-2) analyte testing 
have been added. 
 
Section 11.3 Study Governance Considerations: Additional details added under 
subsection Regulatory and Ethical Considerations to clarify the investigator’s 
responsibility to seek IRB/IEC approval for protocols and ICFs. 
 
Administrative and editorial changes (including grammatical, typographical, and 
formatting) have been made throughout the protocol. 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  20 January 2022                                                                                                              Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 13 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or 
Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid 
Leukemia 
 
Amgen Protocol Number AMG 176 20150161 
 
Amendment Date: 
20 January 2022 
 
Rationale: 
This 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 upper reference limit 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  20 January 2022                                                                                                              Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
(URL) to 0.059 ng/mL and maintaining the URL of 0.04 ng/mL for females in relevant sections of 
the protocol (Sections 5.2, 6.2.1.2.1, 6.2.1.2.2, and 6.2.2.1). 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 March 2022 
Page 1 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 14 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed or 
Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute Myeloid 
Leukemia 
 
Amgen Protocol Number AMG 176 20150161 
NCT02675452 
 
Amendment Date: 
16 March 2022 
 
Rationale:   
The rationale for this protocol amendment is to include the following updates: 
 
To clarify dosing schedules of intravenous infusion of AMG 176 (ie, QW: once weekly 
followed by a 6-day break for 4 consecutive weeks and QD2: once daily for 
2 consecutive days followed by a 5-day break for the first 3 weeks of each 4-week cycle) 
for different parts of the study as well as update the parts of the study that are closed to 
enrollment (Sections 1.1, 4.3).  
 
Study schema (Figure 1-7) for Acute Myeloid Leukemia (AML) Part 4 AMG 176 QW and 
QD2 in Combination with Azacitidine (Dose Exploration) and study schema (Figure 1-9) 
for Acute Myeloid Leukemia Part 5 AMG 176 QW or QD2 in Combination with 
Azacitidine (Dose Expansion) were updated to: 
o Define QD2 dosing schedule for intravenous administration of AMG 176 in terms 
of monthly cycles of treatment.    
o Clarify that lower dose levels of 120 mg/m2 and 180 mg/m2 may be investigated 
on a QD2 schedule, and that QW and QD2 combination cohorts can be 
conducted in parallel.  The QD2 schedule will restrict AMG 176 to 3 out of 4 
weeks, which may reduce the risk of hematological toxicity.  Currently, the 
protocol only allows for the QD2 schedule to be investigated at the highest 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 March 2022 
Page 2 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
combinational dose level of 240 mg/m2.  The rationale for this change is to allow 
evaluation of lower dose levels to be considered for dose optimization.  The QW 
and QD2 combination cohorts will be gated off their respective monotherapy 
dose levels. 
 
Overview of Study Design was updated to add in Part 4 (which investigates AMG 176 in 
combination with azacitidine) that QD2 AMG 176 (cohort 5) dosing schedule may be 
conducted at the same time, in the same dose, or at a lower dose as QW AMG 176 
(cohorts 1-4) dosing schedule (Table 4-1).   
 
Tale 1-3.  Schedule of Activities:  Parts 4 (Cohort 1-4 Only) and 5 (AML) AMG 176 QW 
in Combination with Azacitidine was updated to clarify that timepoints for the schedule of 
activities are relative to start of dosing of either AMG 176 or azacitidine.   
 
Table 1-4.  Schedule of Activities:  Parts 4 (Cohort 5 only) and 5 (AML) AMG 176 QD2 in 
Combination With Azacitidine was updated to correct cycle 1 timepoints for general and 
safety assessments and laboratory assessments:  
o 12-lead electrocardiogram (week 1 day 3) 
o Tumor lysis syndrome monitoring test (week 1 day 3 and week 3 day 17) 
o Cardiac monitoring test (week 1 day 3)  
o AMG 176 pharmacokinetic evaluation (week 1 day 3 and week 3 day 17) 
o 
 
 
Table 1-5.  Schedule of Activities:  Part 3d (AML in United States) Drug-Drug Interaction 
(DDI) Assessment With Itraconazole was updated to correct an error by including a 
missing assessment timepoint – pre-dose for day 15 tumor lysis syndrome monitoring 
test. 
 
Table 1-6.  Schedule of Activities Notes and Abbreviations Definitions was updated to 
clarify: 
o Neuropathy assessments, as a clinical evaluation, must be performed only for 
multiple myeloma subjects.     


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 March 2022 
Page 3 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
o Timepoints for collection of pharmacokinetic samples for AMG 176 or azacitidine 
treatment.  These timepoints are relative to start of dosing of either AMG 176 or 
azacitidine. 
 
A clarification statement was added for the use of core bone marrow biopsy/aspirate 
performed as standard of care to meet study screening requirements as long as it was 
performed within 4 weeks from enrollment and no curative anti-cancer therapy was 
administered during the time from biopsy to enrollment (sections 5.1, 8.1.1, 8.2.2.2.1).   
 
To maintain consistency, the window to accept previously conducted cardiac imaging 
tests to meet screening requirement was changed from 30 days of cycle 1 day 1 to 
4 weeks of cycle 1 day 1 (Table 1-6 and section 8.2.3.4.2).   
 
Since Investigator’s Brochure was recently updated, the corresponding updates were 
made into AMG 176 Clinical Experience and Key Benefits (sections 2.2.2.4 and 2.3.2).   
 
Anti-tumor therapy windows of exclusion criterion 219 were updated to remove reference 
to “or 5 half-lives, whichever is shorter” from the 14 days and 21 days windows of 
enrollment (section 5.2).   
 
Long-term follow up window was increase to  14 days to allow flexibility for these follow 
up visits.  Multiple sections of the protocol were updated to incorporate this change 
(sections 4.1, 4.4.2, 8.1.5, study schemas, and Table 1-6). 
 
Azacitidine accountability instructions were updated to clarify that (section 6.1.2.1): 
o Only for intravenous administration of azacitidine, stop date and time is required 
to be recorded on each subject’s case report form.    
 
Amgen Investigational Product: AMG 176 was updated to (section 6.2.2.1):  
o Clarify dosage adjustments guidelines for AMG 176 by changing the general 
format of the information.   
o  Withholding criteria for elevation of cardiac troponin was modified to elevation 
> 0.1 ng/mL to emphasize the possibility of allowing subjects to restart AMG 176 
treatment even if the elevation is a grade 3. 


Product:  AMG 176 
Protocol Number:  20150161 
Date:  16 March 2022 
Page 4 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
o Clarify that restarting of AMG 176 dosing can be resumed if deemed safe by the 
site investigator instead of investigators as previously stated.   
 
Include updated guidance for collection/report of serious and fatal serious adverse 
events in alignment to current protocol template (Table 1-6, section 8.2.4.1.4).   
 
Include a new footnote in Table 11-1 to instruct that for local laboratory tests, all 
available analytes listed in the table should be recorded in the electronic case report 
form.    
 
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 6.2.2.2.7).   
 
Administrative and editorial changes (including grammatical, typographical, 
abbreviations, and formatting) have been made throughout the protocol. 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  09 February 2023 
Page 1 of 3 
Amendment 15 
Protocol Title:  A Phase 1 First-in-Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed 
or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia 
Amgen Protocol Number 20150161 
EudraCT Number:  
2015-004777-32 
NCT Number:  
NCT02675452 
 
Amendment Date: 
09 February 2023 
Rationale: 
This protocol is being amended for the following reasons:  
 
The background, rationale, and benefit/risk assessments were substantially revised 
to include current data and more recent literature.   
 
Clinical results of the study were updated to reflect the current status of the study as 
of the most recent data cutoff of 06 September 2022.   
 
Details about plans for dose optimization to identify the Recommended Phase 2 
Dose (RP2D) for the combination of AMG 176 with azacitidine were added, which 
will be estimated using the totality of data from across the first-in-human (FIH) study, 
including the pharmacokinetics (PK), safety, efficacy, and other results from the dose 
escalation and dose expansion.   
 
Dosing was revised and clarified for Part 5 dose confirmation/optimization (now 
Part 5a), and an Acute Myeloid Leukemia (AML) conventional dosing schedule was 
added (Part 5b) along with preclinical data and PK modeling to support investigation 
of this schedule.   
 
The dosing language was changed from on 2 consecutive days (QD2) to twice 
weekly (BIW) to comply with standard and accepted dosing abbreviations. 
 
Added further language describing that potential drug-drug interactions (DDI) 
between the study drugs and hormone-based contraceptives are not established.  
Intrauterine device for contraception methods in females was clarified to 
non-hormonal (ie, copper) only.  The use of oral contraceptives was clarified as 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  09 February 2023 
Page 2 of 3 
prohibited for the purpose of pregnancy prevention but allowed for the treatment of 
menorrhagia or other abnormal menstrual bleeding at the discretion of the 
investigator.   
 
Number of subjects to be enrolled on the study was updated as follows:   
o Part 3a (closed) enrolled 17 subjects (previously:  15 subjects).   
o Part 3b (closed) enrolled 11 subjects (previously:  actively enrolling, with up to 
30 subjects planned).   
o Part 3d (open) will enroll up to 11 subjects (previously:  up to 8 subjects).   
o Part 4 (open) will enroll approximately 60 subjects (previously:  up to 
50 subjects).   
o Part 4 Cohort 5 was replaced with Cohorts 5a and 5b, and the figures were 
updated accordingly.   
o Part 5 (open) will enroll approximately 20 subjects per cohort, approximately 
60 subjects in total (previously:  up to 20 subjects).  It will now consist of Part 5a 
of 2 cohorts and the new Part 5b (conventional dosing schedule).   
o Enrollment eligibility worksheet and/or subject registration form will be 
completed and sent to Amgen for verification of eligibility criteria by a site 
representative.   
 
Inclusion criteria:  
o 113:  Added that for Part 5a cohorts 1 and 2, enrollment will be restricted to 
subjects with persisting or recurring AML after 1 to 2 lines of prior therapy.   
o 114:  For acute myeloid leukemia subjects, blast equivalents are now 
permissible for greater than or equal to 5% blasts in bone marrow requirement.  
 
Exclusion criteria: 
o 219, 225, 226, 228, 229:  Updated language to clarify chemotherapy, antibody 
therapy, molecular targeted therapy, investigational agent, strong CYP3A4 
inhibitors, CYP3A4 sensitive substrates, own OATP1B1, and/or OATP1B3 or 
BCRP substrates with a narrow therapeutic window, and any medications are 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  09 February 2023 
Page 3 of 3 
now disallowed within 5 times the t½ of the drug, or until the relevant biological 
effect has resolved (whichever is longer).   
o 226:  Inhibitors of P-glycoprotein (P-gp) were removed from this exclusion 
criterion, since preliminary clinical data analysis from the Part 3d and 
physiologically-based pharmacokinetic (PBPK) modeling and simulation 
indicated weak to no drug-drug interactions.   
 
Observed discrepancies between the Schedule of Assessments and the electronic 
data capture (EDC) were addressed by updating Section 1.3 (Schedule of Activities) 
of the protocol accordingly.  For Part 3d, Part 4, and Part 5a, timepoints of various 
test procedures (eg, cardiac screening, tumor lysis syndrome tests, echocardiogram, 
electrocardiogram, 
 vitals) were revised, and for Part 4 Cohorts 5a 
and 5b, and Part 5a (AML) Cycle 1 Week 4 procedures were added.   
 
The reporting period of serious adverse events was updated from “within 24 hours” 
to “immediately and no later than 24 hours following the investigator’s awareness of 
the event”.   
 
The exclusion of azole antifungal therapy was removed since data from Cohort 3d 
did not identify a DDI between AMG 176 and itraconazole.   
 
The drug supply information has been updated, to show that AMG 176 will be 
supplied as a 10 mL liquid deliverable volume in a single-use 20 cc glass vial or a 
14.4 mL liquid deliverable volume in a single use 30 cc glass vial (the latter was 
previously under development).   
 
The creatinine thresholds for grades 1 through 3 in “Cairo-Bishop Clinical Tumor 
Lysis Syndrome Definition and Grading” table were corrected (Appendix 8).   
 
In addition, administrative and editorial changes (including grammatical, 
typographical, and formatting) have been made throughout the protocol.   


Product:  AMG 176  
Protocol Number:  20150161 
Date:  13 July 2023 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date:  02 Mar 2020, Version:  6.0 
Amendment 16 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 176 in Subjects With Relapsed 
or Refractory Multiple Myeloma and Subjects With Relapsed or Refractory Acute 
Myeloid Leukemia 
Amgen Protocol Number 20150161 
EudraCT Number:  2015-004777-32 
NCT Number:  NCT02675452 
 
Amendment Date: 
13 July 2023 
Rationale: 
This protocol, dated 13 July 2023, is being amended for the following reasons:  
 
To clarify that enrollment in Part 5B will start after Part 5A is complete (Section 1.1, 
Section 4.1, Section 4.1.1) and to provide the dose regimen and number of subjects 
to be enrolled in both Part 5A and Part 5B (Section 4.1.1, Section 4.4.1 and 
Section 6.1.2.1). 
 
To update the Simon’s two-stage minimax design for Part 5A to provide interim 
futility criteria to minimize the number of subjects exposed to a potentially ineffective 
treatment.  The design is based on a two-sided Type I error rate at 0.05 with 
0.8 power (Section 1.1, Section 4.1, Section 4.1.1, and Section 9.4.1.1).  
 
To include omitted pages in Table 1-7 (Schedule of Activities: Part 5B acute myeloid 
leukemia [AML] Conventional Dosing – Regimen 1) and Table 1-8 (Schedule of 
Activities: Part 5B [AML] Conventional Dosing – Regimen 2) from amendment 15 to 
clarify that hospitalization is only required in the first cycle and to indicate the 
procedures for cycle 2 and beyond.  This update allows to monitor safety without 
overburdening the clinical site and subject with unnecessary procedures. 
 
Minor updates in the list of references (Section 10). 
 
In addition, administrative and editorial changes (including grammatical, 
typographical, and formatting) have been made throughout the protocol. 

SAP_001.pdf: 
Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 1 of 38 
CONFIDENTIAL  
 
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 176 in Subjects With 
Relapsed or Refractory Multiple Myeloma and 
Subjects With Relapsed or Refractory Acute Myeloid 
Leukemia 
Short Protocol Title: 
A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 176 
Protocol Number: 
20150161 
NCT Number: 
NCT02675452 
Authors: 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
 
Document Version 
Date 
Amendment 3 (v4.0) 
12 November 
2024 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 2 of 38 
CONFIDENTIAL  
 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
20NOV2015 
 
Amendment 1 (v2.0) 
16MAY2017 
 
Amendment 2 (v3.0) 
26MAY2021 
 
Updates made as per protocol 
amendment 11 superseding 
o 
Study design: Closed enrollment for 
Parts 1A , 1B, 3A and added Parts 
3B, 3C, 3D and 4. 
o 
Sample size section.  
 
Removed the definitions not related to 
analysis; updated the definitions (DOR, EFS, 
PFS, OS, TTR, etc.) per Data Element 
Standards.  
 
Updated the Treatment Emergent 
Adverse Event definition as per the DES 
version 8.0 and DLT Evaluable Analysis Set 
definition.  
 
Added analyses related to the 
adverse events of COVID-19  
 
Updated the imputation rules for non-
pharmacokinetic measurements above or 
below the upper quantification limits.  
 
Added the approach on how to handle 
subjects proceeding to a higher dose or 
crossover from monotherapy to a combination 
therapy cohort.  
Added dose proportionality analysis.   
Amendment 3 (v4.0) 
12NOV2024 
 
Updates made based on protocol 
amendment 16 
o 
QD2 updated to BIW. 
o 
Added part 5 (BIW) objective and 
endpoint; also added exploratory 
objective and endpoints. 
o 
Updated text in the study design.  
o 
Updated sample size  
 
Updated definition of overall response 
rate for MM and AML. 
 
Added dose intensity and relative 
dose intensity in definition and exposure to 
investigational product and non-investigational 
product. 
 
Censoring rule for PFS has been 
updated in definition. 
 
Interim efficacy analysis set added in 
section 6.7.1. 
 
Included the text “Interim safety 
analyses will be performed to support the 
evaluation of safety by the DLRT” in section 
7.1.  
 
Added additional interim analyses 
information in section 7.1. 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 3 of 38 
CONFIDENTIAL  
 
 
 
 
Added Exploratory endpoint in the 
section 9.5.3 
 
Updated the layout in section 9.6.1 
 
Updated MedDRA version from 24.0 
to 26.1 
 
Added details in section 9.6.9 
 
Added details in section 9.6.10 
 
Added Appendix B 
 
Updated section 10 Changes From 
Protocol-specified Analyses 
 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 4 of 38 
CONFIDENTIAL  
 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints  ........................................................................... 9 
2.2 
Hypotheses and/or Estimations ................................................................. 14 
3. 
Study Overview .................................................................................................... 15 
3.1 
Study Design ............................................................................................. 15 
3.2 
Sample Size .............................................................................................. 19 
3.3 
Adaptive Design ........................................................................................ 19 
Table 2.  Guidelines for Dose-level Decisions for 
Part 3b and Part 4 ................................................... 20 
4. 
Covariates and Subgroups ................................................................................... 20 
4.1 
Planned Covariates ................................................................................... 20 
4.2 
Subgroups ................................................................................................. 20 
5. 
Definitions ............................................................................................................. 20 
6. 
Analysis Sets ........................................................................................................ 24 
6.1 
Full Analysis Set........................................................................................ 24 
6.2 
Safety Analysis Set ................................................................................... 24 
6.3 
Per Protocol Analysis Set(s) ...................................................................... 24 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 24 
6.5 
Pharmacokinetic Analyses Set(s) .............................................................. 25 
6.6 
Interim Analyses Set(s) ............................................................................. 25 
6.7 
Study-specific Analysis Set(s) ................................................................... 25 
6.7.1 
Interim Efficacy Analysis Set ..................................................... 25 
6.7.2 
DLT Evaluable Analysis Set ...................................................... 25 
7. 
Planned Analyses ................................................................................................. 25 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 25 
7.2 
Primary Analysis ....................................................................................... 25 
7.3 
Final Analysis ............................................................................................ 26 
8. 
Data Screening and Acceptance ........................................................................... 26 
8.1 
General Principles ..................................................................................... 26 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 26 
8.3 
Handling of Missing and Incomplete Data ................................................. 26 
8.4 
Detection of Bias ....................................................................................... 26 
8.5 
Outliers ..................................................................................................... 26 
8.6 
Distributional Characteristics ..................................................................... 27 
8.7 
Validation of Statistical Analyses ............................................................... 27 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 5 of 38 
CONFIDENTIAL  
 
 
 
9. 
Statistical Methods of Analysis.............................................................................. 27 
9.1 
General Considerations ............................................................................. 27 
9.2 
Subject Accountability ............................................................................... 27 
9.3 
Important Protocol Deviations ................................................................... 28 
9.4 
Demographic and Baseline Characteristics ............................................... 28 
9.5 
Efficacy Analyses ...................................................................................... 29 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 29 
9.5.2 
Analyses of Secondary Efficacy 
Endpoint(s)/Estimand(s) ............................................................ 29 
Table 3. Efficacy Endpoint Summary ......................................... 29 
9.6 
Safety Analyses ........................................................................................ 29 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 29 
Table 4.  Safety Endpoint Summary Table ................................ 29 
9.6.2 
Adverse Events ......................................................................... 29 
9.6.3 
Laboratory Test Results ............................................................ 30 
9.6.4 
Vital Signs ................................................................................. 30 
9.6.5 
Physical Measurements ............................................................ 30 
9.6.6 
Electrocardiogram ..................................................................... 31 
9.6.7 
Antibody Formation ................................................................... 31 
9.6.8 
Exposure to Investigational Product .......................................... 31 
9.6.9 
Exposure to Non-investigational Product(s) ............................... 32 
9.6.10 
Exposure to Concomitant Medication ........................................ 32 
9.7 
Other Analyses ......................................................................................... 32 
9.7.1 
Pharmacokinetic Analyses ......................................................... 32 
9.7.2 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 33 
9.7.3 
Analyses of Clinical Outcome Assessments .............................. 33 
9.7.4 
Analyses of Health Economic Endpoints ................................... 33 
9.7.5 
Analyses of Biomarker Endpoints .............................................. 33 
10. 
Changes From Protocol-specified Analyses.......................................................... 33 
11. 
Literature Citations / References ........................................................................... 33 
12. 
Prioritization of Analyses....................................................................................... 33 
13. 
Data Not Covered by This Plan............................................................................. 33 
14. 
Appendices ........................................................................................................... 34 
Appendix B.  European LeukemiaNet (ELN) Response Criteria in Acute 
Myeloid Leukemia (2017) .......................................................................... 36 
Appendix C.  Code Fragments .............................................................................. 38 
 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 6 of 38 
CONFIDENTIAL  
 
 
 
List of Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
AUC0-168 hr 
area under the concentration-time curve from 0 to 168 hours 
BAK 
B-cell receptor associated kinases 
BAX 
B-cell lymphoma/leukemia 2 associated X protein 
BCL2 
B-cell lymphoma/leukemia 2 
BCL2-L1 
BCL2 like 1 
BCL-XL 
B-cell lymphoma extra large 
BIW 
twice weekly 
CL 
Clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
COVID-19 
coronavirus disease 2019 
CPMS 
clinical pharmacology modeling and simulation 
CR 
complete response 
CrCl 
creatinine clearance 
CRi 
incomplete hematologic recovery; complete response/remission with 
incomplete recovery of peripheral blood counts 
CRF 
case report form  
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DDI 
drug-drug interaction 
DLRM 
dose-level review meeting 
DLRT 
dose-level review team 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
ECHO 
echocardiogram 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 7 of 38 
CONFIDENTIAL  
 
 
 
Abbreviation or Term 
Definition/Explanation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event free survival 
ELN 
European LeukemiaNet 
FAS 
Full Analysis Set 
FIH 
first in human 
FISH 
fluorescent in situ hybridization 
FSH 
follicle stimulation hormone 
heart rate/HR 
number of cardiac cycles per unit of time 
IMWG 
International Myeloma Working Group  
IMWG-URC 
International Myeloma Working Group - Uniform Response Criteria 
IQR 
interquartile range 
IV 
intravenous or roman numeral 4 
MCL1 
myeloid cell leukemia sequence 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
medium fluorescent intensity 
MLFS 
morphologic leukemia free state 
MM 
multiple myeloma 
MRD 
minimal residual disease 
MRD[-] 
minimal residual disease negativity 
MTCD 
maximum tolerated combination dose 
MTD 
maximum tolerated dose 
mTPI 
modified Toxicity Probability Interval 
MUGA 
multigated acquisition scan 
OBD 
optimal biological dose 
OR 
overall response 
OS 
overall survival 
PD 
pharmacodynamics 
PFS 
progression free survival 
PK 
Pharmacokinetics 
PR 
partial response 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG or partial response 
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 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 8 of 38 
CONFIDENTIAL  
 
 
 
Abbreviation or Term 
Definition/Explanation 
QT  
QT interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle as measured 
by ECG 
QTc  
QT interval corrected for heart rate using accepted methodology 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QW 
once weekly 
R/R 
relapsed or refractory 
RP2D 
recommended phase 2 dose 
RUNX1 
runt-related transcription factor 1 
SBP 
systolic blood pressure 
SC 
subcutaneous(ly) 
sCR 
stringent complete response 
Screen 
Screening 
SD 
standard deviation 
SFU 
safety follow-up 
SOC 
standard of care 
t½ 
half-life 
tmax 
time of maximum observed serum concentration 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
UPM 
unit probability mass 
US 
United States 
VGPR 
very good partial response 
WHODRUG 
World Health Organization Drug 
 
 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 9 of 38 
CONFIDENTIAL  
 
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20150161, AMG 176 
dated 13 July 2023.  The scope of this plan includes the primary analysis and the final 
analysis that are planned and will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints  
 
Objectives 
Endpoints 
Primary 
Multiple Myeloma Part 1a (BIW) 
 
Evaluate the safety and tolerability of 
AMG 176 monotherapy in subjects with 
relapsed or refractory multiple myeloma 
(MM) and determine the maximum 
tolerated dose (MTD) for twice weekly 
(BIW) dosing schedule 
 
Incidence of Dose-Limiting Toxicities 
(DLTs), treatment-related and 
treatment-emergent adverse events, and 
clinically significant changes in vital signs, 
electrocardiograms (ECGs), and clinical 
laboratory tests 
 
Evaluate the pharmacokinetics (PK) of 
AMG 176 when administered as 
monotherapy (BIW) 
 
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 (t½) 
Multiple Myeloma Part 1b (QW) 
 
Evaluate the safety and tolerability of 
AMG 176 monotherapy in subjects with 
relapsed or refractory MM and 
determine the MTD for a once weekly 
(QW) dosing schedule 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events and 
clinically significant changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Evaluate the PK of AMG 176 when 
administered as monotherapy (QW) 
 
PK parameters for AMG 176 including, 
but not limited to Cmax, AUC, CL, and t½ 
Acute Myeloid Leukemia Part 3a (BIW) 
 
Evaluate the safety and tolerability of 
AMG 176 monotherapy in subjects with 
relapsed or refractory acute myeloid 
leukemia (AML) and determine the MTD 
for BIW dosing as a monotherapy in 
subjects with relapsed or refractory AML 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events and 
clinically significant changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Evaluate the PK of AMG 176 when 
administered as monotherapy (BIW) 
 
PK parameters for AMG 176 including, 
but not limited to Cmax, AUC, CL, and t½ 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 10 of 38 
CONFIDENTIAL  
 
 
 
Acute Myeloid Leukemia Part 3b (QW) 
 
Evaluate the safety and tolerability of 
AMG 176 QW monotherapy in subjects 
with relapsed or refractory AML 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events and 
clinically significant changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Evaluate the PK of AMG 176 when 
administered as monotherapy (QW) 
 
PK parameters for AMG 176 including, 
but not limited to Cmax, AUC, CL, and t½ 
Acute Myeloid Leukemia Part 3c (QW) in Japan 
 
Evaluate the safety and tolerability of 
AMG 176 QW monotherapy in subjects 
in Japan with relapsed or refractory 
AML 
 
Incidence of DLTs, treatment-related, 
treatment-emergent adverse events and 
clinically significant changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Evaluate the PK of AMG 176 when 
administered as monotherapy (QW) in 
Japan 
 
PK parameters for AMG 176 including, 
but not limited to Cmax, AUC, CL, and t½ 
Acute Myeloid Leukemia Part 3d - Drug-drug Interaction (DDI) Assessment with Itraconazole in 
United States (US) 
 
Evaluate the PK of AMG 176 when 
given alone and in combination with 
itraconazole in subjects with AML 
 
PK parameters for AMG 176 including, 
but not limited to Cmax, AUC, CL, and t½ 
Acute Myeloid Leukemia Parts 4 and 5 (QW, BIW, and conventional AML dosing) in 
combination with azacitidine 
 
Evaluate the safety and tolerability of 
AMG 176 in combination with 
azacitidine in subjects with relapsed or 
refractory AML and in Part 4 only, 
determine the maximum tolerated 
combination dose (MTCD) of AMG 176 
in combination with azacitidine 
 
Incidence of DLTs (Part 4 only), 
treatment-related, treatment-emergent 
adverse events and clinically significant 
changes in vital signs, ECGs, and clinical 
laboratory tests 
 
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 t½ 
Secondary 
Multiple Myeloma Part 1a (BIW) 
 
Demonstrate inactivation of myeloid cell 
leukemia sequence 1 (MCL1) by the 
increase of active B-cell 
lymphoma/leukemia 2 associated 
X protein (BAX) and caspase 3 in 
circulating monocytes and/or the 
decrease of circulating monocytes in 
AMG 176 BIW treated subjects 
 
BAX and caspase 3 expression in 
circulating monocytes and/or circulating 
monocyte counts 
 
Evaluate preliminary efficacy of 
AMG 176 BIW when given as 
monotherapy in relapsed or refractory 
MM 
 
Overall response (OR) according to 
International Myeloma Working Group 
uniform response criteria (IMWG-URC) 
for MM subjects, progression-free survival 
(PFS), time to response, and duration of 
response (DOR) 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 11 of 38 
CONFIDENTIAL  
 
 
 
Multiple Myeloma Part 1b (QW) 
 
Demonstrate inactivation of MCL1 by 
the increase of active BAX and caspase 
3 in circulating monocytes and /or the 
decrease of circulating monocytes in 
AMG 176 QW treated subjects 
 
BAX and caspase 3 expression in 
circulating monocytes and /or circulating 
monocyte counts 
 
Evaluate preliminary efficacy of 
AMG 176 QW when given as 
monotherapy in relapsed or refractory 
MM 
 
Overall response according to 
IMWG-URC for MM subjects, PFS, time 
to response, and DOR 
Acute Myeloid Leukemia Part 3a (BIW), Part 3b (QW), and Part 3c (QW) 
 
Evaluate preliminary efficacy of 
AMG 176 when given as monotherapy 
in relapsed or refractory AML (For 
Part 3c:  Japan subjects only) 
 
Overall response according to the 2017 
European LeukemiaNet (ELN) criteria 
(Döhner et al, 2017) in AML subjects, 
event-free survival (EFS), time to 
response, and DOR 
Acute Myeloid Leukemia Part 3d - DDI Assessment with Itraconazole in US 
 
Evaluate the safety and tolerability of 
AMG 176 when given alone and in 
combination with itraconazole in 
subjects with AML 
 
Treatment-emergent adverse events and 
changes in vital signs, ECGs, and clinical 
laboratory tests 
Acute Myeloid Leukemia Parts 4 and 5 (QW and BIW) 
 
Evaluate preliminary efficacy of 
AMG 176 when given in combination 
with azacitidine in relapsed or refractory 
AML  
 
Overall response according to the 2017 
ELN criteria in AML subjects, EFS, time 
to response, and DOR 
 
Estimand(s) for Primary Objective(s) 
Not applicable. 
Estimand(s) for Key Secondary Objective(s) 
Not applicable. 
Estimand(s) for Secondary Objective(s) 
Not applicable. 
 
Exploratory 
Multiple Myeloma Part 1a (BIW) 
 
To explore PK/pharmacodynamic 
(PD) relationships for safety and/or 
efficacy endpoints 
 
AMG 176 exposure/efficacy and 
exposure/safety relationships 
 
To identify metabolite(s) of AMG 176 
in plasma 
 
AMG 176 metabolites in plasma 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 12 of 38 
CONFIDENTIAL  
 
 
 
 
Evaluate the correlation of clinical 
responses to disease-specific 
features in tumor cells 
 
Relationships of clinical responses to 
biomarkers including but not limited to 
protein levels of pro-survival family 
members, fluorescent in situ 
hybridization (FISH)/cytogenetic 
analysis, gene expression profiling, 
flow cytometric phenotyping and DNA 
sequencing 
Multiple Myeloma Part 1b (QW) 
 
To explore PK/PD relationships for 
safety and/or efficacy endpoints 
 
AMG 176 exposure/efficacy and 
exposure/safety relationships 
 
To identify metabolite(s) of AMG 176 
in plasma 
 
AMG 176 metabolites in plasma 
 
Evaluate the correlation of clinical 
responses to disease specific 
features in tumor cells 
 
Relationships of clinical responses to 
biomarkers including but not limited to 
protein levels of pro survival family 
members, FISH/cytogenetic analysis, 
gene expression profiling, flow 
cytometric phenotyping, and DNA 
sequencing 
Acute Myeloid Leukemia Part 3a (BIW) and 3b (QW) 
 
To explore PK/PD relationships for 
safety and/or efficacy endpoints 
 
AMG 176 exposure/efficacy and 
exposure/safety relationships 
 
To identify metabolite(s) of AMG 176 
in plasma 
 
AMG 176 metabolites in plasma 
 
Evaluate the correlation of clinical 
responses to disease specific 
features in tumor cells 
 
Relationships of clinical responses to 
biomarkers including but not limited to 
protein levels of pro survival family 
members, FISH/cytogenetic analysis, 
gene expression profiling, flow 
cytometric phenotyping, and DNA 
sequencing 
 
Demonstrate AMG 176 inactivation of 
MCL1 by the increase of active BAX 
and caspase 3 in circulating AML 
blasts and /or the decrease of 
circulating blasts or immune cell 
populations 
 
BAX and caspase 3 expression in 
circulating AML blasts and/or 
monocytes, peripheral AML blast 
counts, immune cell subset 
frequencies and medium fluorescent 
intensity (MFI) 
 
Patient Interview Substudy (Part 3b 
only) 
 
To elicit patient reported perceptions 
of disease, associated symptoms, 
and symptom impact/burden and 
interference on patient’s life 
 
Patient reported symptom burden 
including symptom description, 
frequency and severity  
 
Subjective assessment of symptom 
burden interference with daily 
activities and influence on physical, 
role, emotional, social, and cognitive 
function 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 13 of 38 
CONFIDENTIAL  
 
 
 
 
To elicit patient perceptions of 
meaningful changes in symptom 
burden 
 
Subjective assessment of symptoms 
and associated change in burden that 
represents meaningful improvement 
and worsening 
 
To elicit patient perceptions on the 
relationship between symptom 
burden and clinical status 
 
Association between symptom burden, 
interference, and clinical response 
 
To explore patient experience with 
treatment administration 
route/schedule (frequency), and 
related caregiver needs 
 
Subjective assessment of treatment 
administration route and schedule on 
time for administration, time away 
from daily activities due to infusion, 
adherence and persistence, travel time 
to infusion center, and caregiver needs 
to receive infusion 
Acute Myeloid Leukemia Part 3c (QW) 
 
To explore PK/PD relationships for 
safety and/or efficacy endpoints in 
Japan subjects 
 
AMG 176 exposure/efficacy and 
exposure/safety relationships 
 
To identify metabolite(s) of AMG 176 
in plasma in Japan subjects 
 
AMG 176 metabolites in plasma 
 
Evaluate the correlation of clinical 
responses to disease specific 
features in tumor cells in Japan 
subjects 
 
Relationships of clinical responses to 
biomarkers including but not limited to 
protein levels of pro survival family 
members, FISH/cytogenetic analysis, 
gene expression profiling, flow 
cytometric phenotyping, and DNA 
sequencing 
 
Demonstrate AMG 176 inactivation of 
MCL1 by the increase of active BAX 
and caspase 3 in circulating AML 
blasts and/or the decrease of 
circulating blasts or immune cell 
populations in Japan subjects 
 
BAX and caspase 3 expression in 
circulating AML blasts and/or 
monocytes, peripheral AML blast 
counts, immune cell subset 
frequencies and MFI 
Acute Myeloid Leukemia Parts 4 and 5 (QW and BIW) 
 
To explore PK/PD relationships for 
safety and/or efficacy endpoints 
 
AMG 176 exposure/efficacy and 
exposure/safety relationships 
including optimization of dose and 
frequency 
 
To identify metabolite(s) of AMG 176 
in plasma 
 
AMG 176 metabolites in plasma 
 
Evaluate the correlation of clinical 
responses to disease specific 
features in tumor cells 
 
Relationships of clinical responses to 
biomarkers including but not limited to 
protein levels of pro survival family 
members, FISH/cytogenetic analysis, 
gene expression profiling, flow 
cytometric phenotyping, and DNA 
sequencing 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 14 of 38 
CONFIDENTIAL  
 
 
 
 
Demonstrate AMG 176 inactivation of 
MCL1 by the increase of active BAX 
and caspase 3 in circulating AML 
blasts and /or the decrease of 
circulating blasts 
 
BAX and caspase 3 expression in 
circulating AML blasts and/or 
monocytes, peripheral AML blast 
counts, immune cell subset 
frequencies and medium fluorescent 
intensity (MFI) 
 
To evaluate additional measures of 
efficacy of AMG 176 and azacitidine 
via minimal residual disease negative 
(MRD[ ]) assessment 
 
MRD[ ] status at the time of complete 
response (CR) 
 
Patient Interview Substudy 
 
To elicit patient reported perceptions 
of disease, associated symptoms, 
and symptom impact/burden and 
interference on patient’s life 
 
Patient reported symptom burden 
including symptom description, 
frequency and severity  
 
Subjective assessment of symptom 
burden interference with daily 
activities and influence on physical, 
role, emotional, social, and cognitive 
function 
 
To elicit patient perceptions of 
meaningful changes in symptom 
burden 
 
Subjective assessment of symptoms 
and associated change in burden that 
represents meaningful improvement 
and worsening 
 
To elicit patient perceptions on the 
relationship between symptom 
burden and clinical status 
 
Association between symptom burden, 
interference, and clinical response 
 
To explore patient experience with 
treatment administration 
route/schedule (frequency), and 
related caregiver needs 
 
Subjective assessment of treatment 
administration route and schedule on 
time for administration, time away 
from daily activities due to infusion, 
adherence and persistence, travel time 
to infusion center, and caregiver needs 
to receive infusion 
AML = acute myeloid leukemia; BIW = twice weekly; DLRT = dose-level review team; 
IV = intravenous; MM = multiple myeloma; MTCD = maximum tolerated combination dose; 
MTD = maximum tolerated dose; mTPI = modified toxicity probability interval; 
PD = pharmacodynamics; PK = pharmacokinetics; QW = once weekly; RP2D = recommended 
phase 2 dose; SC = subcutaneous; US = United States. 
 
2.2 
Hypotheses and/or Estimations 
 No formal statistical hypothesis will be tested. The clinical hypothesis is that at least 1 
dose level of AMG 176 administered as monotherapy or in combination with azacitidine 
will achieve acceptable safety and tolerability in subjects with relapsed or refractory MM 
and AML.   


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 15 of 38 
CONFIDENTIAL  
 
 
 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1, multicenter, open-label, dose-escalation study to define the MTD 
or recommended dose and maximum tolerated combination dose (MTCD), as well 
as the safety, tolerability, PK, pharmacodynamics (PD), and efficacy of AMG 176 
administered as monotherapy or in combination with SOC.  
The study will be conducted in multiple parts as shown in the table below.   
A dose-level review team (DLRT) will be responsible for dosing recommendations, 
which may include escalation to the next nominal or intermediate dose, 
de-escalation to a lower nominal or intermediate dose; modifications of the 
ramp-up dosing, alternative dose frequencies, continuation, delay or termination 
of dosing; or repetition or expansion of a cohort; or determination of 
recommended dose.  For definition of the DLT evaluation period and of a 
DLT-evaluable subject refer to section 6.7.2.   
Cycles of AMG 176 treatment may continue until confirmed progressive disease 
(PD) defined by 2017 European LeukemiaNet (ELN) criteria for AML subjects 
[Appendix B], the subject becomes intolerant to the study medication, signs and 
symptoms of clinical progression are evident as determined by the principal 
investigator, or the subject withdraws consent.  Evaluation of disease response 
will be performed every 28 days (± 7 days) until PD irrespective of cycle duration 
including dose delays or treatment discontinuation.  The disease assessment 
schedule is independent of treatment schedules.   
Ramp-up dosing in cycle 1 will be utilized whenever the AMG 176 target dose level 
is at 180 mg/m2 or higher to mitigate the risk of tumor lysis syndrome (TLS).   
A safety follow-up (SFU) visit must be performed 30 days (+3 days) after the last 
dose of protocol-required therapies.  Long term follow-up assessments will occur 
every 3 months ( 14 days) after end of treatment (EOT) for 1 year and include 
survival, subsequent anti-cancer therapy, and any cardiac associated serious 
adverse event or studies performed.   
Overview of Study Design 
Part 
Indication/ 
Number of 
Subjects 
Cohort/ 
Treatment Groupa 
Design 
CLOSED TO ENROLLMENT 
1a 
Multiple 
Myeloma 
(36 subjects 
enrolled) 
AMG 176 BIW IV 
monotherapy  
(30, 40, 50, 60, 120, 240 
mg/m2 
Ramp-up Dosing 
implemented: 180, 240, 
360, and 480 mg/m2) 
A standard 3+3 design was used to 
identify the MTD (or recommended dose), 
safety, tolerability, PK, and PD of 
AMG 176 administered BIW. 


Product:  AMG 176  
Protocol Number:  20150161 
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CONFIDENTIAL  
 
 
 
1b 
Multiple 
Myeloma 
(12 subjects 
enrolled) 
AMG 176 QW IV 
monotherapy  
(180, 240, 360, and 480 
mg/m2) 
A standard 3+3 design was used to 
identify the MTD (or recommended dose), 
safety, tolerability, PK, and PD of 
AMG 176 administered QW. The starting 
dose level was 180 mg/m2. 
3a 
AML 
(17 subjects 
enrolled) 
AMG 176 BIW IV 
monotherapy  
(60, 120, and 180 
mg/m2) 
A standard 3+3 design was used to 
identify the MTD, as well as the safety, 
tolerability, PK, and PD of AMG 176 
administered BIW. The starting dose level 
was 60 mg/m2.   
3b 
AML 
(11 subjects) 
AMG 176 QW IV 
monotherapy  
(120, 180, and 
240 mg/m2) 
A modified toxicity probability interval 
(mTPI) model design was used to 
evaluate the safety, tolerability, PK, and 
PD of AMG 176 administered QW. 
3c 
AML 
(4 subjects 
enrolled in 
Japan) 
AMG 176 QW IV 
monotherapy 
(120 mg/m2) 
A standard 3+3 design without dose 
escalation was used to evaluate the 
safety, tolerability, PK, and PD of 
AMG 176 administered QW in subjects 
with AML in Japan. 
 
 
 
 
Part 
Indication/ 
Number of 
Subjects 
Cohort/ 
Treatment Groupa 
Design 
OPEN TO ENROLLMENT 
3d 
AML 
(approximately 
11 subjects in 
US) 
AMG 176 QW IV 
60 mg/m2 in combination 
with itraconazole 
(200 mg) once daily 
(QD) starting on day -3 
through day 4 (total of 
7 days) only in cycle 1 
A fixed sequence design (itraconazole 
plus AMG 176 in week 1, followed by 
AMG 176 in subsequent weeks) will be 
used to evaluate the effect of itraconazole 
(strong cytochrome P450 3A4 [CYP3A4] 
inhibitor) on the PK of AMG 176.   
4 
AML 
(approximately 
60 subjects) 
Cohorts 1-4: AMG 176 
QW IV (60, 120, 180, 
and 240 mg/m2) in 
combination with 
azacitidine, with 
ramp-up dosing of 
AMG 176 as described 
for target doses 
≥ 180 mg/m². 
Cohort 5a: AMG 176 
BIW IV (120 mg/m2) in 
combination with 
azacitidine 
Cohort 5b: AMG 176 
BIW IV (240 mg/m2) in 
combination with 
azacitidine 
An mTPI design will be used to define 
the combination RP2D.  All subjects 
will receive azacitidine at a dose of 
75 mg/m² either IV or SC, as 
recommended in the prescribing 
information, daily for the first 7 days of 
a 28-day cycle.  Safety, tolerability, PK, 
and PD of AMG 176 in combination 
with azacitidine will also be 
established.  Part 4 enrollment will 
begin after the DLRT established the 
120 mg/m2 dose of AMG 176 as safe 
and tolerable in combination with 
azacitidine.   


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
Page 17 of 38 
CONFIDENTIAL  
 
 
 
AML = acute myeloid leukemia; BIW = twice weekly; DLRT = dose-level review team; IV = intravenous; 
MM = multiple myeloma; MTD = maximum tolerated dose; mTPI = modified toxicity probability interval; 
PD = pharmacodynamics; PK = pharmacokinetics; QD = once daily; QW = once weekly; 
RP2D = recommended phase 2 dose; SC = subcutaneous; US = United States 
Note:  Part 2 was designed to be a combination treatment for MM in a previous amendment. It was removed 
due to a change in AMG 176 clinical development.  
 
In this study, Part 1 and Part 2 were initially designed to investigate AMG 176 as 
monotherapy and combinational therapy in subjects with multiple myeloma (MM). As of 
December 2019, 48 subjects were enrolled in Part 1 where clinical responses were 
Part 
Indication/ 
Number of 
Subjects 
Cohort/ 
Treatment Groupa 
Design 
OPEN TO ENROLLMENT 
5 
AML 
(approximately 
68 subjects 
[24 per cohort 
in Part 5A, 
20 in Part 5B]) 
Part 5A:  AMG 176 in 
combination with 
azacitidine 
Cohorts 1 and 2:  OBD 
Selection (QW or BIW).   
Part 5B:  Conventional 
AML Dosing Schedule 
(5 consecutive days) 
Part 5 will begin after the completion of 
Part 4.   
Part 5A:   
 Two cohorts will be enrolled to 
determine the combination 
RP2D/OBD on either a QW or BIW 
dosing schedule.   
 Simon’s two-stage minimax design 
(Simon, 1989) will be used in each 
cohort of Part 5A for conducting the 
trial. 
 Enrollment will be restricted to 
subjects with persisting or recurring 
AML ≤ 2 prior lines of therapy.   
Part 5B (The enrollment of Part 5B will 
start after Part 5A is complete):  
 Two regimens will be tested, both 
continuing to utilize a 28-day cycle. 
 All subjects will receive 7 days of 
azacitidine IV or SC daily at 
75 mg/m² on Days 1 - 5, 8 - 9 of each 
28-day cycle. 
 Regimen 1 will administer AMG 176 
at 240 mg/m² QD for 3 days + 4 days 
off followed by BIW dosing on 
weeks 2 and 3. 
 Regimen 2 will administer AMG 176 
at 240 mg/m² QD for 5 consecutive 
days, and then BIW on week 2 (no 
administration on weeks 3 and 4).  
Regimen 2 will only enroll if no 
safety issues arise after 6 subjects 
have enrolled in Regimen 1. 
 Doses other than the stated 
240 mg/m² based on emerging data. 


Product:  AMG 176  
Protocol Number:  20150161 
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CONFIDENTIAL  
 
 
 
observed at dose levels > 240 mg/m². However, AMG 176 associated elevations of 
troponin were observed at dose levels of 360 and 480 mg/m² in MM subjects. In 
contrast, clinical responses in AML were observed at the lower dose levels, indicating 
that AML may be more susceptible to MCL1 inhibition and can be treated with lower 
doses compared to subjects with MM. The combination of these observations led to 
further development in AML and a pause in MM development for now. Part 1 will remain 
closed to enrollment and Part 2 was removed from the protocol during Amendment 10. 
To avoid the potential for troponin elevations, only doses ≤ 240 mg/m² will be further 
investigated. Additionally, preclinical data demonstrates that MCL1 inhibition is more 
efficacious in combination with other antileukemic therapies. Consequently, 
combinational therapy will be prioritized in this study (Parts 4 and 5) to optimize the 
clinical benefit to subjects, and monotherapy dose escalation will be performed only to 
inform the combinational study, and not to confirm the likely monotherapy maximum 
tolerated dose (MTD) of 240 mg/m². As of November 2022, 33 subjects have been 
enrolled in monotherapy (Part 3b: 11 subjects) and combination therapy (Part 4: 22 
subjects) cohorts at dose levels of ≤ 240 mg/m²; no concerning safety events (including 
elevations of troponin) and no Dose-Limiting Toxicities (DLTs) were observed. 
 
 
Figure 1-1.  Overall Study Design and Treatment Schema 
Phase 1:  Dose Expansion/Exploration Monotherapy
Phase 1:  Dose Exploration/Expansion
Combination Therapy
Phase 1 Multiple Myeloma Part 1a AMG 176 BIWMonotherapy a
CLOSED TO ENROLLMENT
Phase 1 Multiple Myeloma Part 1b AMG 176 QW Monotherapy a
CLOSED TO ENROLLMENT
Phase 1 AML Part 3a AMG 176 BIWMonotherapy b
CLOSED TO ENROLLMENT
Phase 1 AML Part 3b AMG 176 QW Monotherapy a, c
Phase 1 AML Part 3c AMG 176 QW Monotherapy in Japan 
a
CLOSED TO ENROLLMENT
Phase 1 AML Part 3d AMG 176 QW 
in combination with itraconazole (U.S. only) d, e
e
Dose Exploration
Phase 1 AML Part 4 AMG 176 QW and BIW
in combination with azacitidine d
Dose Expansion
Phase 1 AML Part 5 AMG 176 in combination with 
azacitidine(3 cohorts: 120 BIW, 240 BIW, and conventional 
dosing)
MTCD
e
 
AML = acute myeloid leukemia; BIW = twice weekly; MTCD = maximum tolerated combination dose; QW = once 
weekly; US = United States 
a Ramp-up dosing in cycle 1 will be utilized whenever the target dose level is at 180 mg/m² or higher.  Ramp-up 
dosing consists of an initial dose at cycle 1 week 1 of 120 mg/m² followed by an increase to the target dose level 
for subsequent doses. 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
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CONFIDENTIAL  
 
 
 
b The AMG 176 starting dose level will be 60 mg/m² BIW. 
c The AMG 176 starting dose level will be 120 mg/m² QW. 
d The AMG 176 starting dose level was 60 mg/m² QW.  
e After week 3, subjects may crossover to Part 3b or Part 4 for continued treatment if approved by the investigator 
and Amgen medical monitor.  Subjects from Part 3d who crossover to Part 3b, will not crossover (for the second 
time) to Part 4. 
3.2 
Sample Size 
It is anticipated that approximately 219 subjects will be enrolled in the different parts of 
this study. Multiple myeloma Part 1a enrolled 36 subjects for dose escalation. Multiple 
myeloma Part 1b enrolled 12 subjects for dose escalation. Acute myeloid leukemia 
Part 3a enrolled 17 subjects for dose escalation.  Part 3b enrolled 11 subjects. Acute 
myeloid leukemia Part 3c enrolled 4 subjects in Japan. Part 3d will enroll about 
11 subjects in the US. Part 4 will enroll approximately 60 subjects. Part 5 will enroll 
approximately 68 subjects.   
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 MTD or MTCD and 
to evaluate DDI. With 3 subjects in a cohort, there is a 27 to 70 probability of 
observing at least one DLT if the true DLT rate is 10 to 33 and with 6 or 9 subjects in 
a cohort there is a 47 to 91 probability and 61 to 97 probability, respectively.   
3.3 
Adaptive Design 
MM Part 1a, Part 1b,  and AML Part 3a, 3b, Part 3c are closed to enrollment. 
For AML Part 3b and Part 4, each dose level will initially enroll 3-4 subjects and up to 10 
subjects per cohort may be enrolled.  A mTPI design will be used to guide dose 
exploration. The MTD is defined as the highest 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 
MTD if the toxicity probabilities belong to the proper dosing interval [0.15, 0.25] which 
corresponds to staying at the current dose (S). The underdosing interval is defined as (0, 
0.15) in which the doses are deemed lower than the MTD and corresponds to a dose 
escalation (E). The overdosing interval is (0.25, 1) in which the doses are deemed higher 
than the MTD and corresponds to a dose de-escalation (D). 
Guidelines for dose level decisions can be found in Table 2.  Please note one exception 
to the guidelines provided in Table 2, a single grade 3 treatment related troponin 
elevation will result in dose de-escalation regardless of number of subjects treated at 
current dose. 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
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CONFIDENTIAL  
 
 
 
Table 2.  Guidelines for Dose-level Decisions for Part 3b and Part 4 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Number of DLTs 
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 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. 
Covariates and Subgroups 
4.1 
Planned Covariates 
There are no planned covariates in this study. The relationship of biomarker and efficacy 
endpoints may be explored by biomarker team if appropriate. 
4.2 
Subgroups 
Not applicable for this study. 
5. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be collected in years in the clinical database. 
Enrollment Date 
Enrollment Date is defined as the date collected on the Subject Enrollment eCRF. 
Baseline  
Unless otherwise specified, baseline will be defined as the last assessment before the 
first dose of investigational product (AMG 176).   
Change From Baseline 
Change from baseline is the arithmetic difference between post-baseline and baseline. 
Change from Baseline= (Post-baseline Value – Baseline Value) 
Percent Change from Baseline 
Percent change from baseline is the arithmetic difference between post-baseline value 
and baseline value divided by baseline value and multiplied by 100. 


Product:  AMG 176  
Protocol Number:  20150161 
Date:  12 November 2024 
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CONFIDENTIAL  
 
 
 
Percent change from baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
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. 
Duration of Treatment 
Date of last administration of investigational product – Study Day 1 + 1 
Investigational Product (IP) 
IP is used in reference to 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. 
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 
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 
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. 


Product:  AMG 176  
Protocol Number:  20150161 
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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. Events that are directly related to disease progression 
(including, but not limited to, preferred terms “Disease progression” etc.) will be 
excluded from TEAE analysis. 
Best Overall Response (BOR): 
BOR for a subject is the best observed post-baseline disease response based on 
investigator assessment. 
 
AML: BOR is defined as the first response category achieved in the following order: 
CRMRD-, CR, CRi, MLFS, PR, SD, PD. Response criteria for AML are ELN Response 
Criteria.  
 
MM: BOR is defined as the overall response at end of study (data collected on the 
Best Overall Response CRF). If the overall response is missing, BOR will be derived 
from the post-baseline disease assessments in the order of: sCR, CR, VGPR, PR, 
MR, SD, PD. Response criteria for MM are IMWG Uniform Response Criteria. 
Duration of Response (DOR) 
Duration of response is calculated for subjects who have achieved a response (PR or 
better). It is defined as time from the first observation indicating a response to the 
subsequent date of relapse, disease progression or death (due to any cause), whichever 
is earlier. 
DOR time in months: (earliest date of relapse, disease progression or death - date of 
the first observation of response +1)/30.4  
Subjects without relapse, disease progression or death until the analysis data cut-off 
date will be censored at the last adequate disease assessment date after first response; 
otherwise, at first response. 
Event-free Survival (EFS) for AML 
Event-free survival is defined as the interval from the first dose of IP to the earlier date of 
induction treatment failure, relapse for those who have induction treatment success 
(e.g., complete remission), or death due to any cause. Censoring is at the last evaluable 


Product:  AMG 176  
Protocol Number:  20150161 
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post-baseline response assessment; otherwise, at the first dose of IP. The event date for 
induction treatment failure is assigned as the date of the first dose of IP. 
EFS time in months: (event date - first dose of IP date +1)/30.4  
Overall Response Rate (ORR) 
ORR is the incidence of either PR or better based on investigator assessment. All 
subjects that do not meet the criteria for response (PR or better) by the analysis cutoff 
date will be considered as non-responders. 
For MM subjects:  The earliest record where PR or better response has to be 
confirmed by two consecutive same/better response assessments at any time and 
should be on/before new anticancer therapy start date. sCR, CR, VGPR and PR are 
considered as PR or better responses.  
For AML subjects: The earliest record where PR or better response collected does 
not need to be confirmed by subsequent assessment and should be on/before 
new anticancer therapy start date. CRMRD-, CR, CRi(CR with incomplete 
hematologic recovery), MLFS and PR are considered as PR or better responses.  
Overall survival (OS) 
OS is defined as the time from first dose of IP date until death due to any cause.  
OS time in months: (date of death - first dose of IP date +1)/30.4  
Subjects without event will be censored at their last date known to be alive. 
Progression-free survival (PFS) for MM 
PFS time is calculated as time from first dose of IP date to disease progression date or 
death due to any cause, whichever is earlier.  
PFS time in months: (event date - first dose of IP date +1)/30.4  
Subjects without disease progression or death until the analysis data cut-off date will be 
censored at the last non-missing evaluable disease assessment date. Subject will be 
censored at last non-NE post-baseline disease assessment before any anti-cancer 
therapy. If there are no post-baseline disease assessment, then subjects are 
censored at treatment start date. 
Time to Response (TTR) 


Product:  AMG 176  
Protocol Number:  20150161 
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Time to response is defined as the time from the first dose of IP until the first 
documentation of response (PR or better). Only subjects who have achieved a response 
will be evaluated for TTR.  
TTR time in months: (date of the first observation of response - first dose of IP date 
+1)/30. 
Dose intensity 
Dose intensity indicates actual dose (mg) given per cycle, which is the cumulative 
dose divided by the number of cycles started. 
Relative Dose intensity 
Relative dose intensity is calculated as actual cumulative dose / planned 
cumulative dose, where  
• 
Actual cumulative dose [mg] is defined as the total dose given during the 
study treatment exposure till the course of study. For subjects who did not take 
any drug the actual cumulative dose is 0 mg.  
• 
Planned cumulative dose [mg] is defined as the per-protocol planned dose 
accumulated over the actual duration on study treatment, whether the actual visit 
is missing or not. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The FAS is defined as all subjects that are enrolled and receive at least 1 dose of AMG 
176. 
6.2 
Safety Analysis Set 
The Safety Analysis Set is same as the Full Analysis Set as described in Section 
6.1. 
6.3 
Per Protocol Analysis Set(s) 
Not applicable. 
6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
Not applicable. 
6.5 
Pharmacokinetic Analyses Set(s) 
The pharmacokinetic analysis set is defined as all subjects who have received at least 1 
dose of AMG 176 and for whom PK parameters can be adequately estimated. These 


Product:  AMG 176  
Protocol Number:  20150161 
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CONFIDENTIAL  
 
 
 
subjects will be evaluated for PK analysis unless the number of data points required for 
analysis is not enough, or significant protocol deviations have affected the data, or if key 
dosing or sampling information is missing. 
6.6 
Interim Analyses Set(s) 
Not applicable. 
6.7 
Study-specific Analysis Set(s) 
6.7.1 
Interim Efficacy Analysis Set 
Interim Efficacy Analysis Set is a subset of the Full Analysis Set (FAS) and it 
includes subjects whose data cut-off date is at least 4 weeks after the first dose 
date. 
6.7.2 
DLT Evaluable Analysis Set  
A subject is deemed DLT evaluable if during the DLT observation period the subject 
met at least one of the following criteria: 
 
received at least 75% of the planned dose of AMG 176 (and 100% of the planned 
doses of azacitidine in Part 4) and completed the DLT observation period 
 
experienced a DLT 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No formal interim efficacy analysis is planned for this study. Interim safety analyses 
will be performed to support the evaluation of safety by the DLRT. However, safety 
data will be reviewed on an ongoing basis. The Dose Level Review Team (DLRT) will 
review all available cumulative data by cohort prior to making dose escalation decisions. 
Adverse events and DLTs observed in all subjects will be evaluated continually and 
considered in all enrollment and dosing decisions.  
Additional interim analyses will be performed when the target number of subjects 
enrolled in each part has had the opportunity to complete 6 months of treatment. 
7.2 
Primary Analysis 
A primary analysis will occur when the last subject has had opportunity to complete 6 
cycles of the treatment of AMG 176. 
7.3 
Final Analysis 
A final analysis is planned after all subjects have had the opportunity to complete the last 
study visit. 


Product:  AMG 176  
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If FA is close to PA then FA will be performed. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
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 A. 
Non-pharmacokinetic measurements (eg. biomarker data) 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. 


Product:  AMG 176  
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8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Datasets, tables, figures, and listings will be produced and validated in accordance with 
SOP-430399. Standard macros will be used when available. 
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 continuous data will include means, medians, standard 
deviations and ranges, while categorical data will be summarized using frequency 
counts and percentages. Graphical summaries of the data may also be presented.   
When data are summarized by time, the values recorded against the scheduled time 
points listed in the protocol will be used. When assessing minimum/maximum increases 
or decreases over the study, all assessments, including unscheduled assessments will 
be used.  
For each indication, efficacy and safety data will be summarized by dose level.   
For the subjects who complete the DLT period and proceed to a higher dose level or 
crossover to a combinational therapy cohort for the following treatment cycle, efficacy 
and safety will be analyzed by the initial assigned dose level. 
Exploratory analysis will be performed separately if needed.  
9.2 
Subject Accountability 
The number and percent of subjects who are enrolled, receive investigational product, 
completed investigational product, discontinue from investigational product (including 
reasons for discontinuation), complete study, discontinue the study (including reasons 
for discontinuation) will be summarized by cohort. Enrollment by country and study site 
will be summarized. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes and descriptions 


Product:  AMG 176  
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CONFIDENTIAL  
 
 
 
will be used during the course of the study. Eligibility deviations are defined in the 
protocol. IPDs and eligibility deviation will be summarized. A listing will be provided for 
IPD. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced: Demographic (i.e., age, age groups [18 to < 65, 65 to < 75, 75 to < 85, ≥ 
85 years], sex, race, and ethnicity) and baseline characteristics (height, weight, disease 
type/sub-type, prior lines of therapy, and ECOG Performance Status, Multigated 
Acquisition (MUGA) Scan or Echocardiogram, Neurological Status) will be summarized 
using descriptive statistics. If multiple races have been reported for a subject, the subject 
will be categorized as multiple. 


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9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
Not Applicable. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)/Estimand(s) 
Table 3. Efficacy Endpoint Summary 
For time to event endpoints (including DOR, TTR, EFS and PFS), summary table or 
figure may not be generated if the number of events is less than 10. The individual 
subject-level data will be provided. 
9.6 
Safety Analyses 
9.6.1 
 Analyses of Primary Safety Endpoint(s) 
All the safety analysis will be performed based on full analysis set unless 
otherwise specified. 
Table 4.  Safety Endpoint Summary Table 
 
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 or disease related events to a 
Endpoint 
Statistical Analysis Methods 
ORR 
 
The proportion of subjects with response (PR or 
better) with corresponding 2-sided exact 95 CI will 
be calculated using the Clopper-Pearson method 
(Clopper and Pearson, 1934) for the Full Analysis 
Set. Refer Appendix C for code fragment.  
DOR, PFS (for MM) and EFS 
(for AML)  
Kaplan-Meier estimates and Kaplan-Meier curve 
will be provided for the Full Analysis Set. 
TTR 
Descriptive statistics will be provided for subjects 
with response. 
Endpoint 
Statistical Analysis Methods 
Incidence of Dose-Limiting Toxicities 
(DLTs), treatment-related and 
treatment-emergent adverse events, and 
clinically significant changes in vital 
signs, 
electrocardiograms (ECGs), and clinical 
laboratory tests 
 
Treatment-emergent, treatment-
related adverse events, vital signs, 
electrocardiograms, clinical 
laboratory tests will be performed 
based on full analysis set. 
 
Incidence of dose-limiting toxicitites 
will be based on DLT evaluable 
analysis set. 


Product:  AMG 176  
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system organ class and a preferred term. The severity of each adverse event will be 
graded using CTCAE version 4.0. 
Subject incidence of all treatment-emergent adverse events, serious adverse events 
(SAEs), grade 3 or higher, treatment-related, serious treatment-related, adverse events 
leading to withdrawal of investigational product, and fatal adverse events will be 
tabulated by system organ class and preferred term by dose level. The event categories 
of adverse event and disease related event both will be included. 
For subjects who experienced COVID-19, SAEs on or after COVID-19 onset will be 
summarized.  
Subject incidence of DLTs will be summarized by preferred term and dose level using 
the DLT Evaluable Analysis Set. Summary table may not be generated if the number 
of events is less than 5 in each cohort. The individual subject-level data will be 
provided. Similar summaries will also be provided to events of interest. A listing of death 
will be provided. 
9.6.3 
Laboratory Test Results 
 Shifts in CTCAE grades of safety laboratory parameters between baseline and the 
worst post-baseline value for select blood chemistry analytes (creatinine, total bilirubin, 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline 
phosphatase [ALP]) and hematology analytes (hemoglobin, platelet count, absolute 
neutrophil count) will be tabulated by dose level. 
A summary of potential hepatoxicity by Hy’s Law will be tabulated. The criteria are 
defined as AST or ALT ≥ 3 times upper limit of normal (ULN), total bilirubin ≥ 2 times 
ULN, and ALP < 2 times ULN assessed within 30 days. 
Summary statistics of troponin over time by dose level will be provided based on 
data availability. 
9.6.4 
Vital Signs 
 Vital signs (systolic / diastolic blood pressure, heart rate) over time and change from 
baseline will be summarized. The analyses of vital signs will include summary statistics 
over time for AML parts only.   
9.6.5 
Physical Measurements 
Not applicable.  


Product:  AMG 176  
Protocol Number:  20150161 
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9.6.6 
Electrocardiogram 
All on-study ECG data including PR, QRS, QT, RR, QTcB, and QTcF interval will be 
summarized for AML parts only. Mean ± SE by visit graph may be plotted for QTcF 
and QTcB.  
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.   
Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcF. Unscheduled assessments will be included in the determination of the 
maximum change. 
• 
≤30 msec 
• 
>30 – 60 msec 
• 
>60 msec 
The number and percentage of subjects in each group will be summarized. 
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF. Unscheduled assessments will be included in the determination of the 
maximum post baseline value. 
• 
≤450 msec 
• 
>450 – 480 msec 
• 
>480 – 500 msec 
• 
>500 msec 
The number of subjects in each group will be summarized for each dosing group.  
In addition, the relationship between PK concentration of AMG 176 and change from 
baseline in QTcF may be explored graphically and performed by clinical 
pharmacology modeling and simulation (CPMS) team.   
9.6.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 176 antibodies at any 
time will be tabulated. 
9.6.8 
Exposure to Investigational Product 
 Descriptive statistics will be produced to describe the exposure to AMG 176. Number of 
cycles initiated, number of doses, duration of treatment, cumulative dose, average dose 


Product:  AMG 176  
Protocol Number:  20150161 
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delivered per day, average dose delivered per treated week, dose intensity and 
relative dose intensity will be summarized. Summaries of the number and percentage 
of subjects with dose modifications and reason for modification will be provided. 
A listing of the unique manufacturing lot numbers and a listing of the subjects 
administered each manufacturing lot number will be provided. 
9.6.9 
Exposure to Non-investigational Product(s)  
Descriptive statistics will be produced to describe the exposure to azacitidine, 
itraconazole. Number of cycles initiated, number of doses, cumulative dose, 
average dose delivered per day, average dose delivered per treated week, dose 
intensity and relative dose intensity will be summarized. 
9.6.10 
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. In addition, the 
number and proportion of subjects receiving anti-cancer therapies during 
long-term follow-up will be summarized. These analyses will be provided for AML 
parts only. 
9.7 
Other Analyses 
9.7.1 
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.   
The PK parameters for AMG 176 including, but not limited to Cmax, minimum observed 
concentration (Cmin), AUC, CL, and, if feasible, t½ will be estimated using standard 
non-compartmental PK methods and summarized by dose groups using means, 
standard deviations, medians, minimums, and maximums for intensive and peak/trough 
determinations.  AMG 176 concentrations at each time point along with PK parameter 
values may be reviewed for each subject.  Individual AMG 176 concentration/time 
profiles will be plotted by dose groups.  Summary statistics will be computed for each 
sampling time and parameter as appropriate.  For subjects in Part 3d (DDI assessment 
with itraconazole), AMG 176 PK parameters (Cmax, AUC) will be compared from day 1 
(with itraconazole) to day 15 (without itraconazole) to evaluate the effect of itraconazole 
on the PK of AMG 176, if feasible.  Additional analyses to explore relationship between 


Product:  AMG 176  
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CONFIDENTIAL  
 
 
 
exposure and safety and exposure and efficacy may also be performed.  
Pharmacokinetic parameters such as Cmax, AUC, and t½, if feasible, will be estimated 
and summarized for azacitidine. 
9.7.2 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Not applicable. 
9.7.3 
Analyses of Clinical Outcome Assessments 
Not appliable. 
9.7.4 
Analyses of Health Economic Endpoints 
Not applicable. 
9.7.5 
Analyses of Biomarker Endpoints 
Not applicable. 
10. 
Changes From Protocol-specified Analyses 
The study was terminated early. Synopsis CSR will be provided, and thus selected 
planned analyses will be performed. The following analyses will not be performed. 
1. PFS (MM), EFS (AML) 
2. TTR 
3. BAX and caspase 3 
4. Events of interest summaries 
5. Antibody formation 
6. Prior anti cancer therapies 
11. 
Literature Citations / References 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka. 1934;26:404-413. 
American Cancer Society. 2018. https://www.cancer.org/cancer/acute-
myeloidleukemia/about/key-statistics.html. Accessed on 9 September 2018.  
12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
The analyses of PK (including the DDI assessment for Part 3d) and exploratory 
endpoints are not covered by this plan. 


Product:  AMG 176  
Protocol Number:  20150161 
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14. 
Appendices 
Appendix A. Handling of Dates, Incomplete Dates and Missing Dates 
Imputation Rules for Partial or Missing Dates for Adverse Events and Concomitnt 
Medications 
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 
2 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
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: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 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. 
1. Imputation rules for partial or missing stop dates: 
 
Initial imputation 
a. For partial stop date mmyyyy, impute the last of the month. 
b. For partial stop date yyyy, impute December 31 of the year. 
c. For completely missing stop date, do not impute. 
 
 
If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date.  
 
If the stop date imputation leads to a stop date that is before the start date, then set 
the stop date as missing. 
2. Imputation rules for partial or missing death dates:  
 
If death year and month are available but day is missing:  
a. 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.  


Product:  AMG 176  
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b. 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.  
c. If YYYYMM for the date last known to be alive is greater than YYYYMM for death 
date, data error, do not impute and censor subject survival time.  
 
If month and day are missing and year of death is known:  
a. If YYYY for the date last known to be alive equals the YYYY for death date, set 
death date to the day after last known to be alive date.  
b. If YYYY for the date last known to be alive is less than the YYYY for death date, 
set death date to the first day of the death year.  
c. If YYYY for the date last known to be alive is greater than YYYY for death date, 
data error, do not impute and censor the subject survival time.  
 
If a death date is totally missing, do not impute and censor the subject survival time.  
3. General Imputation rules for time to event efficacy endpoints 
Unless otherwise specified, the partial/missing event dates will be imputed as follows: 
 
If event year and month are available but the day is missing:  
a. If mmyyyy for the date last known to be event-free equals mmyyyy for event date, 
set event date to the day after the date last known to be event-free.  
b. If mmyyyy for the date last known to be event-free is less than the mmyyyy for 
event date, set event date to the first day of the event month.  
c. If mmyyyy for the date last known to be event-free is greater than mmyyyy for 
event date, data error and do not impute.  
 
If month and day are missing and year of event is known: 
a. If yyyy for the date last known to be event-free equals the yyyy for event date, set 
event censor date to the date last known to be event-free.  
b. If yyyy for the date last known to be event-free is less than the yyyy for event 
date, set OS censor date to last day of the prior year. 
c. If yyyy for the date last known to be event-free is greater than yyyy for event 
date, data error and do not impute. 
If an event date is totally missing, do not impute. 
 
 
 


Product:  AMG 176  
Protocol Number:  20150161 
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Appendix B.  European LeukemiaNet (ELN) Response Criteria in Acute Myeloid 
Leukemia (2017) 
Category 
Definition 
Comment 
Response 
 CR without minimal 
residual disease 
(CRMRD-) 
If studied pretreatment, CR with 
negativity for a genetic marker by 
RT-qPCR, or CR with negativity by 
MFC 
Sensitivities vary by marker tested, 
and by method used; therefore, test 
used and sensitivity of the assay 
should be reported; analyses should 
be done in experienced laboratories 
(centralized diagnostics) 
 Complete remission 
(CR) 
Bone marrow blasts  5; absence of 
circulating blasts and blasts with Auer 
rods; absence of extramedullary 
disease; ANC 1.0 x 109/L (1000/L); 
platelet count 100 x 109/L 
(100 000/L) 
MRD or unknown 
 CR with incomplete 
hematologic recovery 
(CRi) 
All CR criteria except for residual 
neutropenia (1.0 x 109/L [1 000/L]) 
or thrombocytopenia (100 x 109/L 
[100 000/L]) 
 Morphologic 
leukemia-free state 
(MLFS) 
Bone marrow blasts 5; absence of 
blasts with Auer rods; absence of 
extramedullary disease; no 
hematologic recovery required 
Marrow should not merely be 
“aplastic”; at least 200 cells should 
be enumerated or cellularity should 
be at least 10 
 Partial remission (PR) 
All hematologic criteria of CR; 
decrease of bone marrow blast 
percentage to 5 to 25; and 
decrease of pretreatment bone 
marrow blast percentage by at least 
50 
Especially important in the context 
of phase 1-2 clinical trials 
Treatment failure 
 Primary refractory 
disease 
No CR or CRi after 2 courses of 
intensive induction treatment; 
excluding subjects with death in 
aplasia or death due to indeterminate 
cause 
Regimens containing higher doses 
of cytarabine are generally 
considered as the best option for 
subjects not responding to a first 
cycle of 73; the likelihood of 
responding to such regimens is 
lower after failure of a first 
 Death in aplasia 
Deaths occurring  7 d following 
completion of initial treatment while 
cytopenic; with an aplastic or 
hypoplastic bone marrow obtained 
within 7 d of death, without evidence 
of persistent leukemia 
 Death from 
indeterminate cause 
Deaths occurring before completion 
of therapy, or  7 d following its 
completion; or deaths occurring  7 d 
following completion of initial therapy 
with no blasts in the blood, but no 
bone marrow examination available 
Page 1 of 2 
Footnotes defined on next page 


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Category 
Definition 
Comment 
Response criteria for clinical trials only 
 Stable disease 
Absence of CRMRD-, CR, CRi, PR, MLFS; 
and criteria for PD not met 
Period of stable disease 
should last at least 3 mo 
 Progressive disease 
(PD)a,b 
Evidence for an increase in bone marrow 
blast percentage and/or increase of absolute 
blast counts in the blood: 
  50 increase in marrow blasts over 
baseline (a minimum 15 point increase 
is required in cases with  30 blasts at 
baseline; or persistent marrow blast 
percentage of  70 over at least 3 mo; 
without at least a 100 improvement in 
ANC to an absolute level ( 0.5 x 109/L 
[500/L], and/or platelet count to 
 50 x 109/L [50 000/L] nontransfused); or 
  50 increase in peripheral blasts 
(WBC x  blasts) to  25 x 109/L 
( 25 000/L) (in the absence of 
differentiation syndrome)b; or 
 New extramedullary disease 
Category mainly applies for 
older subject given low 
intensity or single-agent 
“targeted therapies” in 
clinical trials. 
In general, at least 2 cycles 
of a novel agent should be 
administered. 
Some protocols may require 
blast increase in 
2 consecutive marrow 
assessments at least 4 wk 
apart; the date of 
progression should then be 
defined as of the first 
observation date. 
Some protocols may allow 
transient addition of 
hydroxyurea to lower blast 
counts.  Hydroxyurea is 
unapproved for AML in 
Japan. 
“Progressive disease” is 
usually accompanied by a 
decline in ANC and platelets 
and increased transfusion 
requirement and decline in 
performance status or 
increase in symptoms. 
Relapse 
 Hematologic relapse 
(after CRMRD-, CR, CRi) 
Bone marrow blasts  5; or reappearance 
of blasts in the blood; or development of 
extramedullary disease 
 Molecular relapse (after 
CRMRD-) 
If studied pretreatment, reoccurrence of 
MRD as assessed by RT-qPCR or by MFC 
Test applied, sensitivity of 
the assay, and cutoff values 
used must be reported; 
analyses should be done in 
experienced laboratories 
(centralized diagnostics) 
Page 2 of 2 
ANC  absolute neutrophil count; d  day(s); IDH  isocitrate dehydrogenase; MLFS  morphologic 
leukemia-free state; mo  month(s); WBC  white blood cell; wk  week(s)  
a The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at 
harmonizing the various definitions used in different clinical trials. 
b Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation 
syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in 
blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily 
indicate PD. 
 
 


Product:  AMG 176  
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Appendix C.  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;