Conditions: Multiple Myeloma Acute Myeloid Leukemia Non-Hodgkins Lymphoma Myelodysplastic Syndrome AML MDS NHL
Keywords: Multiple Myeloma Acute Myeloid Leukemia Myelodysplastic Syndrome AML MDS MM Myeloid Cell Leukemia 1 Inhibitor MCL1 Inhibitor MCL1
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.

Detailed description:
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies

Arms:
arm 1: This arm includes subjects with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). arm 2: This arm includes subjects with acute myeloid leukemia (AML). arm 3: This arm includes subjects with AML or myelodysplastic syndrome (MDS). arm 4: This arm includes subjects with AML in Japan only. arm 5: This arm includes subjects with MM. arm 6: This arm includes subjects MDS. arm 7: This arm includes subjects AML. arm 8: This arm includes subjects MM.

Interventions: intervention 1: AMG 397 intervention 2: Dexamethasone intervention 3: Azacitidine
Intervention descriptions: intervention 1: AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle. intervention 2: Dexamethasone will be administered intravenously (IV) or orally on Days 1, 8, 15, and 22 of each 28-day cycle. intervention 3: Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.

Protocol document:
Prot_000.pdf: 
Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 1 of 130 
CONFIDENTIAL 
Title:  A Phase 1 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or 
Refractory Hematological Malignancies 
AMG 397 
Amgen Protocol Number AMG 397 20170173 
IND 137128 
Eudra CT 2017-005035-16 
Clinical Study Sponsor: Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805-447-1000 
Key Sponsor Contacts: 
, MD 
Early Development Lead 
Phone:  
 
E-mail:  
 
Clinical Research Study Manager 
Phone:  
 
E-mail:  
Date: 
30 November 2017 
Amendment 1 
28 March 2018 
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).
Approved
NCT Number: NCT03465540
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 2 of 130 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase 1 Open-label Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects with 
Selected Relapsed or Refractory Hematological Malignancies”, dated 28 March 2018, 
and agree to abide by all provisions set forth therein.  I agree to comply with the 
International Conference on Harmonisation (ICH) Tripartite Guideline on Good Clinical 
Practice (GCP) and applicable national or regional regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 3 of 130 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological 
Malignancies 
Study Phase:  1 
Indications:  Relapsed or Refractory (RR) Multiple Myeloma (MM),  Non-Hodgkin’s Lymphoma 
(NHL) or Acute Myeloid Leukemia (AML) 
Primary Objectives:   
• 
Evaluate the safety and tolerability of AMG 397  
• 
Estimate the maximum tolerated doses (MTDs) and/or biologically active doses 
(eg, recommended phase 2 doses [RP2Ds]) of AMG 397 
Secondary Objectives:   
• 
Evaluate the efficacy of AMG 397   
• 
Evaluate the pharmacokinetics (PK) of AMG 397  
Exploratory Objectives: 
• 
Explore pharmacokinetic/pharmacodynamic (PK/PD) relationships for safety and/or 
efficacy endpoints  
• 
Identify metabolite(s) of AMG 397 in plasma and urine 
• 
Demonstrate AMG 397 inactivation of myeloid cell leukemia sequence 1 (MCL1) by the 
activation of BAX and caspase 3 in circulating monocytes or blast cells, and/or the 
decrease of circulating monocytes 
• 
Evaluate patient responses according to disease-specific features in tumor cells such as 
chromosomal amplifications, rearrangements, gene expression profiles, protein 
expression as well as somatic mutations as necessary  
• 
Evaluate changes to immune cell subsets in peripheral blood due to MCL1 inactivation 
• 
Assess Minimal Residual Disease (MRD) status with patient response as necessary 
Hypothesis:  
A safe and tolerable dose of AMG 397 will have evidence of anti-tumor activity in patients with 
selected RR hematological malignancies as measured by Objective Response Rate (ORR).   
Primary Endpoints: 
• 
Incidence of dose limiting toxicities (DLTs), treatment-emergent adverse events, 
treatment-related adverse events and clinically-significant changes in vital signs, physical 
examinations, electrocardiogram (ECGs) and clinical laboratory tests 
Secondary Endpoints: 
• 
Efficacy parameters:  
− 
ORR using response criteria per the following: 
− 
International Myeloma Working Group (IMWG) for MM subjects 
− 
Lugano Classification for NHL subjects  
− 
Revised International Working Group (IWG) for AML subjects 
− 
Duration of response 
− 
Progression Free Survival (PFS) and Overall Survival (OS)  
• 
AMG 397 PK parameters including, but not limited to, maximum observed concentration 
(Cmax), time of maximum observed concentration (Tmax), area under the 
concentration-time curve (AUC), clearance (CL) and half-life (t1/2)  
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 4 of 130 
CONFIDENTIAL 
 
 
Exploratory Endpoints:   
• 
AMG 397 exposure/efficacy and exposure/safety relationships 
• 
AMG 397 metabolites in plasma and urine  
• 
Increased expression of BAX and Caspase 3 in monocytes or blast cells and/or decrease 
in circulating monocyte counts 
• 
Patient responses according to biomarkers of tumor cells including but not limited to 
protein levels of pro-survival family members, FISH/cytogenetic analysis, gene 
expression profiling, flow cytometric phenotyping and DNA sequencing 
• 
Immune cell subset frequencies, absolute counts and MFIs in peripheral blood 
• 
MRD status 
Study Design:   
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating 
AMG 397 administered orally once daily for 2 consecutive days followed by 5 days break at a 
weekly interval, as part of a 28-day treatment cycle in adult subjects with selected RR 
hematological malignancies.  
This study will consist of dose escalation (Part 1) to evaluate safety and tolerability and estimate 
the MTD/RP2D of AMG 397 using a Bayesian Logistic Regression Model (BLRM) in the following 
groups:  
• 
Group 1A will consist of subjects with RR MM and/or NHL 
• 
Group 1B will consist of subjects with RR AML 
This will be followed by a dose expansion (Part 2) to gain further efficacy and safety experience 
with AMG 397 in adult subjects with RR MM, DLBCL, and AML.  
The study will be conducted at up to 20 sites globally in Australia, Europe, Japan, and the United 
States (US).  Other countries or regions may be added.  
Dose Escalation– Part 1 
Dose escalation will estimate MTDs for Groups 1A and Group 1B using an adaptive, BLRM 
design. The Dose Level Review Team (DLRT) will review data, monitor safety, and make 
decisions on dose escalation/change. The table below shows the planned dose levels for dose 
escalation. 
Planned Doses per Dose Cohort Level 
Dose Cohort Levels 
Dose (mg) 
1 
80 
2 
160 
3 
320 
4 
640 
Dose escalation will begin with 2-4 subjects treated at the lowest planned dose level of 80 mg 
with enrollment from Group 1A and 1B. Dose escalation will follow the planned schedule 
described above with 2-4 subjects treated in each cohort.  
DLRT will convene to review the safety data and determine the appropriate dose to be 
implemented. Dose escalation/de-escalation decisions will be guided by the BLRM model of dose 
toxicity. Skipping of planned dose levels is not allowed. Dose escalation decisions will not be 
made until all subjects in a cohort(s) are monitored through the DLT-observation period of 
28 days following treatment initiation. Intermediate dose levels and alternative dosing schedule(s) 
may be explored based on emerging pharmacokinetic and safety data per the decision of the 
DLRT. 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 5 of 130 
CONFIDENTIAL 
 
 
Dose escalation for both Group 1A and 1B will continue until any of the following events: 
• 
The highest planned dose level is determined to be safe and tolerable (minimum of 
6 evaluable subjects) 
• 
MTDs are identified for each group where BLRM repeats the recommendation of a dose level 
(minimum of 6 evaluable subjects) 
• 
The maximum of 30 evaluable subjects have been enrolled in each group.  If fewer than 
6 subjects are treated at the MTD/RP2D, additional subjects may be enrolled to confirm 
safety and tolerability. 
There is a potential for tumor lysis syndrome (TLS) in subjects with 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:  
• 
Tumor lysis syndrome prophylaxis must be initiated in all subjects prior to the first dose of 
AMG 397.  
• 
Additionally, when an event meeting clinical or laboratory TLS per Cairo-Bishop criteria 
(Appendix K and Appendix L) is observed within seven days after therapy with AMG 397, 
lead-in dosing may be initiated to evaluate a step-wise dose escalation for all subsequent 
dosing. See Figure 2 for an example of lead-in dosing.   
• 
For the management of TLS, please refer to Section 6.5.7 for more details 
The DLRT will convene to review the safety data and may determine a lead-in dose, which will 
not exceed the dose where the TLS was observed. Once TLS criteria is resolved, this lead-in 
dose will be administered for the first week of dosing (cycle 1 week 1). Upon completion of the 
lead-in dosing period, subject(s) will receive their designated target dose level of AMG 397 per 
Table 3 beginning on the second week of dosing (cycle 1 week 2) and all subsequent dosing.  
NOTE: Once lead-in dosing is implemented, a maximum of 50% dose escalation of 
AMG 397 will be imposed between dose cohort levels per Table 3 for the target dose.  
Decisions to modify the AMG 397 lead-in dosing period regimen, lead-in period starting dose, and 
dosing increments, will be made in conjunction with the investigator and Amgen medical monitor 
and communicated to the IRB/EC, as appropriate. 
Intra-subject Dose Escalation 
Subjects who complete the DLT period may proceed to a higher dose level for the following 
treatment cycle once the next dose cohort has been deemed safe by the DLRT and after 
consultation with the PI and sponsor, as long as no DLT has been reported for this subject during 
or after completion of the DLT period. 
Dose Expansion – Part 2 
Upon completing the dose escalation part of the study and depending on data obtained, dose 
expansion may proceed in groups with selected RR hematological malignancies below: 
• 
Group 2A will consist of subjects with MM  
• 
Group 2B will consist of  NHL subjects with Diffuse Large B-cell Lymphoma (DLBCL)  
• 
Group 2C will consist of subjects with AML 
Dose expansion in all of these groups may take place concurrently. The maximum tolerated dose 
(MTD) for each indication, identified from the dose escalation phase, will inform the dose 
expansion phase. 
Sample Size:   
Up to 90 evaluable subjects will be enrolled in the study.  Up to 60 evaluable subjects will be 
enrolled during dose escalation (up to 30 in both Groups 1A and 1B).  Up to 30 evaluable 
subjects will be enrolled into the dose expansion part (up to 10 each for Groups 2A, 2B, and 2C). 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 6 of 130 
CONFIDENTIAL 
 
 
Summary of Subject Eligibility Criteria:   
Male or female subjects ≥ 18 year of age at the time of informed consent who have RR MM, NHL 
and AML. For a full list of eligibility criteria, refer to Section 4.1 and Section 4.2. 
Investigational Product   
AMG 397 is a potent and selective inhibitor of protein-protein interactions between myeloid cell 
leukemia sequence 1 (MCL1) and pro-apoptotic members of the lymphoma/leukemia 2 (Bcl-2) 
family. AMG 397 is an oral agent which will be provided as 5 mg, 20 mg, and 100 mg tablets, and 
will be packaged in bottles of 15 tablets. 
Amgen Investigational Product Dosage and Administration:  
AMG 397 is administered orally once daily for 2 consecutive days followed by 5 days break at a 
weekly interval, as part of a 28-day treatment cycle at dose levels detailed in Table 3. 
Procedures:   
For all subjects, after written informed consent has been obtained, all screening tests and 
procedures will be performed within 21 days of administration of the first dose of AMG 397 
(day 1), unless otherwise noted. Once a subject is enrolled into the study, serial clinical safety 
and study evaluations as per the Schedule of Assessments (Table 4 and Table 5) will be 
performed including physical examination, vital signs, clinical laboratory tests, ECGs, and sample 
collections. This treatment period will continue until the subject becomes intolerant to the 
investigational product, signs and symptoms of clinical progression are evident as determined by 
the investigator, or the subject withdraws consent. An end of treatment (EOT) visit will be 
conducted immediately after the decision to discontinue treatment with AMG 397. 
If applicable, the subject will return 28 (+7) days after the last dose of AMG 397 for the Safety 
Follow-Up (SFU) visit. 
In dose expansion part only, long-term follow up (LTFU) will be conducted every 3 months from 
the last visit for up to 1 year from the first dose of AMG 397 for all subjects who have not 
withdrawn consent to assess for survival and/or the commencement of subsequent cancer 
therapy. 
For a full list of study procedures, including the timing of each procedure, please refer to the 
Schedule of Assessments (Table 4 and Table 5) Section 7.1. 
Statistical Considerations:   
The primary analysis will occur when target enrollment is complete and each subject either 
completes 6 months on study or withdraws from the study. During dose escalation, the DLRT will 
review the safety data after each cohort and make a decision on the next dose level to be 
explored for the estimate of RP2D/MTD based on a BLRM design. Descriptive statistics will be 
provided for selected demographics, safety, PK, pharmacodynamic, 
efficacy and biomarker data by dose, dose schedule, and time as appropriate. Descriptive 
statistics on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages. ORR will be 
presented with 80% exact CI. PFS and OS will be summarized using the Kaplan-Meier method.  
Descriptive statistics will be provided for duration of response (DOR) and DOR summarized by 
the Kaplan-Meier method, as appropriate. 
Graphical summaries of the data may also be presented. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 7 of 130 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
Figure 1.  Study Design and Treatment Schema 
 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 8 of 130 
CONFIDENTIAL 
 
 
 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 9 of 130 
CONFIDENTIAL 
 
 
Figure 2.  Example of Lead-in Dosing 
 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 10 of 130 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event  
ALP 
alkaline phosphatase 
ALT 
AML 
alanine aminotransferase (SGPT) 
Acute myeloid leukemia 
ANC 
APML 
absolute neutrophil count 
Promyelocytic leukemia 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
BP 
blood pressure 
CBC 
complete blood count 
CECT 
Contrast-enhanced computed tomography 
CI 
confidence interval  
CL 
Clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CR 
Cri 
complete response 
Complete response/remission with incomplete recovery of peripheral 
blood counts   
CRF 
case report form  
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DILI 
drug-induced liver injury 
DLBCL 
Diffuse Large B-cell Lymphoma 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
ELN 
electronic data capture 
European Leukemia Net 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject. 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 11 of 130 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Treatment 
defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject 
End of Study (primary 
completion) 
defined as when the last subject is assessed or receives an 
Intervention for the purposes of final collection of data for the primary 
endpoints.    
End of Study  
defined as when the last subject completes the safety follow-up 
assessments  
EOI 
eSAE 
ESR 
End of infusion 
electronic serious adverse event 
erythrocyte sedimentation rate 
FIH 
first in human 
FISH 
fluorescent in situ hybridization 
FLC 
serum light chain 
FU 
follow-up 
GCP 
Good Clinical Practice 
h, hr 
Hour 
HBc 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen 
heart rate / HR 
number of cardiac cycles per unit of time 
HepCAb 
HiDAC 
hepatitis C antibody 
high dose cytarabine 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMWG 
International myeloma working group  
IMWG-URC 
International myeloma working group uniform response criteria 
IND 
Investigational new drug 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IV 
LAIP 
intravenous or roman numeral 4 
Leukemia-associated immunophenotype 
LTFU 
Long-term follow-up 
LVEF 
left ventricular ejection fraction  
MAD 
MCL1 
maximum administered dose 
Myeloid Leukemia Cell 1  
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
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CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Mg 
Milligrams 
MM 
Multiple myeloma 
MRD 
minimal residual disease  
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
N, n 
Number 
NHL 
Non-Hodgkin’s Lymphoma 
ORR 
Overall response rate 
PD 
phramacodynamic 
PK 
pharmacokinetics 
PR 
partial response 
PR  
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 
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 
RBC 
RP1BD 
red blood cells 
recommended phase 1b dose 
RP2D 
recommended phase 2 dose  
RR 
Relapsed or refractory 
SAE 
Serious adverse event 
sCR 
stringent complete response 
SD 
standard deviation 
SFLC 
serum free light chain 
SFU 
Safety follow-up 
SOA 
Schedule of assessments 
SPEP 
serum protein electrophoresis 
T1/2 
half-life 
TBL 
TBA 
total bilirubin 
Total Bile Acid 
TLS 
Tumor lysis syndrome 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 13 of 130 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
tmax 
time of maximum observed serum concentration 
UA 
urinalysis 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
WBC 
WHO 
White blood cell 
World Health Organization 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 14 of 130 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 7 
Study Glossary .............................................................................................................. 10 
1. 
OBJECTIVES ....................................................................................................... 20 
1.1 
Primary ..................................................................................................... 20 
1.2 
Secondary ................................................................................................. 20 
1.3 
Exploratory ................................................................................................ 20 
2. 
BACKGROUND AND RATIONALE ...................................................................... 20 
2.1 
Disease ..................................................................................................... 20 
2.1.1 
Multiple Myeloma Background ................................................... 20 
2.1.2 
Non-hodgkin’s Lymphoma Background ..................................... 22 
2.1.3 
Acute Myeloid Leukemia Background ........................................ 23 
2.2 
AMG 397 Product Background .................................................................. 24 
2.2.1 
AMG 397 Preclinical .................................................................. 25 
2.2.2 
Pharmacology ........................................................................... 26 
2.2.3 
Pharmacokinetics ...................................................................... 27 
2.2.4 
AMG 397 Preclinical Toxicology ................................................ 27 
2.3 
Rationale ................................................................................................... 30 
2.3.1 
Dose Selection Rationale .......................................................... 31 
2.3.1.1 
Starting and Maximum Planned Doses ................... 31 
2.4 
Clinical Hypothesis .................................................................................... 33 
3. 
EXPERIMENTAL PLAN ........................................................................................ 33 
3.1 
Study Design ............................................................................................. 33 
3.2 
Number of Sites ........................................................................................ 35 
3.3 
Number of Subjects ................................................................................... 35 
3.4 
Replacement of Subjects .......................................................................... 35 
3.5 
Estimated Study Duration .......................................................................... 36 
3.5.1 
Study Duration for Subjects ....................................................... 36 
3.5.2 
End of Study .............................................................................. 36 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 36 
4.1 
Inclusion Criteria ....................................................................................... 36 
4.2 
Exclusion Criteria ...................................................................................... 38 
5. 
SUBJECT ENROLLMENT .................................................................................... 41 
5.1 
Treatment Assignment .............................................................................. 42 
6. 
TREATMENT PROCEDURES .............................................................................. 42 
6.1 
Classification of Product ............................................................................ 42 
Approved 
 
 


Product:  AMG 397 
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6.2 
Investigational Product .............................................................................. 42 
6.2.1 
Amgen Investigational Product AMG 397 .................................. 42 
6.2.1.1 
Dosage, Administration, and Schedule .................... 43 
6.2.1.2 
Dose-cohort Study Escalation and 
Stopping Rules ........................................................ 45 
6.2.1.3 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 46 
6.2.1.4 
Dose Stopping Rules ............................................... 48 
6.3 
Other Protocol Required Therapies ........................................................... 48 
6.3.1 
Pre-dosing requirements for AMG 397 ...................................... 48 
6.4 
Dose Limiting Toxicities ............................................................................. 48 
6.5 
Potential Risk Management Guidelines for AMG 397 ................................ 50 
6.5.1 
Gastrointestinal Toxicity ............................................................ 50 
6.5.2 
Bone Marrow Toxicity ................................................................ 50 
6.5.3 
Reproductive Toxicity- Male ...................................................... 50 
6.5.4 
Drug-drug interactions ............................................................... 50 
6.5.5 
Hepatobiliary Toxicity ................................................................ 50 
6.5.6 
Cardiovascular Toxicity ............................................................. 51 
6.5.7 
Tumor Lysis Syndrome (TLS) .................................................... 51 
6.6 
Support Care Guidelines for AMG 397 ...................................................... 55 
6.6.1 
Management of Infections ......................................................... 55 
6.6.2 
Management of Renal Toxicities ................................................ 56 
6.7 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 56 
6.7.1 
Criteria for Permanent Withholding of AMG 397 due to 
Potential Hepatotoxicity ............................................................. 56 
6.7.2 
Criteria for Conditional Withholding of AMG 397 due to 
Potential Hepatotoxicity ............................................................. 57 
6.7.3 
Criteria for Rechallenge of AMG 397 After Potential 
Hepatotoxicity............................................................................ 58 
6.8 
Concomitant Therapy ................................................................................ 58 
6.9 
Product Complaints ................................................................................... 58 
6.10 
Excluded Treatments and Procedures During Study Period ...................... 59 
7. 
STUDY PROCEDURES ....................................................................................... 59 
7.1 
Schedule of Assessments ......................................................................... 59 
7.2 
Study Procedures ...................................................................................... 70 
7.2.1 
Medical History .......................................................................... 70 
7.2.2 
Prior Therapy ............................................................................. 70 
7.2.3 
Physical Examinations ............................................................... 70 
7.2.4 
Height Measurements ............................................................... 70 
7.2.5 
Weight Measurements ............................................................... 70 
7.2.6 
Vital Signs ................................................................................. 71 
7.2.7 
Electrocardiogram Performed in Triplicate ................................. 71 
Approved 
 
 


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7.2.8 
Echocardiogram (ECHO) / Multigated Acquisition 
(MUGA) Scan ............................................................................ 72 
7.2.9 
Dosing Diary Review ................................................................. 72 
7.2.10 
Assessments in MM Subjects .................................................... 72 
7.2.10.1 
Serum Protein Electrophoresis (SPEP) 
and Urine Protein Electrophoresis (UPEP) .............. 72 
7.2.10.2 
Serum Free Light Chain .......................................... 72 
7.2.10.3 
Quantitative Immunoglobulin ................................... 72 
7.2.10.4 
Beta-2 Microglobulin................................................ 73 
7.2.10.5 
Skeletal Survey ....................................................... 73 
7.2.10.6 
Bone marrow ........................................................... 73 
7.2.11 
Assessments in NHL Subjects ................................................... 73 
7.2.11.1 
Imaging and Disease assessments ......................... 73 
7.2.11.2 
MRI Brain ................................................................ 74 
7.2.11.3 
Lymph Node and Bone Marrow 
Assessments ........................................................... 74 
7.2.11.4 
Whole Blood Plasma ............................................... 74 
7.2.12 
Assessments in AML Subjects .................................................. 75 
7.2.12.1 
Disease Response in AML Subjects ........................ 75 
7.2.13 
Pharmacokinetic Blood Sampling .............................................. 75 
7.2.14 
Blood Samples .......................................................................... 75 
7.2.15 
Clinical Laboratory Assessments ............................................... 77 
7.3 
Biomarker Development ............................................................................ 78 
7.3.1 
Blood Samples .......................................................................... 78 
7.3.2 
Bone Marrow ............................................................................. 79 
7.3.3 
Tumor Biopsy ............................................................................ 79 
7.4 
General Study Procedures ........................................................................ 80 
7.4.1 
Screening .................................................................................. 80 
7.4.2 
Treatment .................................................................................. 80 
7.4.3 
End of Treatment Visit ............................................................... 81 
7.4.4 
Safety Follow-Up (SFU) Visit ..................................................... 82 
7.4.5 
Long-term Follow-up (Dose expansion subjects only) ................ 82 
7.5 
Pharmacogenetic Studies ......................................................................... 82 
7.6 
Sample Storage and Destruction ............................................................... 82 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 84 
8.1 
Subjects’ Decision to Withdraw ................................................................. 84 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 84 
8.3 
Reasons for Removal From Treatment or Study ....................................... 85 
8.3.1 
Reasons for Removal From Treatment ...................................... 85 
8.3.2 
Reasons for Removal From Study ............................................. 85 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 85 
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9.1 
Definition of Safety Events ........................................................................ 85 
9.1.1 
Adverse Events ......................................................................... 85 
9.1.2 
Serious Adverse Events ............................................................ 86 
9.2 
Safety Event Reporting Procedures .......................................................... 87 
9.2.1 
Adverse Events ......................................................................... 87 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 87 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 88 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 89 
9.3 
Pregnancy and Lactation Reporting .......................................................... 89 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 90 
10.1 
Study Endpoints ........................................................................................ 90 
10.1.1 
Analysis Sets ............................................................................. 91 
10.2 
Covariates and Subgroups ........................................................................ 91 
10.3 
Sample Size Considerations ..................................................................... 91 
10.4 
Adaptive Design ........................................................................................ 92 
10.5 
Planned Analyses ..................................................................................... 93 
10.5.1 
Interim Analyses ........................................................................ 93 
10.5.2 
Dose Level Review Team (DLRT) ............................................. 94 
10.5.3 
Primary Analysis ........................................................................ 94 
10.5.4 
Final Analysis ............................................................................ 94 
10.6 
Planned Methods of Analysis .................................................................... 94 
10.6.1 
General Considerations ............................................................. 94 
10.6.2 
Primary Endpoints ..................................................................... 94 
10.6.3 
Secondary Endpoints ................................................................ 95 
10.6.3.1 
Efficacy Endpoint Analyses ..................................... 95 
10.6.3.2 
Pharmacokinetics Data Analysis ............................. 96 
10.6.4 
Exploratory Endpoints ............................................................... 96 
11. 
REGULATORY OBLIGATIONS ............................................................................ 96 
11.1 
Informed Consent ...................................................................................... 96 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 97 
11.3 
Subject Confidentiality ............................................................................... 98 
11.4 
Investigator Signatory Obligations ............................................................. 98 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 99 
12.1 
Protocol Amendments and Study Termination .......................................... 99 
12.2 
Study Documentation and Archive ............................................................ 99 
12.3 
Study Monitoring and Data Collection ..................................................... 100 
12.4 
Investigator Responsibilities for Data Collection ...................................... 101 
12.5 
Language ................................................................................................ 101 
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12.6 
Publication Policy .................................................................................... 102 
12.7 
Compensation ......................................................................................... 103 
13. 
REFERENCES ................................................................................................... 104 
14. 
APPENDICES .................................................................................................... 108 
List of Tables 
Table 1.  Binding Activity and Selectivity Profile of AMG 397 in a BIM Binding 
Assay ..................................................................................................... 26 
Table 2.  Predicted Human Exposures and Exposure Multiples at 
Steady-state After Oral Dosing of AMG 397 ........................................... 32 
Table 3.  Planned Doses per Dose Cohort Level ........................................................... 33 
Table 4.  Schedule of Assessments ............................................................................... 60 
Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is 
Implemented).......................................................................................... 64 
Table 6.  Approximate Blood Volumes Collected for MM Subjects Only ........................ 76 
Table 7.  Approximate Blood Volumes Collected for NHL Subjects Only ....................... 76 
Table 8.  Approximate Blood Volumes Collected for AML Subjects Only ....................... 77 
Table 9.  Clinical Laboratory Assessments .................................................................... 77 
Table 10.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 90% and Grade 4 or Higher Adverse Event Limit of 20% .................... 93 
Table 11.  Operating Characteristics With Batch Size of 10 Subjects ............................ 93 
List of Figures 
Figure 1.  Study Design and Treatment Schema ............................................................. 7 
Figure 2.  Example of Lead-in Dosing .............................................................................. 9 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 109 
Appendix B.  eSerious Event Contingency Form ......................................................... 111 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 114 
Appendix D.  Operating Characteristics for 2-Parameter BLRM Design ....................... 116 
Appendix E.  International Myeloma Working Group Uniform Response 
Criteria for Multiple Myeloma (IMWG-URC) .......................................... 119 
Appendix F.  ECOG Performance Status and NYHA Classification ............................. 121 
Appendix G.  Definition of Relapsed or Refractory Progressive Disease and 
Line of Therapies .................................................................................. 122 
Appendix H.  World Health Organization Classification for Acute Myeloid 
Leukemia .............................................................................................. 124 
Appendix I.  Response Assessment per the Lugano Classification for NHL ................. 126 
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Appendix J.  European Leukemia Network (ELN) Response Criteria in AML 
(2017) ................................................................................................... 127 
Appendix K.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 129 
Appendix L.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome ................ 130 
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1. 
OBJECTIVES 
1.1 
Primary 
• 
Evaluate the safety and tolerability of AMG 397  
• 
Estimate the maximum tolerated doses (MTDs) and/or biologically active doses 
(eg, recommended phase 2 doses [RP2Ds]) of AMG 397 
1.2 
Secondary 
• 
Evaluate the efficacy of AMG 397  
• 
Evaluate the pharmacokinetics (PK) of AMG 397   
1.3 
Exploratory 
• 
Explore pharmacokinetic/pharmacodynamic (PK/PD) relationships for safety and/or 
efficacy endpoints  
• 
Identify metabolite(s) of AMG 397 in plasma and urine 
• 
Demonstrate AMG 397 inactivation of MCL1 by the activation of BAX and caspase 3 
in circulating monocytes or blast cells, and/or the decrease of circulating monocytes 
• 
Evaluate patient responses according to disease-specific features in tumor cells such 
as chromosomal amplifications, rearrangements, gene expression profiles, protein 
expression as well as somatic mutations as necessary  
• 
Evaluate changes to immune cell subsets in peripheral blood due to MCL1 
inactivation 
• 
Assess Minimal Residual Disease (MRD) status with patient response as necessary 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
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%) hematological cancer.  It is 
responsible for 15-20% of all deaths from hematological cancer and about 2% of all 
cancer deaths. Recent improved understanding of the pathogenesis of myeloma has led 
to the development of new treatments. Survival is improving, with median overall survival 
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, RR multiple myeloma is still an unmet medical need 
(Smith and Yong 2013). 
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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 production, and renal insufficiency (Durie, 2011). Symptomatic 
(active) disease should be treated immediately, whereas asymptomatic (smoldering) 
myeloma requires clinical observation. Investigational trials are currently evaluating the 
ability of immunomodulatory drugs to delay the progression from asymptomatic to 
symptomatic myeloma. Current data would support the initiation of induction therapy with 
thalidomide, lenalidomide, or bortezomib plus hematopoietic stem-cell transplantation for 
subjects under the age of 65 years who do not have substantial heart, lung, renal, or 
liver dysfunction. Autologous stem-cell transplantation with a reduced-intensity 
conditioning regimen should be considered for older subjects or those with coexisting 
conditions. Less intensive approaches that limit toxic effects or prevent treatment 
interruption that would reduce the intended treatment effect should be considered in 
subjects over 75 years of age or in younger subjects 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).  
Treatment of RR 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. In the past 5 years, carfilzomib, pomalidomide, elotuzumab, ixazomib, 
daratumumab, were granted approval by US FDA for RR MM.  , Despite advances in the 
management of multiple myeloma, however, relapse is inevitable in almost all subjects. 
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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, 2015). Thus, there remains an urgent need for treatment options for 
patients with RR MM.  
2.1.2 
Non-hodgkin’s Lymphoma Background 
About 74,680 people (41,730 males and 32,950 females) will be diagnosed with Non 
Hodgkin’s Lymphoma (NHL), and about 19,910 people will die from this malignancy.  
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting 
for 30% to 40% of cases and 13% of all hematologic disorders. The incidence is 
approximately 8 cases per 100,000 and rises with age; the median age at diagnosis is 
70 years (Haematological Malignancy Research Network).  Morphologically similar 
entities have historically been treated in a similar manner as DLBCL, and thus are 
collectively known as aggressive B-cell lymphomas. DLBCL, as a uniform diagnostic 
entity, makes up approximately 85% of aggressive B-cell lymphomas 
(Ziepert et al, 2010). However, distinct patterns of gene expression are observed within 
DLBCL, with different prognostic and potentially predictive implications 
(Swerdlow et al, 2016). Left untreated, DLBCL is uniformly fatal. Anthracycline-based 
frontline chemotherapy, introduced in the 1970s, resulted in the long term cure of 30% of 
patients (DeVita et al, 1975). Twenty-five years later, introduction of the human-mouse 
chimeric monoclonal anti-CD20 immunoglobin G (IgG) rituximab increased the cure rate 
significantly and is now a standard agent in frontline therapy, resulting in cure for 60% of 
patients (Sehn and Gascoyne 2015). Patients with DLBCL who do not respond to 
frontline therapy, or who experience relapse after a remission, are generally considered 
incurable unless able to receive either high dose chemotherapy (HDT) with autologous 
HSCT or allogeneic HSCT (Robinson et al, 2016). HSCT is preceded by a course of 
salvage chemotherapy. “Chemoresponsivess”, indicating a partial response (PR) or 
complete response (CR) to salvage chemotherapy, has been as used as 1 criterion to 
define HSCT eligibility, since early trials demonstrated the extremely poor outcomes of 
patients without an objective response to salvage chemotherapy (Philip et al, 1987). It is 
not known if responsiveness to newer classes of therapies, such as those that are 
immune-based, may also be sufficient to permit the successful use of HDT. 
The most commonly used regimens in the S1 treatment of transplant-eligible patients 
contain rituximab and a platinum-based agent such as cisplatin (eg, R-DHAP, R-GDP, 
R-ESHAP) or carboplatin (eg, R-ICE) (Crump et al, 2014; Martin et al, 2008; 
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Witzig et al, 2008; Kewalramani et al, 2004). Patients who do not respond to S1 may be 
offered alternative therapies (hereafter referred to as S2) and HSCT provided that there 
is a response to S2 and that performance status and organ function are relatively 
preserved.  There is no standard S2 regimen for transplant eligible patients. The ESMO 
and NCCN guidelines are relatively silent on appropriate S2 regimens 
(Zelenetz et al, 2016; Tilly et al, 2015). Results of small, single-center retrospective 
analyses support the conclusion that standard cytotoxic therapy is of limited value in 
patients not responsive to S1 chemotherapy and that novel therapies should be explored 
in this setting (Elstrom et al, 2010; Ardeshna et al, 2005;). 
2.1.3 
Acute Myeloid Leukemia Background 
Acute myeloid leukemia (AML) is characterized by accumulation of abnormal blasts in 
the 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) 
AML is the most common form of acute leukemia in adults in the United States (US).   
In 2017, an estimated 21,380 new cases of AML are expected in the US with 
approximately 10,590 deaths from this disease (American Cancer Society, 2017). 
Outcomes for most subjects with AML remain poor (Burnett et al, 2011a). In particular, 
relapsed disease is associated with unsatisfactory outcomes in the majority of subjects 
(Ravandi, 2013). Although the majority of subjects with AML initially achieve CR, over 
60% will eventually relapse after a variable period of remission. Using the traditional 
cytotoxic chemotherapy regimens, the likelihood of achieving a second CR is low 
especially if the first CR was short in duration, particularly if less than one year 
(Estey et al, 1996). 
This is particularly true for subjects who have primary refractory disease and have never 
achieved a morphological response. For example, subjects with AML refractory to one 
course of high dose cytarabine (HiDAC) containing regimen have a median overall 
survival of only 3.8 months (Ravandi et al, 2010). Subjects whose initial CR duration is 
more than one year have been traditionally treated with HiDAC containing salvage 
regimens but only a minority achieve a second CR and many are not candidates for a 
potentially curative allogeneic hematopoietic stem cell transplant (HSCT) performed in 
second CR (Estey, 2000). Apart from duration of first CR, other predictors of outcome in 
first relapse include age, cytogenetics, and whether the patient received an allogeneic 
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HSCT in first CR (Breems et al, 2005). However, in the study reported by 
(Breems et al, 2005), only a minority of subjects with AML in first relapse had a 
successful long-term outcome and the long-term prognosis of the majority of subjects 
with relapsed or refractory AML remains dismal. 
2.2 
AMG 397 Product Background 
AMG 397 is a potent and selective inhibitor of protein-protein interactions between MCL1 
(myeloid cell leukemia sequence 1) and pro-apoptotic members of the B-cell 
lymphoma/leukemia 2 (Bcl-2) 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 Bcl-2 protein family. (Kozopas, Yang et al. 1993, 
Strasser, Cory et al. 2011, Czabotar, Lessene et al. 2014). MCL1 is an anti-apoptotic 
member of this family and promotes cell survival. In contrast, pro-apoptotic family 
members such as Bak, Bax, or the Bcl-2 homology 3 (BH3)-only protein family 
members, such as BIM and PUMA, are critical effectors for the induction of apoptosis. 
Upon the induction of apoptotic stimuli, pro-apoptotic BH-3 only proteins bind MCL1 and 
other pro-survival Bcl-2 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 (Strasser, Cory et al. 2011) 
(Czabotar, Lessene et al. 2014).  
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 Bcl-2 family members, such 
as MCL1 and Bcl-2, has emerged as a central mechanism by which cancers buffer 
pro-apoptotic stress. There is now considerable data suggesting that MCL1 is integral to 
the resistance of apoptosis in a substantial number of solid and hematopoietic cancers. 
Genetic ablation of MCL1 has been shown to protect mice from the development of 
acute-myeloid leukemia (AML) (Glaser, Lee et al. 2012). Additional mouse knockout 
studies have implicated MCL1 in the maintenance of plasma cells, an observation that 
suggests MCL1 may be a critical pro-survival factor in multiple myeloma 
(Peperzak, Vikstrom et al. 2013).  MCL1 is highly expressed in a variety of human 
tumors, and over-expression of MCL1 has been implicated in resistance to 
chemotherapy and to Bcl-2/Bcl-xL inhibitors (van Delft, Wei et al. 2006, 
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Wertz, Kusam et al. 2011). 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, Mermel et al. 2010). These data suggest that the inhibition of MCL1 
represents a novel and compelling therapeutic strategy for the treatment of cancer. A 
promising strategy for targeting MCL1 takes advantage of specific small molecules that 
selectively bind to MCL1 and disrupt its interactions with the BH3 domain of 
pro-apoptotic partner proteins such as Bak, and Bim, leading to the activation of the 
intrinsic apoptotic cascade and death in cells dependent on MCL1 for survival. The 
MCL1 inhibitor AMG 397 is a first in class therapeutic with novel MOA (disruption of 
protein-protein interactions) with the potential to directly induce apoptosis in cells 
dependent on MCL1 for survival, Furthermore, the activity of AMG 397 in pre-clinical 
models suggests that AMG 397 may have utility in hematological malignancies, 
particularly multiple myeloma,  NHL and AML. 
Refer to the specific section of the Investigator’s Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(S) 
2.2.1 
AMG 397 Preclinical 
AMG 397 neutralizes the interaction between human MCL1 and Bim in a biochemical 
TR-FRET based assay with an IC50 of 0.116 nM in serum free conditions.  In addition, 
AMG 397 exhibits comparable potency against cynomolgus monkey, dog and rabbit Mcl 
1, but is less potent against mouse and rat MCL1 in a serum free TR-FRET-based 
potency assay (IC50 values of 0.380, 0.112, and 0.144, 22.4 and 221 nM for dog, 
monkey, rabbit, rat and mouse MCL1, respectively) (Table 1) (Study R20150152).  
Examination of the AMG 397 binding pocket in human MCL1 suggests a leucine residue 
at amino acid position 248 contributes to the high affinity interaction between AMG 397 
and human MCL1.  In mouse and rat MCL1, the corresponding amino acid is a 
phenylalanine, which may contribute to the reduced affinity of AMG 397 for rat and 
mouse MCL1 (Study R20150152).  AMG 397 is highly selective for MCL1 over the 
related Bcl-2 family members, Bcl-2 and Bcl-xL, exhibiting IC50 values of > 5000 nM in a 
TR-FRET BIM binding assay (Study R20150153) (Table 1). 
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Table 1.  Binding Activity and Selectivity Profile of AMG 397 in a BIM Binding 
Assay 
Binding Activity and Selectivity Profile in 
Cell-Free TR-FRET Bim Binding Assays 
AMG 397 
Human MCL1 IC50 (nM) 
Dog MCL1 IC50 (nM) 
Monkey MCL1 IC50 (nM) 
Rabbit MCL1 IC50 (nM) 
Mouse MCL1 IC50 (nM) 
Rat MCL1 IC50 (nM) 
Human Bcl-2 IC50 (nM) 
Human Bcl-xL IC50 (nM) 
0.116 
0.380 
0.112 
0.144 
221 
22.4 
> 5000 
> 5000 
Bcl-2 = B-cell lymphoma-2; Bcl-xL = B-cell lymphoma- extra-large; IC50 = half maximal inhibitory 
concentration; MCL1= Myeloid Cell Leukemia 1; TR-FRET = time-resolved fluorescence energy transfer 
The IC50 values of AMG 397 were determined from duplicate measurements by fitting 
concentration-response data of individual replicates with a four-parameter sigmoidal model in Genedata 
Screener (Genedata, Basel, Switzerland).  
Source: Study R20150152 and Study R20150153 
AMG 397 inhibited the interaction between MCL1 and Bak in transfected HEK 293M 
cells with a mean IC50 of 71.1 nM in serum free growth medium (Study R20150154).  
Upon AMG 397 treatment for 16 hours, OPM-2 cell viability was reduced in a dose 
dependent manner under all conditions tested (ie, serum-free, with 10% FBS (1) and 
with 5% HS).  The IC50 values of AMG 397 induced cell death were determined to be 
0.020 ± 0.039 µM in the absence of serum, 0.0946 ± 0.025 µM in the presence of 
10% FBS and 0.159 ± 0.039 µM in the presence of 5% HS (Study R20150154).   
2.2.2 
Pharmacology 
AMG 397 interacted in vitro with several off-target receptors; however, none of these is 
expected to result in clinically significant effects over the proposed clinical dose range.  
The AMG 397 hERG 50% inhibition concentration (IC50) was > 1.1 µM, the highest 
tested concentration that could be evaluated, thus, no clinically significant interaction 
with the hERG channel is expected over the proposed clinical dose range.  In an isolated 
rabbit heart study, the no-effect concentration was 1 µM; thus, no clinically significant 
effects on cardiac electrical or functional activity over the proposed clinical dose range 
are expected.  There were no AMG 397-related changes in electrocardiograms (ECGs), 
respiratory rate, or neurological clinical signs in the GLP 23-day dog toxicology study 
conducted at doses up to 15 mg/kg. 
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2.2.3 
Pharmacokinetics 
AMG 397 was characterized in vitro and in vivo preclinical studies.  In animal species 
AMG 397 had low clearance (CL) relative to hepatic blood flow, moderate volume of 
distribution (Vss) and mean terminal elimination half-life (t1/2z) ranging from 8.3 to 
19 hour. The observed bioavailability was variable across species ranging from 23% in 
dogs and monkeys, 39% in rats and 56% in mice. In vitro, AMG 397 was highly bound to 
plasma proteins in all species including human (mean fraction unbound ranging from 
0.0048 to 0.027), and did not partition into red blood cells. These data were used to 
predict the human AMG 397 PK parameters, with a CL of 0.057 L/hr/kg, Vss of 1.0 L/kg, 
and t1/2z of 12 hours. Bioavailability after oral dosing was estimated to be 31%, an 
average across preclinical species.   
AMG 397 was an inducer of CYP2B6, CYP2C9, and CYP3A4, and reversible inhibitor of 
CYP2B6, CYP2C8, and CYP3A4 in vitro while it was not an inhibitor of other major drug 
metabolizing human CYP enzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, 
and CYP2E1. AMG 397 was also a time-dependent inhibitor of CYP3A4 but not of any of 
the other CYPs tested. Additionally, AMG 397 was identified as an inhibitor of 
P-gp (IC50 of 8.7 µM). For BCRP, MATE1, MATE2-K, and OATP1B1, incomplete 
inhibition (36 - 54%) was observed at the highest test concentration (100 μM) of 
AMG 397, suggesting weak inhibition. Considering dose levels and frequency, based on 
physiologically based pharmacokinetic modelling, it was determined that AMG 397 has a 
potential to interact with CYP3A4 and P-gp. 
2.2.4 
AMG 397 Preclinical Toxicology  
AMG 397 was well tolerated in a GLP 23-day rat toxicology study conducted at doses of 
5, 15 and 500 mg/kg.  The severely toxic dose in 10% of the animals (STD10) was 
≥ 500 mg/kg.  Key AMG 397-related findings in the rat included minimally to moderately 
increased serum transaminases and bilirubin that were associated with periportal 
vacuolation of hepatocytes, dilatation of lacteals and hypertrophy/hyperplasia of the 
mucosa in the small intestine, dilatation of the subcapsular space of the mesenteric 
lymph node, and atrophy of the zona glomerulosa of the adrenal gland.  
AMG 397-related changes in the rat fully or partially reversed by the end of a 28-day 
recovery period.   
In an exploratory 14-day dog toxicology study, 30 mg/kg was poorly tolerated (liquid 
stools, decreased food consumption, body weight loss) that resulted in early euthanasia 
and/or early termination of dosing of some animals.  AMG 397 was generally well 
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tolerated in a GLP 23-day dog toxicology study at doses of 3, 7.5 and 15 mg/kg.  The 
highest nonseverely toxic dose (HNSTD) in dogs was 15 mg/kg.  Key AMG 397-related 
findings in the dog included soft feces, dose-dependent reductions in monocytes and 
other leukocyte subsets, minimally to mildly increased serum transaminase without light 
microscopic correlates in the liver, decreased lymphoid cellularity in lymphoid tissues, 
decreased bone marrow cellularity, vacuolation of the lamina propria of the small 
intestine, and dose-dependent decreased testes weight with the light microscopic 
correlate of tubular degeneration/atrophy of seminiferous tubules. Although the 23-day 
dog study did not include a recovery period, AMG 397-related changes are expected to 
be reversible based on the nature, incidence and severity of the changes.   
AMG 397 was not mutagenic or clastogenic in exploratory genetic toxicology studies.  
AMG 397 was not photototoxic in rats. 
Overall, the results of the nonclinical safety studies support the initiation of AMG 397 
clinical trials and the initial clinical plan. 
Risk Assessment 
AMG 397 interacted in vitro with several off-target receptors; however, none of these is 
expected to result in clinically significant effects over the proposed clinical dose range.  
The AMG 397 hERG 50% inhibition concentration (IC50) was > 1.1 µM, the highest 
tested concentration that could be evaluated, thus, no clinically significant interaction 
with the hERG channel is expected over the proposed clinical dose range.  In an isolated 
rabbit heart study, the no-effect concentration was 1 µM; thus, no clinically significant 
effects on cardiac electrical or functional activity over the proposed clinical dose range 
are expected.  There were no AMG 397-related changes in electrocardiograms (ECGs), 
respiratory rate, or neurological clinical signs in the GLP 23-day dog toxicology study 
conducted at doses up to 15 mg/kg. 
Potential risks are safety concerns based on mechanism of action, nonclinical data, or 
clinical data from AMG 397 or similar compounds that have either not yet been observed 
in human subjects or for which a causal association with AMG 397 has not yet been 
established. The potential risks and proposed clinical monitoring strategies are 
described below. All potential risks presented below have shown reversibility in 
preclinical studies: 
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Gastrointestinal toxicity 
In the 23-day rat study, AMG 397 caused minimal to mild lacteal dilation in the small 
intestine.  The lacteal dilation change may affect dietary lipid absorption and chylomicron 
synthesis (Boyle et al, 2012).  In the 23-day dog study, AMG 397 caused mild 
vacuolation in the lamina propria of the small intestine.  In an exploratory 14-day dog 
study, AMG 397 at a higher dose than used in the 23-day study was poorly tolerated due 
to GI clinical signs.  There was no GI mucosal degeneration except in the pylorus where 
it was noted to be minimal to mild in the dog.  Based on these observations, GI toxicity is 
a potential risk for patients. 
Bone marrow toxicity 
In early exploratory toxicology studies, a dose-dependent decrease in monocytes was 
seen in dogs.  In the 23-day dog toxicology study, AMG 397-related decreased bone 
marrow cellularity with decreased lymphocytes, monocytes, and basophils was likely 
related to the primary pharmacology of AMG 397, ie, inhibition of MCL-1.  White blood 
cell counts should therefore be monitored during clinical studies. 
Reproductive toxicity (Male) 
AMG 397 caused degeneration/atrophy of the seminiferous tubules with depletion of 
spermatogonia, spermatocytes, and spermatids of the testis along with decreased 
testicular weight in the dog.  Patients should be advised of the potential effect on male 
fertility. 
Drug-drug interactions 
Data from in vitro nonclinical studies indicate that AMG 397 is an inhibitor of various 
CYP450s when tested in human liver microsomes.  It is a reversible inhibitor of CYP2B6, 
CYP2C8, and CYP3A.  AMG 397 is also a mechanism-based inhibitor of CYP3A4.  
Additionally, AMG 397 has the potential to be an inducer of CYP3A4, CYP2B6, and 
CYP2C9.  It is also an inhibitor of the drug transporters, namely P-gp, MATE-1, and 
BCRP.  AMG 397 is a substrate of P-gp and is expected to be predominantly eliminated 
as unchanged parent drug via biliary elimination. 
Although AMG 397 inhibits multiple CYPs and transporters in vitro, based on 
physiologically based pharmacokinetic modeling and in considering predicted human PK 
and efficacious dose, AMG 397 has the potential to inhibit CYP3A and P-gp.  Inhibition 
of other CYPs and transporters is unlikely to result in a drug-drug interaction. 
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Hepatobiliary toxicity 
AMG 397-related elevations in total bilirubin occurred in the rat.  These changes were 
at times accompanied by increases in urinary bilirubin and increases in AST and ALT; 
however, there was only minimal periportal vacuolation in the liver.  Serum 
transaminases were also increased in the dog but without accompanying bilirubin 
increases or correlative light microscopic changes in the liver. 
Cardiovascular toxicity 
MCL1 is highly expressed in the myocardium, but its effect upon cardiac cells has not 
been established. In studies conducted in knockout mice with ablation of MCL-1, these 
animals showed reduced cardiac function. In mouse models, it has been suggested 
cardiac specific ablation of MCL1 resulted in fatal dilated cardiomyopathy manifested by 
a loss in cardiac contractility, abnormal mitochondria structure and abnormal 
mitochondrial respiration (Thomas et al, 2013; Wang et al, 2013).  In the 23-day 
toxicology studies in the rat with AMG 397, reduction in cardiac weight was noted; 
however, there were no light microscopic correlates and no apparent clinical 
manifestations were noted.  Additionally, no ECG, heart weight, or cardiac light 
microscopic changes were observed in dogs. 
Tumor Lysis Syndrome 
Clinical tumor lysis syndrome has been observed in a clinical trial with a drug of the 
same mechanism of action. Subjects with a high tumor burden or compromised renal 
function (eg, International Staging System [ISS] Stage II/III) may be at elevated risk for 
tumor lysis syndrome. 
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 397. In addition, subjects must be appropriately hydrated 
prior to each dose of AMG 397. Further details regarding mandatory tumor lysis 
syndrome prophylaxis are provided in the study protocol in Section 6.5.7.  
2.3 
Rationale 
MCL1 is a member of the BCL2 family of proteins integral to the control of apoptosis 
(programmed cell death). MCL1 is an anti-apoptotic member of the BCL2 family and 
promotes cell survival. In contrast, pro-apoptotic family members, such as BAK and BAX 
are critical effectors for the induction of apoptosis. Upon apoptotic stimuli, pro-apoptotic 
BH-3 only proteins (eg, Bid) bind MCL1, and disrupt the interaction between MCL1 and 
BAK or BAX. This leads to the oligomerization of BAK/BAX, mitochondrial outer 
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membrane permeabilization (MOMP), and the release of cytochrome C, caspase 
activation and cell death (Youle and Strasser 2008). 
The acquired resistance and evasion of apoptosis, which is central to therapeutic 
resistance, is an established hallmark of cancer (Hanahan and Weinberg 2011). MCL1 is 
integral to the resistance of apoptosis in a substantial number of solid and hematopoietic 
cancers, as supported by a wealth of genetic and functional data. Internal efforts have 
demonstrated that knockdown of MCL1 expression by siRNA induces cell death in 
multiple cancer cell lines.  
Mouse knockout studies have implicated MCL1 in the maintenance of plasma cells, an 
observation that suggests MCL1 may be a critical pro-survival factor in multiple myeloma 
(Peperzak, Vikstrom et al. 2013). 
The current data package is supportive of multiple myeloma as an initial study 
population. MCL1 also provides a useful target for the treatment of subjects with AML as 
it is essential for the development and sustained growth of AML. MCL1 dependency was 
detected in AML mouse models (Xiang et al. 2010) and in human AML-derived cell lines. 
It was shown that deletion of MCL1 but not loss or pharmacological blockade of BCL-XL, 
BCL-2 or BCL-W induced the death of transformed AML and cured the disease in 
AML-afflicted mice (Glaser, et al 2012). The upregulation of MCL1 has been described 
at the time of AML relapse (Kaufmann et al, 1998). In FLT3-ITD AML, upregulation of 
MCL1 is dependent on FLT3 signaling and an essential effector of FLT3-ITD-mediated 
drug resistance (Bose et al 2013). Targeting MCL1 sensitizes FLT3-ITD-positive 
leukemia to cytotoxic therapies (Kasper et al 2012). 
2.3.1 
Dose Selection Rationale 
2.3.1.1 
Starting and Maximum Planned Doses 
The proposed AMG 397 doses are 80, 160, 320, and 640 mg. During dose escalation 
(Part 1), AMG 397 will be given once daily for 2 consecutive days followed by 5 days 
break and repeated each week for 4 weeks of treatment cycle.  One treatment cycle is 
28 days in length and includes 8 administrations of AMG 397.   
For dose expansion (Part 2), AMG 397 will be given once daily for 2 consecutive days 
followed by 5 days break and repeated each week for 4 weeks of treatment cycle.  One 
treatment cycle is 28 days in length and includes 8 administrations of AMG 397.  The 
planned dose level(s) for dose expansion (MTD/RP2D) will be determined based on data 
collected during dose escalation. 
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The proposed clinical starting dose of 80 mg is based on the highest non-severely toxic 
dose (HNSTD) noted in a GLP toxicology study in beagle dogs. The HNSTD dose of 
15 mg/kg/day in beagle dogs corresponds, per ICH S9 Guidance, to a human daily 
equivalent dose of 83 mg. AMG 397 human pharmacokinetics (PK) parameters were 
predicted from a combination of in vitro and in vivo nonclinical data. At the starting dose 
of 80 mg administered orally once daily for 2 consecutive days followed by 5 days break, 
the predicted exposure margins of maximum plasma concentration (Cmax) and area 
under the concentration-time curve (AUC) to the rat STD10 are 116-fold and 211-fold, 
respectively. The predicted exposure margins of Cmax and AUC to the dog HNSTD are 
estimated at 15-fold and 15-fold, respectively, at the starting dose administered orally 
once daily for 2 consecutive days followed by 5 days break.  
Table 2.  Predicted Human Exposures and Exposure Multiples at Steady-state 
After Oral Dosing of AMG 397 
Clinical Dosea  
Predicted Exposure b 
Exposure Margins 
AUC0-96 c 
Cmax c 
(mg) 
AUC0-96 
(hr⋅µg/mL)c 
Cmax 
(µg/mL) 
Rat 
4-week 
Dog 
4-week 
Rat 
4-week 
Dog 
4-week 
80 
12.2 
0.35 
211 
15 
116 
15 
160 
24.5 
0.70 
105 
8 
58 
7 
320 
48.9 
1.39 
53 
4 
29 
4 
640 
97.8 
2.79 
26 
2 
15 
2 
AUC0-96 = area under the concentration time curve from 0 to 96 hr; Cmax = maximum observed 
concentration; HNSTD = highest non-severely toxic dose; STD10 = severely toxic dose in 10% of the 
animals. 
a Once daily dosing for 2 consecutive days followed by 5 days break 
b Human PK was simulated based on human body weight of 60 kg and height of 170 cm  
c Rat day 22 exposure at 500 mg/kg (STD10): Cmax = 40.6 µg/mL, AUC = 2580 µg/mL·hr (Study 122859).   
Dog (male) day 15 exposure at 15 mg/kg (HNSTD): Cmax = 5.13 µg/mL, AUC = 186 µg/mL (Study 122859).  
Male value used because exposure was lower than in females. 
The highest planned dose is 640 mg. Safety and tolerability data from prior dose levels 
will guide the dose escalations and the planned top dose for AMG 397 in the dose 
escalation phase. The maximum tolerated dose (MTD) identified from the dose 
escalation phase will inform the dose expansion phase. The planned dose level(s) for 
dose expansion will be determined based on data collected during dose escalation. 
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2.4 
Clinical Hypothesis 
A safe and tolerable dose of AMG 397 will have evidence of anti-tumor activity in 
subjects with selected RR hematological malignancies as measured by Objective 
Response Rate (ORR).   
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study 
evaluating AMG 397 administered orally in adult subjects with selected RR 
hematological malignancies.  
This study will consist of dose escalation (Part 1) to evaluate safety and tolerability and 
estimate the MTD/RP2D of AMG 397 using a Bayesian Logistic Regression Model 
(BLRM) in the following groups:  
• 
Group 1A will consist of subjects with RR MM and/or NHL 
• 
Group 1B will consist of subjects with RR AML 
This will be followed by a dose expansion (Part 2) to gain further efficacy and safety 
experience with AMG 397 in adult subjects with RR MM, DLBCL, and AML.  
Dose Escalation– Part 1 
During dose escalation (Part 1), AMG 397 will be administered orally once daily for 
2 consecutive days followed by 5 days break at a weekly interval, as part of a 28-day 
treatment cycle.   
Dose escalation will estimate MTDs for Group 1A and Group 1B using an adaptive, 
BLRM design. Table 3 shows the planned dose levels for dose escalation. The Dose 
Level Review Team (DLRT) will review data, monitor safety, and make decisions on any 
dose escalation/change. For more details regarding the dose escalation, please see 
Section 6.2.1.2 
Table 3.  Planned Doses per Dose Cohort Level 
Dose Cohort Levels 
Dose (mg) PO 
1 
80 
2 
160 
3 
320 
4 
640 
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Dose escalation for Group 1A and Group 1B will begin with 2-4 subjects treated at the 
lowest planned dose level of 80 mg. Dose escalation will follow the planned schedule 
described above with 2-4 subjects treated in each cohort.  
DLRT will convene to review the safety data and determine the appropriate dose to be 
implemented. Dose escalation/de-escalation decisions will be guided by the BLRM 
model of dose toxicity. Skipping of planned dose levels is not allowed. Dose escalation 
decisions will not be made until all subjects in a cohort(s) are monitored through the 
DLT-observation period of 28 days following treatment initiation. Intermediate dose 
levels and alternative dosing schedule(s) may be explored based on emerging 
pharmacokinetic and safety data per the decision of the DLRT. 
Dose escalation for both Group 1A and 1B respectively, will continue until any of the 
following events: 
• 
The highest planned dose level for each group is determined to be safe and tolerable 
(minimum of 6 evaluable subjects) 
• 
MTDs are identified for each group where BLRM repeats the recommendation of a 
dose level (minimum of 6 evaluable subjects) 
• 
The maximum of 30 evaluable subjects have been enrolled in each group.  If fewer 
than 6 subjects are treated at the MTD/RP2D, additional subjects may be enrolled to 
confirm safety and tolerability. 
Intermediate doses and alternative dosing schedule(s) may be explored based on 
emerging pharmacokinetic and safety data as decided by the DLRT. 
Lead-in Dosing 
Due to the potential risk of TLS for subjects affected by hematologic malignancies, it is 
anticipated that lead-in dosing may be implemented. At any point during the study, when 
an event meeting clinical or laboratory TLS per Cairo-Bishop criteria (Appendix K and 
Appendix L) is observed within seven days after therapy with AMG 397, lead-in dosing 
may be initiated to evaluate a step-wise dose escalation for all subsequent dosing. See 
Figure 2 for an example of lead-in dosing.  See Section 6.2.1.1.1 for more details 
Dose Expansion – Part 2 
Upon completing the dose escalation part of the study and depending on data obtained, 
dose expansion may proceed in groups with selected RR hematological malignancies 
below: 
• 
Group 2A will consist of subjects with Multiple Myeloma (MM)  
• 
Group 2B will consist of  NHL subjects with Diffuse Large B-cell Lymphoma 
(DLBCL)  
• 
Group 2C will consist of subjects with Acute Myeloid Leukemia (AML)  
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Dose expansion in all of these groups may take place concurrently. The maximum 
tolerated dose (MTD) for each indication, identified from the dose escalation phase, will 
inform the dose expansion phase. 
Intra-subject Dose Escalation 
Subjects who complete the DLT period may proceed to a higher dose level for the 
following treatment cycle once the next dose cohort has been deemed safe by the DLRT 
and after consultation with the PI and sponsor as long as no DLT has been reported for 
this subject during or after completion of the DLT period. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1. 
3.2 
Number of Sites 
This study will be conducted at up to 20 sites globally in Australia, Europe, Japan and 
the United States.  Additional regions, countries, or sites may be added. 
Sites that do not enroll subjects into an open cohort within 4 months of site initiation 
during dose escalation or expansion may be closed or replaced. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Up to 90 evaluable subjects will be enrolled in the study.  Up to 60 evaluable subjects 
will be enrolled during dose escalation (up to 30 in both Groups 1A and 1B).  Up to 
30 evaluable subjects will be enrolled into the dose expansion part (up to 10 each for 
Groups 2A, 2B, and 2C). Based on emerging data, additional subjects may be enrolled. 
The rationale for the number of subjects required is detailed in Section 10.3. 
3.4 
Replacement of Subjects 
During dose escalation, subject(s) may be replaced if: 
• 
Subject(s) is not DLT-evaluable. See Section 6.2.1.2 for definition of 
DLT-evaluable 
• 
Subject(s) discontinues treatment for any reason other than a DLT during the 
DLT-observation period    
Additional subjects may also be enrolled if Amgen’s medical monitor determines that the 
minimum required number(s) of evaluable subjects have not been enrolled in each 
cohort. 
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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The study duration for each subject is approximately 8 months consisting of up to 
21 days in the screening period, approximately 6 months of treatment period, an 
EOT visit, and a SFU visit approximately 28 (+ 7) days after their last dose of AMG 397.  
For dose expansion part only, long-term follow up (LTFU) will be conducted every 
3 months from the last visit for up to 1 year from the first dose of AMG 397, for all 
subjects who have not withdrawn consent to assess for survival and/or the 
commencement of subsequent cancer therapy. 
This study duration may vary depending on the subject’s disease, ability to tolerate 
AMG 397 and/or willingness to participate in the study. 
End of study (EOS) for an individual subject: The date when the subject completes 
the final protocol-specified procedure or SFU/LTFU visit whichever is later. This date will 
be recorded on the EOS electronic CRF (eCRF)   
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.   
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
4.1 
Inclusion Criteria 
101. Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102. Age ≥ 18 years old 
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103. Pathologically-documented, definitively-diagnosed relapsed or refractory MM, 
NHL, or AML (Appendix G) and is intolerant to, or considered ineligible for 
available therapies known to provide clinical benefit.   
104. MM subjects only: 
• 
Measurable disease per the IMWG response criteria (Appendix E; assessed within 
21 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  
− For 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 
105. NHL subjects only: 
• 
Radiographically measurable disease with a clearly demarcated nodal lesion at 
least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in 
its largest dimension 
106. AML subjects only: 
• 
Pathologically confirmed diagnosis of AML as defined by the WHO Classification 
(Appendix H) 
• 
More than 5% blasts in bone marrow 
107. MM and  NHL subjects only:  
• 
Hematological function, as follows without transfusion or growth factor support 
within 2 weeks prior to study day 1: 
− Absolute neutrophil count ≥ 1.0 X 109/L  
− Hemoglobin > 8 g/dL 
− Platelet count ≥ 75  X 109/L   
NOTE for MM subjects only: Platelet count ≥ 50 X 109/L (in subjects where 
< 50% of bone marrow nucleated cells were plasma cells) OR ≥ 30 X 109/L 
(in subjects where ≥50% of bone marrow nucleated cells were plasma cells) 
without transfusion or growth factor support are allowed into the study. 
108. Eastern Cooperative Oncology Group (ECOG) performance status of 
≤ 2 (Appendix F) 
109. Life expectancy of > 3 months, based on the opinion of the investigator  
110. Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption  
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111. Hepatic function, as follows: 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
< 3 x upper limit of normal (ULN) 
• 
Total bilirubin (TBIL) < 1.5 X ULN (except subjects with Gilbert’s 
syndrome) 
112. Cardiac function, as follows: 
• 
Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion as 
determined by an ECHO or MUGA 
• 
No clinically significant ECG findings.  
113. Renal function as follows:  
• 
Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute 
calculated using the formula of Cockcroft and Gault [(140 – Age) × Mass 
(kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female.  
Additional criteria for Part 2 - Dose Expansion subjects 
114. MM subjects only 
• 
Pathologically documented, definitively diagnosed, relapsed or refractory disease 
following at least 3 lines of therapy including but not limited to a proteasome 
inhibitor, an immunomodulatory agent and/or CD38-targeted 
immunochemotherapy.  
NOTE: The investigator must be of the opinion that no other treatment option will 
result in a durable response. 
115. NHL subjects only 
• 
Pathologically confirmed DLBCL that has demonstrated clinical or radiographic 
progression on at least two prior therapies 
NOTE: For subjects with refractory disease and who have received radiotherapy, 
PET positivity should be demonstrated no less than 6 weeks after the last dose of 
radiotherapy. 
116. AML subjects only 
• 
Pathologically confirmed diagnosis of AML as defined by the WHO Classification 
(Appendix H) persisting or recurring following no more than 2 lines of prior 
therapies   
4.2 
Exclusion Criteria 
201. Previously received an allogeneic stem cell transplant within 6 months of study 
day 1  OR having signs or symptoms of acute or chronic graft-versus-host disease 
202. Autologous stem cell transplant < 90 days prior to study day 1  
203. Candidates for stem cell transplant should have failed or are not considered 
eligible for either allogeneic and autologous transplant  
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204. History of other malignancy except: 
• 
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   
205. 
Myocardial infarction within 6 months of study day 1 
206. Symptomatic congestive heart failure (New York Heart Association > Class II) 
(Appendix F) 
207. History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 
6 months prior to study day 1 
208. Uncontrolled active infection requiring intravenous anti-infective treatments within 
1 week of study day 1 
209. Known positive results for human immunodeficiency virus (HIV) 
210. Active hepatitis B and C 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: hepatitis 
B virus DNA by polymerase chain reaction (PCR) is 
necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. 
• 
Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by 
PCR is necessary. Detectable hepatitis C virus RNA suggests chronic 
hepatitis C 
211. Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved 
to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
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 
prior to study day 1 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) 
212. Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, 
retinoid therapy, or investigational agent or procedures) within 14 days of day 1. 
213. Prior systemic radiation therapy must have been completed at least 28 days 
before study day 1. Prior focal radiotherapy completed at 14 days before study 
day 1.  
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214. Males and females of reproductive potential who are unwilling to practice an 
acceptable method(s) of effective birth control while on study through 3 months 
after receiving the last dose of study drug. Acceptable methods of effective birth 
control include sexual abstinence (males, females); vasectomy; bilateral tubal 
ligation/occlusion; or a condom with spermicide (men) in combination with barrier 
methods (diaphragm, cervical cap, or cervical sponge), hormonal birth control or 
IUD (females).  
NOTE: A woman is considered of childbearing potential (WOCBP), (ie, fertile) 
following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. 
• 
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 post-menopausal 
state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.  
215. Females who are lactating/breastfeeding or who plan to breastfeed while on study 
through 3 months after receiving the last dose of study drug. 
216. Females with a positive pregnancy test or planning to become pregnant while on 
study through 3 months after receiving the last dose of study drug. 
217. Males who are unwilling to abstain from sperm donation while on study through 
3 months after receiving the last dose of study drug. 
218. 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. 
219. Use of any over-the-counter or prescription medications within 14 days or 
5 half-lives (whichever is longer), prior to study day 1 that was not reviewed and 
approved by the principal investigator and the Amgen medical monitor   
220. Use of herbal medicines (eg, St. John’s wort), vitamins, and supplements 
consumed by the subject within 14 days prior to study day 1 that was not reviewed 
and approved by the principal investigator and the Amgen medical monitor  
221. Use of any known inhibitors of P-gp within 14 days or 5 half-lives (whichever is 
longer) or grapefruit juice or grapefruit containing products within 7 days prior to 
study day 1 that was not reviewed and approved by the principal investigator and 
the Amgen medical monitor 
222. Use of known cytochrome P450 (CYP) 3A4 sensitive substrates, (with a narrow 
therapeutic window), within 14 days or 5 half-lives (whichever is longer) of the 
drug or its major active metabolite, whichever is longer, prior to study day 1 that 
was not reviewed and approved by the principal investigator and the Amgen 
medical monitor    
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223. Use of known P-gp substrates (with a narrow therapeutic window) within 
14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not 
reviewed and approved by the principal investigator and the Amgen medical 
monitor  
224. 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, long term 
follow-up) to the best of the subject and investigator’s knowledge 
225. Known sensitivity to any of the products or component to be administered during 
dosing 
226. MM subjects with any of the following criteria are excluded: 
• 
Multiple myeloma with IgM subtype 
• 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) 
• 
Existing plasma cell leukemia  
• 
Waldenstrom’s macroglobulinemia 
• 
Amyloidosis 
227. NHL subjects with the following criteria are excluded: 
• 
CNS lymphoma or evidence of uncontrolled CNS disease  
• 
Burkitt’s lymphoma 
• 
Lymphoblastic lymphoma 
228. AML subjects with any of the following criteria are excluded: 
• 
Circulating white blood cells > 25,000 /µl.  Hydroxyurea to control peripheral blood 
leukemic cell counts, within 24 hours of study day 1 is permitted. 
• 
Promyelocitic leukemia  
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.   
A subject is considered enrolled when they have met all eligibility criteria, including 
completing any pre-treatment safety assessment(s) prior to initial dosing on day 1. The 
Investigator is to document the enrollment decision and date, in the subject’s medical 
record and in/on the enrollment eCRF. 
Approved 
 
 


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An Amgen representative will notify the sites in writing when a cohort is open to screen 
new subjects.  Each subject who enters into the screening period for the study (defined 
as the point at which the subject signs the informed consent) receives a unique subject 
identification number before any study procedures are performed.  The subject 
identification number will be assigned manually.  This number will be used to identify the 
subject throughout the clinical study and must be used on all study documentation 
related to that subject.  The unique number will consist of 11 digits: digits 1 to 
3 represent the last 3 digits of the protocol (eg, 173), digits 4 to 8 the country code and 
site number, digits 9 to 11 the subject number at the site.   
Subjects who fail to meet the eligibility criteria will be allowed to rescreen once with 
agreement between the Amgen Medical Monitor and PI.  Re-screened subjects must 
perform all qualifying assessments required for eligibility, including reconsenting the 
subject, within 21 days of their D1 visit. The subject identification number, assigned 
during the original screening period must remain constant throughout the entire clinical 
study if a subject is rescreened. 
5.1 
Treatment Assignment 
An Amgen representative will notify the site(s) in writing when a dose cohort/group (dose 
escalation part) or the dose expansion part, respectively, are open to screen and enroll 
new subjects.  The notification will include the cohort/group and dose level in which 
subjects will be enrolled.  The treatment assignment date is to be documented in the 
subject’s medical record and on the enrollment eCRF.  
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product  
The Amgen Investigational Product used in this study is AMG 397. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 397.  
6.2 
Investigational Product  
6.2.1 
Amgen Investigational Product AMG 397 
AMG 397 is an oral MCL1 inhibiting agent.  AMG 397 will be manufactured and 
packaged by Amgen Inc. and distributed using Amgen clinical study drug distribution 
procedures.  AMG 397 will be provided as 5 mg, 20 mg, and 100 mg tablets, and will be 
packaged in bottles of 15 tablets. 
Approved 
 
 


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AMG 397 will be dispensed and administered at the research facility by qualified staff 
member(s). 
6.2.1.1 
Dosage, Administration, and Schedule 
During dose escalation (Part 1), AMG 397 will be given orally once daily for 
2 consecutive days followed by 5 days break at a weekly interval, as part of a 28-day 
treatment cycle. Table 3 shows the planned dose levels for dose escalation. 
During dose expansion (Part 2) AMG 397 will be given orally once daily for 
2 consecutive days followed by 5 days break at a weekly interval, as part of a 28-day 
treatment cycle.  The planned dose level(s) for dose expansion will be determined based 
on data collected during dose escalation. 
On days of hospitalization and during clinic visits, doses will be administered at the 
clinic.  Subjects will self-administer AMG 397 on all other designated timepoints per 
Table 4 and Table 5 on days without clinic visits. 
AMG 397 can be taken with or without food (ie, subjects may choose to eat prior to or 
after taking study drug). The tablet should be swallowed whole without crushing or 
breaking.  No tablet should be ingested if it is broken, cracked, or otherwise not intact.  
Subjects will be asked to record the date, time, and number of tablets consumed in a 
subject drug diary that must be brought to each study visit and will be reviewed by study 
staff.  The amount dosed, lot number of IP, and start date will be recorded on each 
subject’s eCRF(s). 
The amount dispensed, amount returned, date dispensed, date returned, and lot number 
of AMG 397 are to be recorded in the site’s drug accountability log for each subject.  
Please refer to the Investigational Product Instructional Manual for more details on 
dosage, administration and schedule of AMG 397. 
If a subject develops a reaction, subjects should acutely be treated according to best 
clinical practice.  Medication may be administered as deemed appropriate by the 
investigator to control any reactions 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.  Amgen must be notified within 24 hours when a subject has 
had ≥ Grade 3 AE. 
The effects of overdose of this product are not known. 
Approved 
 
 


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6.2.1.1.1 
Lead-in Dosing 
There is a potential for tumor lysis syndrome (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, tumor lysis syndrome prophylaxis must be 
initiated in all subjects prior to the first dose of AMG 397 and prior to any dose escalation 
(Section 6.5.7).  
Additionally, when an event meeting clinical or laboratory TLS per Cairo-Bishop criteria 
(Appendix K and Appendix L) is observed, lead-in dosing may be initiated to evaluate a 
step-wise dose escalation for all subsequent dosing. See Figure 2 for an example of 
lead-in dosing.  . 
The DLRT will convene to review the safety data and may determine a lead-in dose, 
which will not exceed the dose where the TLS was observed. Once TLS criteria is 
resolved, this lead-in dose will be administered for the first week of dosing (cycle 1 
week 1). Upon completion of the lead-in dosing period, subject(s) will receive their 
designated target dose level of AMG 397 per Table 3 beginning on the second week of 
dosing (cycle 1 week 2) and all subsequent dosing.  
NOTE: Once lead-in dosing is implemented, a maximum of 50% dose escalation 
of AMG 397 will be imposed between dose cohort levels per Table 3 for the 
target dose.  
Once lead-in dosing is initiated, additional monitoring of electrolyte values is required 
prior to dosing at the following times (see Table 4 and Table 5): 
• 
Prior to the Week 1, Day 1 Dose 
• 
Prior to each dose during the Lead-in Period 
• 
Prior to the initial dosing at the target dose level 
Prior to administering AMG 397, all electrolyte values (ie, potassium, uric acid, inorganic 
phosphorus, calcium) must be within normal range.  
NOTE: Laboratory value changes must be confirmed by another laboratory test 
(1-2 hours later) prior to assigning a TLS grade.    
Dose Adjustments for Lead-In Dosing 
Evidence of TLS will be carefully monitored on study and AMG 397 will be held until 
resolution of TLS abnormalities. Following lead-in dosing of AMG 397, if one or more 
Approved 
 
 


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Protocol Number:  20170173 
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Cairo-Bishop criteria is met (See Appendix K and Appendix L), no additional AMG 397 
doses will be administered until it is resolved (eg, laboratory values are no longer within 
range of the values stated in Appendix K and Appendix L). Upon resolution, the subject 
will repeat the lead-in dosing for an additional week prior to receiving the target dose.  
NOTE: Lead-in dosing will be repeated if the subject is observed to meet one or 
more of the Cairo-Bishop criteria post-dose. 
Decisions to modify the AMG 397 lead-in dosing period regimen, lead-in period starting 
dose, and dosing increments, will be made in conjunction with the investigator and 
Amgen medical monitor and communicated to the IRB/EC, as appropriate. 
6.2.1.2 
Dose-cohort Study Escalation and Stopping Rules 
The Dose Level Review Team (DLRT) will convene before decisions to dose escalate or 
de-escalate is made or when cohorts are suspended per protocol.  The DLRT will be 
composed of select Investigator(s), Amgen medical monitor, Amgen Global Safety 
Officer or designee, Amgen Clinical Research Study Manager (CRSM) and Biostatistics 
representative or designee.  Additional members may be added as needed (eg, clinical 
pharmacologist).  The DLRT voting members include the Amgen Medical Monitor and 
Global Safety Officer or designee, in consultation with the investigator(s) or designee.  
The DLRT members are responsible for dosing decisions, which may include escalation 
to the next nominal or intermediate dose, de-escalation to a lower nominal or 
intermediate dose; alternative dose frequencies, continuation, delay or termination of 
dosing; or repetition or expansion of a cohort; implementation of lead-in dosing, or 
determination of RP2D. See Section 3.1 for more details regarding the study design and 
the dose escalation plan for this study.  
The DLT-observation period is defined as, at minimum, 28 days after the initial dose of 
AMG 397. Once lead-in dosing period is initiated, the DLT-observation period is defined 
as the amount of time for subject(s) for each dose cohort to receive at least 1 week of 
lead-in dose and 3 weeks of target dose. 
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 397   
• 
Experienced a DLT  
Available study data, including data collected after the initial DLT-observation period 
along with demographics, IP administration, medical history, concomitant medications, 
Approved 
 
 


Product:  AMG 397 
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adverse events (AE), 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. 
Dose escalation/de-escalation decisions will be guided by the BLRM model of dose 
toxicity described by Appendix D. An Amgen representative will notify the sites in writing 
the dosing decision from the DLRM and when a cohort is open to screen new subjects. 
DLTs experienced by subjects after completing the DLT period will be considered in the 
BLRM design to account for any late onset toxicity.  
Dose escalation for each group will continue until any of the following events occur: 
• 
The highest planned dose level is determined to be safe and tolerable (minimum 
of 6 evaluable subjects) 
• 
MTDs are identified for each group where BLRM repeats the recommendation of 
a dose level (minimum of 6 evaluable subjects) 
• 
The maximum of 30 evaluable subjects have been enrolled in each group.  If 
fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability. 
If there are concerns about the tolerability of the current dosing schedule, alternative 
dosing schedules or lower dose(s) may be explored, including modification of the lead-in 
period dosing regimen. The alternative dose and schedule will be jointly determined by 
the investigators and the Amgen medical monitor, based on pharmacokinetic and safety 
and toxicity data. 
6.2.1.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
NOTE: For subjects who meet clinical or laboratory TLS per Cairo-Bishop criteria 
(Appendix K and Appendix L) see Section 6.2.1.1.1 for dose adjustment details.  
Dosage Adjustments 
The subject should continue on the same dose of AMG 397 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. 
• 
AMG 397 can be resumed once the adverse events recover to baseline or Grade 1 
and the reintroduction of AMG 397 is deemed safe by the Investigator, Amgen’s 
Medical Monitor, and Global Safety Officer.  
Approved 
 
 


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NOTE: Subjects must be informed of the risk of continuing on therapy.  Each subject 
is only allowed a single dose reduction. 
Subjects should not be re-challenged with AMG 397 if the following AMG 397-related 
adverse events occur: 
• 
Any life-threatening adverse events 
• 
DILI (Drug Induced Liver Injury) meeting Hy’s law  
• 
Persistent grade 3 adverse events that do not recover to baseline or Grade 1 within 
4 weeks of last dose 
• 
Any treatment-related adverse event meeting DLT-criteria that recurs 
Dosage Delays  
The investigator should inform the Amgen Clinical team as soon as the unexpected 
dosage delay occurs. The following dosage delay rules apply: 
• 
If the dosing delay is ≤ 3 weeks, the subject should resume the treatment as soon as 
possible if deemed safe by the investigator.  
• 
If the dosing delay is more than 4 weeks (missing 1 cycle): 
 
Due to treatment related AEs, the subject will be removed from the study. 
 
Due to other conditions other than treatment related AEs, the case will be 
reviewed by Amgen medical monitor to determine whether the subject will be 
allowed to resume AMG 397 treatment. 
Rules for Dose Withholding  
AMG 397 should be withheld for any of the following: 
• 
Suspected DLT (including AEs that meet DLT definition outside DLT-observation 
period)  
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 
3 x ULN or total bilirubin greater than 1.5 x ULN 
Rules for Restarting 
AMG 397 dosing can be resumed: 
• 
If the toxicities resolve to grade ≤ 1 or return to subjects’ baseline values 
• 
Restarting of therapy is deemed safe by the investigators and Amgen’s medical 
monitor.  
Approved 
 
 


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Rules for Permanent Discontinuation 
Subjects will permanently discontinue from the investigational product if: 
− 
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 397 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 397, may have the option to continue 
therapy once the adverse events recover to baseline or Grade 1 and the 
re-introduction of AMG 397 is deemed safe by the investigator, Amgen’s 
medical monitor, and Global Safety Officer. The subject should restart at a 
reduced dose.  
− 
Subjects who experience TLS as detail, see Section 6.2.1.1.1 for dosing 
details. 
− 
Intolerability of the study treatment 
− 
The dosing is delayed > 4 weeks due to AMG 397-related adverse events  
− 
Disease progression according to IMWG (MM), Lugano classification (NHL), or 
2017 ELN response criteria (AML) and/or per institutional guidelines as applicable 
− 
Clinical significant deterioration of health status  
− 
Withdrawal of informed consent 
− 
Subject becomes pregnant or is breastfeeding 
− 
Initiation of new systemic anti-cancer therapy not provided in this study 
− 
Study is terminated by the sponsor.   
6.2.1.4 
Dose Stopping Rules 
Please refer to Section 10.4 for dose stopping rules.  
6.3 
Other Protocol Required Therapies 
6.3.1 
Pre-dosing requirements for AMG 397 
To mitigate risk of TLS, all subjects are to receive TLS prophylaxis prior to first dose of 
AMG 397 and prior to any dose escalation.  Refer to Section 6.5.7 for specific 
requirements.   
6.4 
Dose Limiting Toxicities  
The grading of adverse events will be based on the guidelines provided in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 (available online at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). Determination of the severity of adverse 
events will be consistent with Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
Approved 
 
 


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For MM and NHL subjects only: 
A DLT is defined as a treatment-related AE(s), that occur during the DLT-observation 
period (see Section 6.2.1.2) including any: 
• 
≥ Grade 3 non-hematological AE’s EXCEPT: 
o ≥ Grade 3 fatigue if <7 days 
o Grade 3 nausea, vomiting and/or diarrhea if < 3 days and controlled with medical 
management 
o Laboratory parameters of grade ≥ 3 that improve with medical management to 
grade ≤ 2 within 3 days  
• 
≥ Grade 4 hematologic AE’s AND: 
o ≥ Grade 3 neutropenia with fever  
o ≥ Grade 3 thrombocytopenia with Grade ≥ 2 hemorrhage  
o ≥ Grade 3 anemia with symptoms requiring intervention (eg, transfusion)  
NOTE: ≥ Grade 4 neutropenia must be lasting > 7 days  
• 
Any grade 5 AE that is not clearly due to disease progression  
For AML subjects only:  
Due to the nature of AML, hematologic adverse events will not be considered DLTs. 
However, prolonged pancytopenia in the presence of a hypocellular bone marrow 
(ie, cellularity 5% or less without evidence of leukemia) that lasts longer than 42 days will 
be considered dose-limiting myelosuppression. 
Non-hematological toxicity:   
• 
≥ 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 397 related toxicities to grade ≤ 1 or baseline 
severity after delaying next cycle up to 14 days 
For all subjects:  
• 
Any Clinical TLS (refer to Appendix K) 
If a DLT of TLS is observed during the lead-in period, it will be attributed to the lead-in 
period and a modification may be made to the lead-in period regimen for subsequent 
cohorts. Any other DLTs observed during the lead-in and/or designated cohort dosing 
period may require a modification of the designated cohort dose (and/or lead-in period 
regimen, if appropriate) as directed per the Dose Escalation Guidelines.  
Approved 
 
 


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Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver injury) 
will be considered a DLT.  A Hy’s Law case is defined as: AST or ALT values of 
≥ 3x ULN AND with serum total bilirubin level (TBL) of > 2x ULN without signs of 
cholestasis and with no other clear alternative reason to explain the observed 
liver-related laboratory abnormalities (see Section 6.7 for hepatotoxicity management 
and Appendix A for further explanation of Hy’s law case and Management of Hepatic 
Function). Grade 3 or 4 elevation of serum lipase without clinical signs or symptoms of 
pancreatitis. 
6.5 
Potential Risk Management Guidelines for AMG 397 
6.5.1 
Gastrointestinal Toxicity 
Evidence of gastrointestinal toxicity will be monitored in the FIH study through clinical 
evaluations, safety laboratory tests, stopping rules, and associated adverse events. 
Management should be tailored to the appropriate treatment according to the local 
standard of care and institutional guidelines. 
6.5.2 
Bone Marrow Toxicity 
Monitoring of vital signs, hematology parameters and associated adverse events will be 
conducted in the FIH study. Specific eligibility criteria, stopping rules and dose-hold 
rules, pertaining to hematology parameters, are provided in Section 6.2.1.3. 
6.5.3 
Reproductive Toxicity- Male 
Men of reproductive potential who are unwilling to practice an acceptable method of 
effective birth control will be excluded from the study. See section 4.2 for list of 
acceptable methods of effective birth control. 
6.5.4 
Drug-drug interactions 
A list of prohibited drugs as well as subject exclusion criteria are included in the protocol. 
Subjects receiving any of the drugs cited in the exclusion criteria and/or prohibited drugs 
as listed in the FIH protocol will be excluded from this study. Caution should be 
exercised when administering AMG 397 with drugs that have a narrow therapeutic 
window and prescribing information that includes contraindications, warnings or 
precautions related to their use with known inhibitors of CYP34A and P-gp.  
6.5.5 
Hepatobiliary Toxicity 
Evidence of hepatobiliary toxicity will be monitored as outlined in the study protocol 
through clinical evaluations, safety laboratory tests, stopping rules, and associated 
adverse events.  
Approved 
 
 


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6.5.6 
Cardiovascular Toxicity 
Adverse events associated with cardiac function will be monitored through blood 
pressure, heart rate, echocardiogram, and ECG measurements. Subsequent withholding 
rules, as outlined in the study protocol, will be followed. 
6.5.7 
Tumor Lysis Syndrome (TLS) 
Prophylaxis and Management of TLS 
Tumor lysis syndrome prophylaxis must be initiated in all subjects prior to the first dose 
of AMG 397 and prior to every dose escalation.  
The management recommendations below focus on the minimum initial responses 
required. If a diagnosis of TLS is established, ongoing intensive monitoring and multi-
disciplinary management will be conducted per institutional protocols 
(Coiffier et al, 2008; Cairo et al, 2004). 
• 
Initiate allopurinol or equivalent 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 PI discretion. Dosing per institutional guidelines. 
• 
All subjects will be hospitalized for intensive monitoring:  
− 
For the first 2 doses received, beginning 24 hours prior to first dosing day 
(Day -1) until 24 hours post the second dose 
− 
Once lead-in dosing is initiated (see Section 6.2.1.1.1): 
 
For the first 2 doses received (Lead-in dosing), beginning at least 
24 hours prior to first dosing day (Day -1) until 24 hours post the 
second dose 
 
Each time an additional week of lead-in dosing is instituted 
(Section 6.2.1.1.1) 
 
For the first 2 doses received after the dose is escalated (target 
dose) beginning at least 24 hours prior to dosing day (usually 
day 7) until 24 hours post the second dose  
• 
During hospitalization, intensive safety laboratory monitoring per designated 
timepoints per Table 4 and/or Table 5 to identify and prompt management of any 
metabolic changes. 
• 
Pre-treatment serum chemistry and hematology laboratory samples must 
be drawn within 24 hours prior to first dose, and electrolyte values 
(ie, potassium, uric acid, inorganic phosphorus, calcium) must be 
reviewed and within normal range prior to AMG 397 dosing. The 
investigator's decision to proceed with AMG 397 treatment initiation may 
be based on these laboratory values. These labs must be reviewed in real 
time by the investigator.  
NOTE: 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, dosing can be resumed following review of 
Approved 
 
 


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laboratory values and agreement between the Amgen medical monitor 
and investigator. 
• 
Prophylactic reductions of potassium, inorganic phosphorus and/or uric 
acid above of normal range prior to dosing are recommended per PI 
discretion. 
• 
Day 2 dosing of AMG 397 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. 
• 
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria (Appendix L) are met, no additional AMG 397 doses should be 
administered until resolution. A rapidly rising serum potassium is a medical 
emergency.  
• 
Upon admission, 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 and as needed per Investigator discretion.  
• 
Monitor for signs and symptoms of TLS (eg, fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion and seizures). If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour.  
• 
Nephrology (or other acute dialysis service) consultation should be considered 
upon admission per institutional standards at investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared. 
• 
Management recommendations of laboratory abnormalities as stated below:  
Approved 
 
 


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Approved 
 
 


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Protocol Number:  20170173 
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Approved 
 
 


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6.6 
Support Care Guidelines for AMG 397 
6.6.1 
Management of Infections 
Subjects with evidence of existing infection should be closely monitored while being 
treated with AMG 397.  Subjects with active systemic infections requiring IV antibiotics, 
antivirals, or antifungals should not be dosed with AMG 397 until infection per exclusion 
criteria in Section 4.2. Management should be tailored to the appropriate prophylaxis 
and/or treatment for the underlying infection according to the local standard of care and 
institutional guidelines. 
Approved 
 
 


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CONFIDENTIAL 
 
 
Subjects who may experience neutropenia are at a high risk for infectious complications. 
As appropriate, these subjects should be administered prophylactic antibacterial 
(treatment with ciprofloxacin) and antifungal (treatment with posaconazole). 
These subjects should be monitored for early signs of breakthrough infections after the 
initiation of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. Subjects experiencing diarrhea should be closely monitored for their 
electrolyte levels. 
6.6.2 
Management of Renal Toxicities 
Renal dysfunction is one of the multiple myeloma-related organ/tissue dysfunction. 
Renal function must be monitored closely during treatment with AMG 397.  Serum 
chemistry values, including BUN, serum creatinine, and urine for urinalysis and 
microscopic exam (microscopic exam only needed for positive dipstick), must be 
obtained per the schedule of assessments (see Table 4).  Management should be 
tailored to the appropriate treatment for the underlying renal disorder according to the 
local standard of care and institutional guidelines. 
6.7 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBIL]) 
or international normalized ratio [INR]) or signs/symptoms of hepatitis may meet the 
criteria for withholding of investigational product.  Withholding is either permanent or 
conditional depending upon the clinical circumstances discussed below (as specified in 
the FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009).  
6.7.1 
Criteria for Permanent Withholding of AMG 397 due to Potential 
Hepatotoxicity 
AMG 397 should be permanently withheld and the subject should be followed according 
to the recommendations in Appendix A (Additional Safety Assessment Information) for 
possible drug-induced liver injury (DILI), if ALL of the criteria below are met:  
• 
Increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
AND   
• 
TBIL > 2x upper limit of normal (ULN) or INR > 1.5 
Approved 
 
 


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AND  
• 
No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
elevated TBIL values include, but are not limited to: 
• 
Hepatobilliary 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 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 (NASH) 
• 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.7.2 
Criteria for Conditional Withholding of AMG 397 due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of AMG 397 
outlined above and have no underlying liver disease and eligibility criteria requiring 
normal transaminases and TBIL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of Amgen investigational product and other protocol-required therapies:   
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or 
ALT value 
AST or ALT elevation 
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice.   
• 
OR: TBIL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 
Approved 
 
 


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AMG 397 should be withheld pending investigation into alternative causes of DILI.  If 
investigational product(s) is withheld, the subject should be followed according to 
recommendations in Appendix A for possible DILI.  Rechallenge may be considered if an 
alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBIL, is 
discovered and the laboratory abnormalities resolve to normal or baseline.  
6.7.3 
Criteria for Rechallenge of AMG 397 After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, Principal Investigator, and Amgen.   
If signs or symptoms recur with rechallenge, then AMG 397 should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.2.1.3) should not be rechallenged.  If signs or symptoms recur 
with rechallenge, then AMG 397 should be permanently discontinued. 
6.8 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.10 
Concomitant therapies are to be collected from screening start through the EOS visit.  All 
concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter, herbal supplements, and IV medications, transfusions and fluids. 
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. For subjects with AML hydroxyurea for 7 days at a dose of 
1 – 10 g/day is allowed prior to the first cycle of AMG 397 treatment for subjects with 
high WBC (> 25,000 cells/ul) and during the first cycle but not on dosing days at a dose 
of up to 5 g/day. 
For all concomitant medication collect therapy name, indication, dose, unit, frequency, 
route, start date, and stop date.  
6.9 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 59 of 130 
CONFIDENTIAL 
 
 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.   
This includes any drug(s), device(s), or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.10 
Excluded Treatments and Procedures During Study Period  
The following medications and/or therapies should not be administered during the study:  
• 
Allogeneic stem cell transplant  
• 
Autologous stem cell transplant   
• 
Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, 
retinoid therapy, or investigational agent or procedures)  
• 
Systemic or focal radiotherapy  
• 
Over-the-counter medication(s) that was not reviewed and approved by the principal 
investigator and the Amgen medical monitor 
• 
Any known inhibitors of P-gp or grapefruit juice or grapefruit containing products that 
were not reviewed and approved by the principal investigator and the Amgen 
medical monitor   
• 
Herbal medicines (eg, St. John’s wort), vitamins, and supplements that were not 
reviewed and approved by the principal investigator and the Amgen medical monitor 
• 
Any known cytochrome P450 (CYP) 3A4 sensitive substrates, with a narrow 
therapeutic window, that were not reviewed and approved by the principal 
investigator and the Amgen medical monitor 
If use of any other prior or concomitant medication or procedure is in question, please 
refer to prescribing information and/or consult with Amgen Medical Team.  
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
Please refer to Table 4 for Schedule of Assessments. 
Once lead-in dosing is initiated follow Table 5 for Cycle 1 only. For all subsequent cycles 
and study periods follow Table 4. 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 60 of 130 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments 
 
SCREENING 
TREATMENT 
EOT 
SAFETY FOLLOW-UP 
LTFU (26) 
CYCLE(S) 
 
1 
2 
Every cycle 
from 3 & 
beyond 
WEEK(S) 
 
1 
2 
3 
 
1 
2 
3 
1 
DAY(S) 
-21 
to 
 -2 
-1 
1 
2 
3 
4 
8 
15 
22 
1 
8 
15 
1 
 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
Pre
0 
2 
3 
5 
Pre-dose unless specified 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation 
(1)  
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
Vital signs (T, BP, 
HR, RR)  
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
12-lead ECG (2) 
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 
 
Echocardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hospitalization (3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis (4) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 397 Dosing 
(5) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
AMG 397 is taken orally once daily 
 for 2 consecutive days followed by  
5 days break at a weekly interval,  
as part of a 28-day treatment cycle 
 
 
 
Dosing diary review 
(5) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
AE Reporting 
 
 
 
 
 
SAE Reporting 
 
Prior /concomitant 
medication(s) 
 
Page 1 of 4  
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 61 of 130 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments 
 
SCREENING 
TREATMENT 
EOT 
SAFETY FOLLOW-UP 
LTFU (26) 
CYCLE(S) 
 
1 
2 
Every cycle 
from 3 & 
beyond 
WEEK(S) 
 
1 
2 
3 
 
1 
2 
3 
1 
DAY(S) 
-21 
to 
 -2 
-1 
1 
2 
3 
4 
8 
15 
22 
1 
8 
15 
1 
 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
Pre
0 
2 
3 
5 
Pre-dose unless specified 
Survival/Subsequen
t anti-cancer 
therapy (6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LAB ASSESSMENTS  
AMG 397 PK  (7) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
 
 
 
 
 
X 
 
 
CBC with diff (8) 
X 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
Chemistry (9) 
X 
X X 
 
 
 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
Coagulation  
X 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
Pregnancy test (10) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Urine sample 
collection (11) 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Hepatitis serology, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 4  
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 62 of 130 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments 
 
SCREENING 
TREATMENT 
EOT 
SAFETY FOLLOW-UP 
LTFU (26) 
CYCLE(S) 
 
1 
2 
Every cycle 
from 3 & 
beyond 
WEEK(S) 
 
1 
2 
3 
 
1 
2 
3 
1 
DAY(S) 
-21 
to 
 -2 
-1 
1 
2 
3 
4 
8 
15 
22 
1 
8 
15 
1 
 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
Pre
0 
2 
3 
5 
Pre-dose unless specified 
BIOMARKER and DISEASE ASSESSMENTS 
Bone marrow 
aspirate (12) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood Na/Hep 
(13) 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
Cytochex (14) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cell Pellet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MM SUBJECTS ONLY 
SPEP/UPEP/ 
Immunofixation (15)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
SFLC (16) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Beta-2 
microglobulin  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Quantitative Ig (17) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Page 3 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 63 of 130 
CONFIDENTIAL 
 
 
Table 4.  Schedule of Assessments 
 
SCREENING 
TREATMENT 
EOT 
SAFETY FOLLOW-UP 
LTFU (26) 
CYCLE(S) 
 
1 
2 
Every cycle 
from 3 & 
beyond 
WEEK(S) 
 
1 
2 
3 
 
1 
2 
3 
1 
DAY(S) 
-21 
to 
 -2 
-1 
1 
2 
3 
4 
8 
15 
22 
1 
8 
15 
1 
 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
Pre
0 
2 
3 
5 
Pre-dose unless specified 
Bone marrow 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate (18) 
 
------------------------------------------------------------- Repeat collection in case of CR -------------------------------------------------------------- 
Plasmacytoma (19) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey (20) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NHL SUBJECTS ONLY 
Lymph Node Biopsy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
plasma 
(Dose expansion 
only)  (21) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X 
(21) 
X 
 
 
 
Bone marrow 
biopsy (22) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT and CECT 
Imaging (23) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X  
(23) 
X 
 
 
MRI Brain (24) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AML SUBJECTS ONLY 
Bone marrow 
aspirate 
 (25) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X (25) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 64 of 130 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 12 
24h 
after 
D2 
dose
48h 
after
D2 
dose
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 12 
24h 
after 
D9 
dose
48h 
after 
D9 
dose 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation 
(1)  
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
Vital signs (T, BP, 
HR, RR)  
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X X 
X 
X 
X 
X 
12-lead ECG (2) 
X 
X 
X 
(2) 
 
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 
Echocardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization (3) 
 
 
 
 
 
 
 
 
 
TLS prophylaxis (4) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 397 dosing 
(5) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X (5) 
Dosing diary review 
(5) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X X 
AE Reporting 
 
 
 
 
 
 
SAE Reporting 
 
 
Prior /concomitant 
medication(s) 
 
 
Page 1 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 65 of 130 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 
0 
1 
2 
3 
5 
8 12 
Pre-
dose 
0 
1 
2 
3 
5 
8 12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
 
Pre-
dose 0 
1 
2 
3 
5 
8 12 
Pre-
dose 
0 
1 
2 
3 
5 
8 12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose 
 
 
LAB ASSESSMENTS 
 
 
 
AMG 397 PK  (7) 
 
 
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 
 
 
CBC with diff (8) 
X 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
Chemistry (9) 
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 
Coagulation  
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
Pregnancy test (10) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample 
collection (11) 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
Hepatitis serology, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER and DISEASE ASSESSMENTS 
 
 
 
Bone marrow 
aspirate (12) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood Na/Hep 
(13) 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
Cytochex (14) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Plasma 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cell Pellet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 66 of 130 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after
D9 
dose
48h 
after 
D9 
dose 
 
 
BIOMARKER and DISEASE ASSESSMENTS 
 
 
 
MM SUBJECTS ONLY 
SPEP/UPEP/ 
Immunofixation (15)  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SFLC (16) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2 
microglobulin  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative Ig (17) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasmacytoma (19) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey (20) X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date:  28 March 2018 
Page 67 of 130 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose 
 Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose
 
 
NHL SUBJECTS ONLY 
Lymph Node 
Biopsy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
plasma  
(Dose expansion 
only)  (21) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy (22) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT and CECT 
Imaging (23) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Brain (24) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 4 
Footnotes are defined at the end of Table 5 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 68 of 130 
CONFIDENTIAL 
 
 
Footnotes for Table 4 and Table 5 
1 
Clinical evaluations will be collected pre-dose on dosing days and include: physical exam, ECOG status, and weight.  Medical and surgical history, and height 
need only be collected at the screening visit. 
2 
• 
Three baseline ECGs (pre-dose on day 1) will be collected approximately ≥ 15 minutes apart (+/- 5 minutes), with each baseline ECG in triplicate run 
consecutively (ie, < 30 seconds apart); Total of 9 ECGs] 
• 
Triplicate ECGs run consecutively (ie, < 30 seconds apart) , at time points designated in the schedule of assessments 
3 
• 
See Section 6.5.7 for more details regarding hospitalization for TLS prophylaxis 
• 
Hospitalization for the purpose of TLS prophylaxis will not be captured as an SAE. 
4 
• 
See Section 6.5.7 for more details regarding TLS prophylaxis. 
5 
• 
See Section 6.2.1.1 for details regarding dosage, administration, and schedule. 
• 
See Section 6.2.1.1.1 and Table 5 for details regarding dosage, administration, and schedule once lead-in dosing is implemented. 
6 
For Dose Expansion subjects only: 
o 
Collected during LTFU period 
7 
• 
For PK collections on Cycle 1, PK samples should be collected within +/- 15 min of the designated time points.  
• 
PK samples should be collected at the exact nominal time point as noted. If unable to collect a PK sample at the specified nominal time point collect it as 
close as possible and record the actual collection time in the eCRF. 
Note: It is important to document the exact date and time of IP administration and PK collection. 
8 
Refer to Section 7.2.15 for list CBC lab tests required. 
Note: Subjects with a Grade 4 neutropenia should have their counts repeated every 24-48 hours until return to baseline and the use of G-CSF should 
be considered. 
9 
• 
Refer to Section 7.2.15 for list Chemistry panel lab tests required. 
• 
See Section 6.5.7 for chemistry lab tests required for TLS prophylaxis and management 
10 
Serum pregnancy test performed at screening; urine or serum pregnancy test at all other timepoints for females of childbearing potential. 
11 
• 
Please collect urine for UA, which is done per local lab.  
• 
Any remaining urine will be sent to the central lab for analysis. Please refer to lab manual for preparation and transport procedures. 
• 
On cycle 1, day 1, collect urine sample at least 5 hours post-dose of AMG 397. 
• 
After cycle 1, urine sample may be collected at the following designated timepoints. 
12 
A bone marrow aspirate will be collected from all subjects during screening for IHC testing, to quantify percent tumor involvement, for fluorescent in situ 
hybridization (FISH) and other biomarker assays.  
13 
• 
Biomarker NaHep whole blood samples will be collected pre-dose on Cycle 1 day 1, 3 and 5 hours post dose on day 1, and 24 hours after day 1 during 
week 1 as indicated in Table 4. 
• 
Upon commencement of Lead-In dosing, additional samples will be collected indicated in Table 5 as follows: In the second week of Cycle 1, samples will be 
collected pre-dose on day 8, 3 and 5 hours post dose on day 8, and 24 hours after day 8. 
14 
• 
Biomarker Cytochex whole blood samples will be collected pre-dose on days 1, 2, 3, 4, and 8 as indicated in Table 4. 
• 
 Upon commencement of Lead-In dosing, additional samples will be collected indicated in Table 5 as follow: pre-dose on days 9, 10, and 15. 
 
Approved 
 
 


Product:  AMG 397 
Protocol Number:  20170173 
Date: 28 March 2018 
Page 69 of 130 
CONFIDENTIAL 
 
 
For MM subjects only [15-20]: 
15 
• 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis (UPEP) is required for all subjects at screening.  
• 
Thereafter, SPEP is to be done at each time point for all patients as indicated in the schedule of assessment.  
• 
UPEP with 24-hour urine collection is required at each time point only if screening UPEP shows measurable paraprotein in the urine. 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. 
• 
See lab manual for collection and shipment details.  
16 
Serum free light chain (SFLC) assay and ratio will be performed at each marked time point.  
17 
Quantitative Immunoglobulin (Total IgG, IgA, IgM) obtained at screening and will be repeated only if clinically indicated (ie; frequent infection despite multiple 
myeloma disease control). 
18 
Additional bone marrow samples are to be collected to confirm CRs as well as for MRD biomarker analysis. Additional samples may be obtained every six 
months after CR and/or at time of relapse. 
19 
Plamacytoma survey 
• 
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 PR 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, CT scan, MRI, PET, or other standard-of-care 
method) must be employed for each measurement. 
20 
Skeletal survey to be repeated Q8W if clinically indicated ie; new symptoms (bone pain) arises, consider obtaining MRI for subjects with bone pain but skeletal 
survey is normal. 
NHL ( subjects only [21-24]: 
21 
For dose expansion subjects only: 
• 
Whole blood plasma may be obtained pre-dose on day 1 of Cycle 2, and every 8 weeks thereafter, and EOT. Samples must be collected, processed, and 
frozen within 4 hours of phlebotomy and per the laboratory manual. 
• 
Additional whole blood plasma samples are obtained at time of relapse.  
22 
Bone marrow evaluation (core biopsy with or without aspirate) may be performed if there has been previous histologic evidence of bone marrow involvement. 
An optional tumor biopsy may be collected at time of relapse per institutional guidelines at PI discretion. 
23 
PET-CT and CECT Imaging with time points at screening, Cycle 2, every 8 weeks thereafter, and EOT. If not acquired on the same day, every effort should be 
made to complete PET-CT and CECT within 3 days of each other. 
24 
For Both Part 1 (dose escalation) and Part 2 (dose expansion), all NHL subjects must have MRI/CT of the brain performed within 21 days prior to enrollment.  
All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.  Subsequently, MRI brain can be 
performed at any time if clinically indicated per standard of care. 
25 
For AML Subjects only [25]:  
• 
Bone marrow samples must be obtained at pre-dose on day 1 of Cycle 2, every 8 weeks thereafter, and EOT. 
• 
Additional bone marrow sampling may occur at other time points at the PI’s discretion as clinically indicated throughout course of treatment 
26 
For Dose Expansion subjects only:  
Long-term follow up (LTFU) will be conducted every 3 months from the last visit for up to 1 year from the first dose of AMG 397 for all subjects who have not 
withdrawn consent by telephone or chart review to assess for survival, disease progression and/or the commencement of subsequent cancer therapy only.  
 
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7.2 
Study Procedures 
A signed and dated IRB-approved informed consent must be obtained before any study 
specific procedures are performed. All subjects will be screened for eligibility before 
enrollment. Only eligible subjects will be enrolled into the study.  
For more information regarding subject enrollment, refer to Section 5.  
7.2.1 
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 through first dose of AMG 397. 
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. 
7.2.2 
Prior Therapy 
The Investigator or designee will collect relevant prior therapy, which includes previous 
chemotherapy, radiotherapy, investigational drug, and any anticancer therapies 
(eg, stem cell transplant). Prior therapies that were being taken prior to enrollment 
through the first dose of IP should be collected. 
Record all findings on the prior therapy eCRF. 
7.2.3 
Physical Examinations 
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 7.1).  
7.2.4 
Height Measurements 
Height (cm) will be measured without shoes at screening. 
7.2.5 
Weight Measurements 
Weight (kg) without shoes will be obtained at screening and time points specified in the 
Schedule of Assessments (see Section 7.1) 
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7.2.6 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure (BP), 
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 by the investigator or qualified site personnel at screening and time 
points specified in the Schedule of Assessments (see Section 7.1). 
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. 
7.2.7 
Electrocardiogram Performed in Triplicate 
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, prior to blood draws or other invasive 
procedures. Each ECG must include the following measurements: QRS, QT, QTc, RR, 
and PR intervals. 
Electrocardiograms will be performed as follows: 
 
Three baseline ECGs (pre-dose on day 1) will be collected approximately 
≥ 15 minutes apart (+/- 5 minutes), with each baseline ECG in triplicate run 
consecutively (ie, < 30 seconds apart); Total of 9 ECGs] 
 
Triplicate ECGs run consecutively (ie, < 30 seconds apart) , at time points 
designated in the schedule of assessments 
The principal investigator or qualified site personnel will review all ECGs. 
Electrocardiograms will be transferred electronically to an ECG central vendor for 
reconciliation and storage per Amgen instructions. Once reviewed, the original ECG 
tracing will be retained with the subject’s source documents. At the request of Amgen, a 
copy of the original ECG will be made available to Amgen. 
Standard ECG machines should be used for all study-related ECG requirements, this will 
be provided to the site as ECG data will need to be transmitted to the selected vendor. 
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7.2.8 
Echocardiogram (ECHO) / Multigated Acquisition (MUGA) Scan 
ECHO or MUGA will be performed to assess cardiac ejection fraction and cardiac valve 
abnormalities and will be performed at time points specified in the Schedule of 
Assessments (see Section 7.1).  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.  
7.2.9 
Dosing Diary Review 
A dosing diary will be provided for subjects to record the date, time, and number of 
tablets consumed each dose. The dosing diary is to be brought to each study visit and 
reviewed by study staff (see Section 7.1). 
The dates of any missed doses or instances of emesis associated with tablet 
administration will asked to be recorded in the subject drug diary.  
7.2.10 
Assessments in MM Subjects 
7.2.10.1 
Serum Protein Electrophoresis (SPEP) and Urine Protein 
Electrophoresis (UPEP) 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis (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.  
UPEP 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 VGPR or CR 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.  
7.2.10.2 
Serum Free Light Chain  
Serum free light chain (SFLC) assay and ratio will be performed at each time point as 
specified in the schedule of assessments.  
7.2.10.3 
Quantitative Immunoglobulin  
Quantitative Immunoglobulin (Ig) will be performed at screening and at each time point 
as specified in the schedule of assessments. Quantitative Immunoglobulin will be 
repeated only if clinically indicated, ie, frequent infection despite Multiple Myeloma 
disease control or deemed clinically indicated by the investigator.  
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7.2.10.4 
Beta-2 Microglobulin  
Beta-2 microglobulin will be performed at baseline as part of risk stratification and at 
each time point as specified in the schedule of assessments. 
Plasmacytoma Survey 
Plasmacytoma survey will be performed at the time points as specified in the schedule of 
assessments (Section 7.1). 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 PR 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, 
CT scan, MRI, PET, or other standard-of-care method) must be employed for each 
measurement. 
7.2.10.5 
Skeletal Survey  
Skeletal Survey (conventional radiography, whole body low-dose CT, PET-CT or MRI) 
will be performed at the time points as specified in the schedule of assessments 
(Section 7.1). It can also be done if clinically indicated, ie, new symptoms (bone pain) 
arise. MRI should be performed in subjects with bone pain but skeletal survey is normal. 
7.2.10.6 
Bone marrow  
Bone marrow sample and biopsy will be collected during the screening to quantify 
percent myeloma involvement and for fluorescent in situ hybridization (FISH).  
Additional bone marrow samples are to be collected to confirm CRs as well as for MRD 
biomarker analysis. Additional samples may be obtained every six months after CR 
and/or at time of relapse. 
7.2.11 
Assessments in NHL Subjects  
7.2.11.1 
Imaging and Disease assessments 
Clinical tumor assessments will be performed as indicated in the schedule of 
assessments and per institutional guidelines.  The Lugano Classification will be used to 
assess treatment response as described in Appendix I.  
PET-CT and CECT scans required in this protocol will be performed according to the 
Imaging Manual provided by the central vendor.  However, depending on scanner types 
and availability, as well as local regulations, institutional guidelines may be followed 
upon consultation with, and approval by, the central vendor.  Combined PET-CT whole 
body scans will be acquired from base of skull to mid-thigh, with the CT portion of the 
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scan used only for attenuation correction.  CECT anatomical coverage includes the 
chest, abdomen, and pelvis (and neck, if not visualized with chest), and the acquisition 
of separate CECT scans is strongly recommended for staging evaluation.  Refer to the 
Imaging Manual for complete details about PET-CT and CECT scanning procedures and 
instructions. 
PET-CT images should be converted to standardized uptake values (SUV) maps to 
support comparison across timepoints and to standardize viewing conditions. 
If PET-CT and CECT are acquired on the same day, it is strongly recommended that 
PET-CT is performed prior to CECT.  If acquired separately, every attempt should be 
made to complete PET-CT and CECT within 3 days of each other.   
Refer to the Imaging Manual for additional details. Findings will be recorded per eCRF 
guidelines. 
7.2.11.2 
MRI Brain 
For both Part 1 (dose escalation) and Part 2 (dose expansion), all NHL subjects must 
have MRI or CT of the brain performed within 21 days prior to enrollment.  All brain 
scans on protocol are required to be MRI unless MRI is contraindicated, then CT with 
contrast is acceptable.  Subsequently, MRI brain can be performed at any time if 
clinically indicated per standard of care. 
7.2.11.3 
Lymph Node and Bone Marrow Assessments 
Lymph node and bone marrow biopsy are to be collected as per schedule of 
assessments.   
Bone marrow evaluation (core biopsy with or without aspirate) should be performed if 
there has been previous histologic evidence of bone marrow involvement plus a 
negative or ambiguous PET-CT, or if bone marrow involvement is suspected with an 
ambiguous or negative PET-CT. An optional tumor biopsy may be collected at time of 
relapse per institutional guidelines at PI discretion.  
Refer to the Laboratory Manual for additional information for these procedures. 
7.2.11.4 
Whole Blood Plasma 
For dose expansion subjects (DLBCL subjects) only: 
• 
Whole blood plasma may be obtained at pre-dose on day 1 of Cycle 2, every 
8 weeks thereafter, and EOT. Samples must be collected, processed, and frozen 
within 4 hours of phlebotomy. See laboratory manual for more details 
• 
Additional whole blood plasma samples are obtained at time of relapse. 
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7.2.12 
Assessments in AML Subjects 
Bone marrow aspirate will be performed for the following: 
• 
Hematocytology and cytochemistry to establish WHO subtype of AML – local site 
laboratory according to local procedures using slides of bone marrow and 
peripheral blood 
• 
Immunological phenotyping to verify myeloid leukemia. Additional immunological 
phenotyping and/or MRD will be performed/done at the investigator’s discretion, 
for relapsed and/or for response confirmation 
• 
Cytogenetics (gene expressions, gene mutations, cell culture and banding 
analysis) - a local laboratory may perform cytogenetics to determine eligibility at 
screening. Previous bone marrow aspirate or biopsy performed within 6 months 
of day 1 may be used to determine eligibility for subjects. A bone marrow biopsy 
or aspirate will still be required during screening for all subjects.  
• 
Additional cytogenetics will be performed/done at the investigator’s discretion, for 
relapsed and/or for response confirmation. 
• 
Bone marrow biopsy for histopathology in case of dry tap 
Additional bone marrow sampling may occur at other time points at the investigator’s 
discretion as clinically indicated. Unscheduled bone marrow aspirate results will be 
captured in the respective eCRFs. 
7.2.12.1 
Disease Response in AML Subjects 
Disease response assessments will be based upon review of bone marrow aspirates, 
and peripheral blood count. Refer to the 2017 ELN criteria in Appendix J for additional 
details. Complete response/complete recovery with incomplete count recovery (CRi) 
must be established from a 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. 
7.2.13 
Pharmacokinetic Blood Sampling 
For pharmacokinetic assessment blood samples for quantitative determination of 
AMG 397, will be collected at time points specified in the Schedule of Assessments 
(Section 7.1). Sample collection, processing, storage, and shipping instructions are 
provided in a separate laboratory manual.  
7.2.14 
Blood Samples 
Approximate blood volumes expected to be collected during study participation 
(screening, treatment period of 6 months, and EOT/SFU visits) are presented in the 
tables below. 
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Table 6.  Approximate Blood Volumes Collected for MM Subjects Only 
 
 
No Lead-In Dosing 
With Lead-In Dosing 
Test 
Volume 
(mL) per 
Collection 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
CBC with diff 
4  
18 
72 
21 
84 
Chemistry 
• 
Pregnancy test 
(childbearing 
females only) 
8.5 
25 
212.5 
33 
280.5 
Coagulation  
3 
18 
54 
21 
63 
Serology (HIV, Hepatitis 
panel) 
5  
1 
5  
1 
5 
Quantitative 
Immunoglobulin  
10  
2 
20 
2 
20 
Blood samples for 
biomarkers 
5  
9 
45 
16 
80 
Blood samples for PK  
5  
20 
100 
32 
160 
Beta-2 microglobulin, 
SPEP and SFLC 
10  
7 
70 
7 
70 
Total approximate blood volume  
520 
 
762.5 
Table 7.  Approximate Blood Volumes Collected for NHL Subjects Only 
 
 
No Lead-In Dosing 
With Lead-In Dosing 
Test 
Volume 
(mL) per 
Collection 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
CBC with diff 
4  
18 
72 
21 
84 
Chemistry 
• 
Pregnancy test 
(childbearing 
females only) 
8.5 
25 
212.5 
33 
280.5 
Coagulation  
3 
18 
54 
21 
63 
Serology (HIV, Hepatitis 
panel) 
5  
1 
5  
1 
5 
Blood samples for 
biomarkers 
5  
9 
45 
16 
80 
Blood samples for PK  
5  
20 
100 
32 
160 
Total approximate blood volume for dose escalation 
488.5 
 
672.5 
Whole blood plasma 
(Dose expansion subjects 
only) 
5 
5 
25 
5 
25 
Total approximate blood volume for dose expansion 
513.5 
 
697.5 
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Table 8.  Approximate Blood Volumes Collected for AML Subjects Only 
 
 
No Lead-In Dosing 
With Lead-In Dosing 
Test 
Volume 
(mL) per 
Collection 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
CBC with diff 
4  
18 
72 
21 
84 
Chemistry 
• 
Pregnancy test 
(childbearing 
females only) 
8.5 
25 
212.5 
33 
280.5 
Coagulation  
3 
18 
54 
21 
63 
Serology (HIV, Hepatitis 
panel) 
5  
1 
5  
1 
5 
Blood samples for 
biomarkers 
5  
9 
45 
16 
80 
Blood samples for PK  
5  
20 
100 
32 
160 
Total approximate blood 
volume 
 
 
488.5 
 
672.5 
7.2.15 
Clinical Laboratory Assessments 
The following laboratory analytes in Table 9 will be assessed as specified in the 
Schedule of Assessments (Section 7.1) collected by standard laboratory procedures. 
Table 9.  Clinical Laboratory Assessments 
Chemistry 
Hematology  
Urinalysis 
Coagulation  
For MM Subjects 
only: 
SPEP 
UPEP 
SFLC 
Quantitative 
Immunoglobulin 
Beta-2 
microglobulin 
 
For NHL subjects 
only: 
Whole blood 
plasma  
Lymph node 
biopsy 
 
Albumin 
ALP 
ALT 
AST 
Bicarbonate 
BUN or Urea 
Calcium 
Chloride 
Creatinine 
Direct bilirubin 
GGT 
Glucose 
LDH 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Total bile acid 
Uric acid 
Haptoglobin 
ANC 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
Platelets 
RBCs  
WBCs 
Differential: 
 
Neutrophils  
 
Lymphocytes 
 
Monocytes  
 
Eosinophils 
 
Basophils 
Specific gravity 
pH 
Blood 
Protein 
Ketones 
Bilirubin 
Glucose 
Leucocytes 
esterase (WBC) 
Microscopic exam 
(only needed for 
positive dipstick 
and should include 
the following): 
Epithelial, 
Bacteria, Casts, 
Crystal, RBCs, 
WBCs 
PT or INR 
Activated Partial 
Thromboplastin Time 
(APTT) 
 
Other Labs 
Pregnancy 
Hep B surface antigen 
Hep B antibody 
Hep C antibody 
HCV PCR (if 
applicable) 
HBV PCR (if 
applicable) 
 
PK (including urine for 
analysis) 
Biomarker analytes 
(See Section 7.3) 
Bone marrow aspirate 
as applicable 
Bone marrow biopsy 
as applicable 
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7.3 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to AMG 397 or protocol required therapies. Amgen may attempt to develop test(s) 
designed to identify subjects most likely to respond positively or negatively to AMG 397 
to investigate and further understand the importance of the intrinsic apoptotic pathway 
family members in heme malignancies. 
Biomarker development may be pursued by use of advanced biochemical analyses in 
blood, bone marrow, or tumor tissue samples, encompassing proteomic methods, 
genomic sequencing, or ribonucleic acid transcript profiling. Biomarkers such as 
pro-survival family members will be explored (eg, MCL1, BCL2, and BCL2L1 
expression), as well as the larger family of apoptosis pathway proteins, chromosomal 
aberrations and translocations, somatic mutations, molecularly defined disease 
subgroups,  and analysis of minimal residual disease. 
Please NOTE: Sample collection, processing, storage, shipping instructions and 
schedules are provided in a separate laboratory manual. 
7.3.1 
Blood Samples 
Whole blood samples are to be collected for biomarker measurement at several time 
points as listed in the schedule of assessments. The first set of samples will be collected 
for Flow cytometric analysis to measure the increase in BAX and Caspase 3 activity in 
circulating monocytes (MM, NHL) or peripheral blasts (AML) following treatment with 
AMG 397.  
Initially, these blood samples will be collected on Cycle 1 pre-dose on day 1, 3 and 5 
hours post-dose on day 1, as well as pre-dose on day 2 according to Table 4. If Lead-in 
dosing is initiated due to TLS symptoms, additional samples will be collected for 
remaining subjects according to Table 5 as follows: Cycle 1 pre-dose on Days 1 and 
2, 3 and 5 hours post-dose on Day 1, as well as pre-dose on Days 8 and 9, 3 and 
5 hours post-dose on Day 8. 
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In AML subjects, these whole blood samples may also be used to measure pro-survival 
family members (such as MCL1, BCL2, and BCL2L1 expression) in peripheral leukemic 
blasts.  
A second set of biomarker blood collections will be used to monitor cell counts of 
immune cell subsets, including T cells, B cells, NK cells, monocytes, and Myeloid 
Derived Suppressor Cells (MDSCs) following treatment with AMG 397. Initially, these 
samples will be collected on Cycle 1 pre-dose on days 1, 2, 3, 4, and 8 according to 
Table 4 above. If Lead-in dosing is initiated due to TLS symptoms, additional samples 
will be collected for remaining subjects according to Table 5 as follows: Cycle 1 pre-dose 
on days 1, 2, 3, 4, 8, 9, 10, and 15. 
For NHL subjects in Part 2 during dose expansion, additional whole blood samples may 
be taken to assess clinical responses through depth of minimal residual disease status 
as indicated in schedule of assessments. 
7.3.2 
Bone Marrow 
During screening, bone marrow aspirates are required for all subjects. A core bone 
marrow biopsy is required for all multiple myeloma subjects. Samples may be analyzed 
for protein expression and activity using immunohistochemistry and/or flow cytometry, 
and RNA transcript expression using platforms including Nanostring, RNA sequencing, 
and/or droplet digital PCR. Analyses of tumor specific mutations or epigenetic changes 
may be performed using FISH, array technologies or next generation sequencing. In 
Part 2, minimal residual disease may be evaluated on additional bone marrow 
specimens as indicated in the schedule of assessments (Table 4. and/or Table 5) in MM 
and AML subjects. 
7.3.3 
Tumor Biopsy 
For NHL subjects, a tumor biopsy at the primary lymph node site is required at 
screening. An additional tumor biopsy may be collected at time of relapse per 
institutional guidelines and PI discretion.  
Protein expression of pro-survival family members (such as MCL1, BCL2, and BCL2L1) 
will be analyzed via immunohistochemical methods. Genomic and RNA transcriptional 
analyses may be further performed including but not limited to FISH, and determination 
of MRD by NGS. 
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7.4 
General Study Procedures 
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. 
7.4.1 
Screening  
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Section 7.1). 
• 
Confirmation that the Informed Consent Form has been signed  
• 
Demographic data including sex, age, race, and ethnicity 
• 
Clinical evaluations include physical exam, ECOG status, and weight.  Medical and 
surgical history, and height need only be collected at the screening visit. 
• 
Vital signs (eg, blood pressure, heart rate, respiratory rate, temperature) 
• 
Laboratory Assessments including local and central laboratories, as applicable  
• 
Pregnancy test as applicable 
• 
Bone marrow aspirate or biopsy as applicable 
• 
Biopsy Assessments, as applicable 
• 
Imaging Assessments, as applicable 
• 
ECG  
• 
ECHO/MUGA 
• 
For NHL subjects, MRI brain (See Section 7.2.11.2) 
• 
Serious Adverse Event reporting 
• 
Documentation of concomitant and rescue medications 
Subjects may be rescreened at the discretion of the investigator after consultation with 
the Amgen Medical Monitor.  Refer to Section 5 for instructions on rescreening and 
enrolling subjects. 
7.4.2 
Treatment 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Section 7.1).  Administration of AMG 397 is 
to be administered as applicable during each visit that it is required. 
Treatment visits to include the following: 
• 
Hospitalization (See Section 6.5.7) 
• 
TLS prophylaxis (See Section 6.5.7) 
• 
Clinical evaluations will be collected pre-dose on dosing days and include: physical 
exam, ECOG status, and weight.   
• 
AMG 397 dosing 
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• 
Dosing diary review 
• 
PK (including intensive PK assessments) 
• 
ECG 
• 
Vital signs (eg, blood pressure, heart rate, respiratory rate, temperature) 
• 
Laboratory assessments including local and central laboratories, as applicable 
• 
Pregnancy tests, as applicable 
• 
Bone marrow aspirate or biopsy as applicable 
• 
Biopsy Assessments, as applicable 
• 
Imaging Assessments, as applicable  
• 
Disease assessments, as applicable 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.4.3 
End of Treatment Visit 
The end of treatment (EOT) visit will occur after the last dose of AMG 397. The end of 
treatment (EOT) visit will occur upon the decision to end the treatment, disease 
progression, intolerable adverse event, documented clinical progression or consent 
withdrawal.  
For subjects who choose to discontinue investigational product treatment, the EOT visit 
should occur as soon as possible after the last dose of investigational product is 
administered. Serious adverse events considered related to the investigational product, 
by the Investigator, or Amgen will be followed until resolved or considered stable. 
EOT visits to include the following: 
• 
Clinical evaluations include: physical exam, ECOG status, and weight.   
• 
Dosing diary review 
• 
PK  
• 
ECG 
• 
Vital signs (eg, blood pressure, heart rate, respiratory rate, temperature) 
• 
Laboratory assessments including local and central laboratories, as applicable 
• 
Pregnancy tests, as applicable 
• 
Bone marrow aspirate or biopsy as applicable 
• 
Biopsy Assessments, as applicable 
• 
Imaging Assessments, as applicable  
• 
Disease assessments, as applicable 
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• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.4.4 
Safety Follow-Up (SFU) Visit 
The SFU visit must be performed approximately 28 (+7) days after the last dose of 
AMG 397. All efforts should be made to conduct this visit. If it is not possible to conduct 
the SFU visit, documentation of efforts to complete the visit should be provided in the 
source documents and noted as not done in the eCRFs. 
• 
Clinical Evaluation 
• 
ECG  
• 
Visit signs (eg, blood pressure, heart rate, respiratory rate, temperature) 
• 
Laboratory assessments  including local and central laboratories, as applicable 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.4.5 
Long-term Follow-up (Dose expansion subjects only) 
Long-term follow up (LTFU) will be conducted every 3 months from the last visit for up to 
1 year from the first dose of AMG 397 for all subjects who have not withdrawn consent 
by telephone or chart review to assess for survival, disease progression and/or the 
commencement of subsequent cancer therapy only.  
7.5 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, 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 investigation of MM, NHL and/or 
AML and to identify subjects who may have positive or negative response to AMG 397.  
No additional samples are collected for this part of the study.  
7.6 
Sample Storage and Destruction 
Any blood, bone marrow or tumor sample collected according to the Schedule of 
Assessments (Section 7.1) can be analyzed for any of the tests outlined in the protocol 
and for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
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study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
Multiple Myeloma, NHL, and AML, disease indications, the dose response and/or 
prediction of response to AMG 397, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development, or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the Investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, bone marrow, 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. 
Amgen is the exclusive owner of any data, discoveries, or derivative materials from the 
sample materials and is responsible for the destruction of the sample(s) at the request of 
the subject through the investigator, at the end of the storage period, or as appropriate 
(eg, the scientific rationale for experimentation with a certain sample type no longer 
justifies keeping the sample).  If a commercial product is developed from this research 
project, Amgen owns the commercial product.  The subject has no commercial rights to 
such product and has no commercial rights to the data, information, discoveries, or 
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derivative materials gained or produced from the sample. See Section 11.3 for subject 
confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product, device or other 
protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments (Section 7.1) including different options of 
follow-up (eg, in person, by phone/mail, through family/friends, in 
correspondence/communication with other treating physicians, from the review of 
medical records) and collection of data, including endpoints, adverse events, and 
disease related events, as applicable.  Subjects who have discontinued investigational 
product and/or protocol required therapies or procedures should not be automatically 
removed from the study.  Whenever safe and feasible it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data.  The 
investigator must document the level of follow-up that is agreed to by the subject.  
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, and/or other protocol required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
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local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor  
• 
disease progression 
• 
protocol specified criteria 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study, or involves 
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an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.  
Record a single event for each increased level of severity on the Event eCRF.   
For situations when an adverse event or serious adverse event is due to Multiple 
Myeloma or Non-Hodgkin’s Lymphoma report all known signs and symptoms.  Death 
due to disease progression in the absence of signs and symptoms should be reported as 
the primary tumor type (eg, multiple myeloma). 
Note:  The term “disease progression” should not be used to describe the adverse 
event.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
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9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of Safety Follow-Up(SFU)/end of study (EOS) visit are reported 
using the Event eCRF. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity [and/or toxicity per protocol], 
• 
Assessment of relatedness to investigational product, and 
• 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.  The grading scale used in this study is 
described in Appendix A.  The investigator must assess whether the adverse event is 
possibly related to the investigational product. This relationship is indicated by a “yes” or 
“no” response to the question:  Is there a reasonable possibility that the event may have 
been caused by the investigational product?  If the severity of an adverse event changes 
from the date of onset to the date of resolution, record a single event for each increase 
in level of severity on the Adverse Event Summary eCRF. 
The investigator must assess whether the adverse event is possibly related to any study 
mandated activity (eg, administration of investigational product, protocol-required 
therapies, use of medical device(s) and/or procedure (including any screening 
procedure(s)).  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by a study 
activity (eg, administration of investigational product, protocol-required therapies, use of 
medical device(s)), and/or procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the Investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
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or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval of investigational 
product are recorded in the subject’s medical record and are submitted to Amgen.  All 
serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event eCRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event. See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form. 
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product. This relationship is indicated by a “yes” or “no” response to 
the question: Is there a reasonable possibility that the event may have been caused by 
the investigational product?  Relatedness means that there are facts or reasons to 
support a relationship between investigational product and the event.  
The investigator is expected to follow reported serious adverse events until stabilization, 
resolution or patient death. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
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Information provided about the serious adverse event must be consistent with that 
recorded on the Event eCRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event.  
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking AMG 397 report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 3 months after the last dose of AMG 397. 
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The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur through 3 months after the last dose of protocol-required 
therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
Primary Endpoints: 
• 
Incidence of dose limiting toxicities (DLTs), treatment-emergent adverse events, 
treatment-related adverse events, and clinically-significant changes in vital signs, 
physical examinations, electrocardiogram (ECGs) and clinical laboratory tests 
Secondary Endpoints: 
• 
Efficacy parameters: 
o ORR using response criteria per the following: 
 
International Myeloma Working Group (IMWG) for MM subjects 
 
Lugano Classification for NHL subjects  
 
Revised International Working Group (IWG) for AML subjects 
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• 
Duration of response 
• 
Progression Free Survival (PFS) and Overall Survival (OS)  
• 
 AMG 397 PK parameters including, but not limited to, maximum observed 
concentration (Cmax), time of maximum observed concentration (Tmax), area under the 
concentration-time curve (AUC), clearance (CL) and half-life (t1/2)  
Exploratory Endpoints: 
• 
AMG 397 exposure/efficacy and exposure/safety relationships 
• 
AMG 397 metabolites in plasma and urine  
• 
Increased expression of BAX and Caspase 3 in monocytes or blast cells and/or 
decrease in circulating monocyte counts 
• 
Patient responses according to biomarkers of tumor cells including but not limited to 
protein levels of pro-survival family members, FISH/cytogenetic analysis, gene 
expression profiling, flow cytometric phenotyping and DNA sequencing 
• 
Immune cell subset frequencies, absolute counts and MFIs in peripheral blood 
• 
MRD status 
10.1.1 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 397.  The analysis of DLT will be restricted to DLT-evaluable subjects 
(see Section 6.2.1.1.1).  The PK Analysis Set will contain all subjects who have received 
at least 1 dose of AMG 397 and have at least 1 PK sample collected.  These subjects 
will be evaluated for PK analysis unless the number of data points required for analysis 
is not enough, or significant protocol deviations have affected the data, or if key dosing 
or sampling information is missing. 
10.2 
Covariates and Subgroups 
The relationship between baseline covariates and safety/efficacy endpoints will be 
explored. Safety and efficacy endpoints will be summarized separately for each tumor 
type. Details regarding covariates and subgroups and respective analyses are described 
in the Statistical Analysis Plan.   
10.3 
Sample Size Considerations 
Up to 90 subjects will be enrolled in the study.  Up to 60 subjects will be enrolled during 
dose escalation (up to 30 in both Group 1A and 1B).  Up to 30 subjects will  be enrolled 
into the dose expansion part (up to 10 in each Group 2A, 2B & 2C). 
The sample sizes are based on practical considerations and it is consistent with 
conventional oncology studies with the objective to identify the MTD. During 
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dose-escalation and 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%. With 10 subjects 
respectively in in dose expansion group, there is a 40% to 65% probability of observing 
at least 1 adverse event if the true event rate is 5% to 10%.  Exact 80% binomial CI will 
be provided for ORR.  With the 10 subjects in each dose expansion group and a 
20% ORR, the 80% CI would be 5% to 45%.  
10.4 
Adaptive Design 
A 2-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
escalation.  The MTD target Toxicity Probability Interval (TPI) for DLT is (0.20, 0.33] and 
TPIs of (0.33, 0.60] and (0.60, 1.00] are defined as excessive and unacceptable, 
respectively.  The design seeks to identify a dose most likely to have a DLT rate in the 
target TPI, but with overdose control that limits the possibility the dose has an excessive 
or unacceptable DLT rate (Babb et al, 1998). The overdose control limit is defined as 
less than a 0.40 probability of an excessive or unacceptable TPI. Based on accumulating 
safety data, the DLRT may implement an overdose control limit of less than a 
0.25 probability of an excessive or unacceptable TPI. The probability of a DLT at dose 
level di is assumed to follow a Bernoulli distribution with probability pi where the logit of pi 
increases linearly with the log of the standardized dose in the following 2-parameter 
logistic model: 
 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is 1 of the planned dose selected as the 
reference dose.   
A bi-variate normal prior distribution (Neuenschwander et al, 2008) is used for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose of 80 mg is 0.90 and the probability the true DLT rate is ≤ 0.05 at the 
reference dose of 640 mg is 0.05.  These values are selected such that pi is 0.05 for the 
starting dose and 0.25 for the reference dose. Model sensitivity to the prior will also be 
investigated and in particular the BLRM will be examined using a prior having a lower 
reference dose (eg, 320 mg). Operating characteristics for this BLRM design are 
described in Appendix D. 
During dose expansion, Amgen will conduct evaluations of the ongoing grade 4 or higher 
adverse event rate to assess if the threshold for early trial termination has been reached. 
The stopping rules use a Bayesian approach proposed by Thall, et al (1995) to terminate 
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the study if the posterior probability that the grade 4 or higher adverse event rate is 
greater than 20% is > 90%. The stopping boundaries assuming a prior distribution of 
Beta (0.40, 1.60) are presented in Table 10 and the operating characteristics with 
pre-specified batch size of 10 new subjects per batch are presented in Table 2. Subjects 
including in a batch may come from different tumor types. The evaluations could occur 
more frequently if necessary to address emerging safety concerns. The operating 
characteristics in Table 11 provide the probability of stopping the study early for given 
hypothetical true rate of grade 4 or higher adverse events, whereas the stopping criteria 
in Table 10 are based on situations where the empirical evidence would result in a 
posterior probability of ≥ 90% that the true grade 4 or higher adverse event rate is 
≥ 20%. 
Table 10.  Stopping Boundary for Dose Expansion With Posterior Probability of 
90% and Grade 4 or Higher Adverse Event Limit of 20% 
Number of subjects 
Stop study if observing these many grade 4 or higher adverse 
events 
10 
≥5 
20 
≥7 
30 
Study Complete 
Table 11.  Operating Characteristics With Batch Size of 10 Subjects 
True grade 4 or higher 
adverse event rate 
Probability of early stopping of 
dose expansion 
Average dose expansion 
sample size 
0.10 
0.4% 
29.9 
0.15 
2.7% 
29.6 
0.20 
9.7% 
28.7 
0.25 
22.9% 
26.9 
0.30 
40.8% 
24.4 
10.5 
Planned Analyses 
10.5.1 
Interim Analyses 
Safety data will be reviewed on an ongoing basis.  Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations.  In dose level review 
team meetings (DLRMs), Amgen, in consultation with the site investigators, will review 
the BLRM recommended dose level and will review all available cumulative data by 
cohort prior to making dose escalation decisions.  As a sensitivity analysis, a 
one-parameter Continual Reassessment Method (CRM) model may be used to estimate 
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the dose-toxicity relationship to help making dose escalation decisions.  Adverse events 
and DLTs observed in all subjects will be evaluated continually and fully integrated into 
all DLRMs and considered in all enrollment and dosing decisions.  
An interim analysis for efficacy parameters will be conducted after dose escalation is 
completed.   
10.5.2 
Dose Level Review Team (DLRT) 
After reviewing all available safety data and reviewing the dose recommendation from 
the BLRM, the DLRT will make all dose level and dosing schedule decisions. Details 
regarding the DLRT and the process for making dosing decisions are described in 
Section 6.2.1.2. 
10.5.3 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or withdraws from the study.   
10.5.4 
Final Analysis 
The final analysis will occur after all subjects have ended the study.    
10.6 
Planned Methods of Analysis 
10.6.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic and biomarker data by tumor type, 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.  
10.6.2 
Primary Endpoints 
Safety Endpoints: 
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the safety analysis set, which includes subjects that are enrolled and 
received at least 1 dose of AMG 397. 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels. 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  The number and percentage of subjects reporting 
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adverse events will be evaluated overall and by dose level and will also be tabulated by 
relationship to study drug. 
Tables of adverse events, fatal adverse events, serious adverse events, adverse events 
leading to withdrawal from investigational product or other protocol-required therapies, 
and significant treatment-emergent adverse events will also be provided. 
Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each 
subject.  Values outside the normal laboratory reference ranges will be flagged as high 
or low on the listings.  Depending on the size and scope of changes in laboratory data, 
summaries of laboratory data over time and/or changes from baseline over time may be 
provided.  Tables of maximum shifts from baseline for selected laboratory values may 
also be provided. 
Vital Signs 
Vital signs data will be listed and reviewed for each subject.  Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline 
over time may be provided. 
Electrocardiograms 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects’ maximum change from baseline in QT interval corrected by 
Fridericia’s formula will be categorized and the number and percentage of subjects in 
each group will be summarized. Subjects’ maximum post baseline values will also be 
categorized and the number and percentage of subjects in each group will be 
summarized. All on-study ECG data will be listed, and select parameters of interest may 
be plotted.  
10.6.3 
Secondary Endpoints 
10.6.3.1 
Efficacy Endpoint Analyses 
The analyses on PFS and OS will be done only using data from dose expansion 
subjects; other efficacy endpoints will be analyzed using data from both dose escalation 
and dose expansion.  
The number and percentage of subjects by overall response and overall response 
category will be calculated and tabulated.  Using the Kaplan Meier estimate, the PFS at 
6 and 12 months and the OS at 6 and 12 months with corresponding 90% CI will be 
tabulated.  Listings will be produced for all subjects indicating the OS, PFS, time to 
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response and duration of response.  Kaplan Meier curve will be presented for OS, PFS, 
time to response and duration of response with estimates for rates and 80% CI at 
selected weeks. 
10.6.3.2 
Pharmacokinetics Data Analysis 
For AMG 397, PK parameters including including Cmax, Tmax, AUC, CL and half-life will be 
determined from the time-concentration profile using standard non-compartmental 
approaches and considering the profile over the complete sampling interval.  Based on 
the review of the data, analyses to describe the relationship between AMG 397 exposure 
and either pharmacodynamic effects and/or clinical outcome may also be performed. 
10.6.4 
Exploratory Endpoints 
The following statistical analyses will be considered exploratory and will be performed 
only when deemed appropriate. 
Summary statistics over time will be provided and graphical presentations may be used 
to describe the following. 
• 
AMG 397 exposure/efficacy and exposure/safety relationships 
• 
AMG 397 metabolites in plasma and urine  
• 
Increased expression of BAX and Caspase 3 in monocytes or blast cells and/or 
decrease in circulating monocyte counts 
• 
Patient responses according to biomarkers of tumor cells including but not limited 
to protein levels of pro-survival family members, FISH/cytogenetic analysis, gene 
expression profiling, flow cytometric phenotyping and DNA sequencing 
• 
Immune cell subset frequencies, absolute counts and MFIs in peripheral blood 
• 
MRD status 
The relationship between AMG 397 exposure and PD effects and related biomarkers in 
blood, or tumor specimens and/or AMG 397 exposure and clinical outcomes (eg, tumor 
response) will be also explored if deemed appropriate. Based on the review of the safety 
and efficacy data, analyses to describe the relationship between AMG 397 exposure and 
safety/efficacy endpoints may also be performed.  
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Study Manager to the investigator.  
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The written informed consent form is to be prepared in the language(s) of the potential 
subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician  is 
to be documented in the subject’s medical records, and the informed consent form is to 
be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject. 
If a potential subject is illiterate or visually impaired, 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.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
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document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below. 
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
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Elements to include: 
• 
Subject files containing completed eCRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, 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. 
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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
• 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the eCRF, the data queries, and agrees with the content. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the eCRF Standard 
Instructions and the eCRF Specific Instructions, both of these will be available through 
the EDC system.  Examples of obvious data errors that may be corrected by Amgen 
(or designee) include deletion of obvious duplicate data (ie, the same results sent twice 
with the same date with different visit, [eg, week 4 and early termination]) and updating a 
specific response if the confirming datum is provided in the “other, specify” field 
(eg, for race, reason for ending study). 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Section 7.1), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
eCRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.   
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
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12.6 
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 Publication of Scholarly Work in Medical 
Journals, which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, and 3 and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
Additional information on the current guidelines for publications can be found at the 
following location:  http://www.icmje.org/  
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
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12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
AMG 397 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, 
Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 
19;127(20):2391-405. 
Ardeshna KM, et al. Conventional second-line salvage chemotherapy regimens are not 
warranted in patients with malignant lymphomas who have progressive disease after 
first-line salvage therapy regimens. Br J Haematol. 2005;130(3):363-372. 
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Statistics in medicine. 1998: 17(10):1103-1120 
Beroukhim R, Mermel CH, Porter D, et al. The landscape of somatic copy-number 
alteration across human cancers. Nature. 2010:463:899-905. 
Bose P and Grant S. Mcl-1 as a therapeutic target in acute myelogenous leukemia 
(AML). Leukemia Research Reports;2013;2(1):12-14. 
Boyle MC, Crabbs TA, Wyde ME, et al.  Intestinal lymphangiectasis and lipidosis in rats 
following subchronic exposure to indole-3-carbinol via oral gavage.  Toxicol Pathol.  
2012;40:561-562. 
Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with 
acute myeloid leukemia in first relapse. J Clin Oncol 2005;23:1969-78. 
Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J 
Clin Oncol 2011a;29:487-94. 
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and 
classification. Br J Haematol. 2004;127(1):3-11. 
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):2767-78. 
Crump M, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin 
versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous 
stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG 
LY.12. J Clin Oncol. 2014;32(31):3490-3496. 
Czabotar PE, Lessene G, Strasser A and Adams JM. Control of apoptosis by the BCL-2 
protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 
2014:15;49-63. 
DeVita VT Jr, et al. Advanced diffuse histiocytic lymphoma, a potentially curable 
disease. Lancet. 1975;1(7901):248-50. 
Dimopoulos MA, Richardson PG, Moreau P, Anderson KC.  Current treatment 
landscape for relapsed and/or refractory multiple myeloma.  Nat Rev Clin Oncol.  
2015;12:42-54. 
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, 
Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele 
GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European 
LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74.  
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Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid 
leukemia in adults: 2017 ELN recommendations from an international expert panel, on 
behalf of the European LeukemiaNet. Blood 2017;129(4):424-447. 
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. 
International Myeloma Working Group. International uniform response criteria for 
multiple myeloma. Leukemia. 2006;20(9):1467–73. Erratum in: Leukemia. 
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. 
Elstrom RL, et al. Response to second-line therapy defines the potential for cure in 
patients with recurrent diffuse large B-cell lymphoma: implications for the development of 
novel therapeutic strategies. Clin Lymphoma Myeloma Leuk. 2010;10(3):192-196.  
Estey E. Acute myeloid leukemia: 2016 Update on risk-stratification and management. 
Am J Hematol. 2016 Aug;91(8):824-46.  
Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 
2000;14:476-9. 
Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M. A stratification system 
for evaluating and selecting therapies in patients with relapsed or primary refractory 
acute myelogenous leukemia. Blood 1996;88:756 
Fisher SG and Fisher RI. The Epidemiology of Non-Hodgkin's Lymphoma. Oncogene. 
2004;23(38):6524-534. 
Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, et al. "Anti-apoptotic Mcl 
1 is essential for the development and sustained growth of acute myeloid leukemia." 
Genes & Development 2012; 26(2): 120-125. 
Haematological Malignancy Research Network.https://www.hmrn.org/statistics/incidence 
Hanahan D and Weinberg RA. "Hallmarks of Cancer: The Next Generation." Cell 2011; 
144(5): 646-674. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013. http://www.icmje.org/ 
Kasper S, Breitenbuecher F, Heidel F, Hoffarth S, Markova B, Schuler M and Fischer T 
“Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies” Blood 
Cancer J 2012; 2, e60. 
Kaufmann SH, Karp JE, et al. "Elevated Expression of the Apoptotic Regulator Mcl-1 at 
the Time of Leukemic Relapse”. Blood 1998; 91(3)991-1000. 
Kewalramani T, et al. Rituximab and ICE as second-line therapy before autologous stem 
cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. 
Blood. 2004;103(10):3684-3688. 
Kozopas KM, Yang T, Buchan HL, Zhou P, and Craig RW. MCL1, a gene expressed in 
programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl 
Acad Sci U S A. 1993:90;3516-3520. 
Martin A, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory 
diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. 
A GEL/TAMO study. Haematologica. 2008;93(12):1829-1836. 
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Neuenschwander B, Branson M, Gsponer T.  Critical aspects of the Bayesian approach 
to phase I cancer trials.  Statistics in Medicine.  2008;27(13):2420-2439 
Palumbo A, Anderson K. Multiple Myeloma. N Engl J Med 2011;364:1046-60 
Peperzak V, Vikström I, Walker J, Glaser SP, LePage M, Coquery CM, et al. "MCL1 is 
essential for the survival of plasma cells." Nat Immunol 2013; 14(3): 290-297. 
Philip T, et al. High-dose therapy and autologous bone marrow transplantation after 
failure of conventional chemotherapy in adults with intermediate-grade or high-grade 
non-Hodgkin's lymphoma. N Engl J Med. 1987;316(24):1493-1498. 
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-4695 
Ravandi F. Relapsed acute myeloid leukemia: why is there no standard of care? Best 
practice & research 2013;26:253-9. 
Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of patients with acute 
myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction 
chemotherapy. Blood 2010;116:5818-23; quiz 6153. 
Robinson SP, et al. Autologous stem cell transplantation for relapsed/refractory diffuse 
large B-cell lymphoma: efficacy in the rituximab era and comparison to first allogeneic 
transplants. A report from the EBMT Lymphoma Working Party. Bone Marrow 
Transplant. 2016;51(3):365-371. 
Sehn LH and Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the 
context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32.  
Smith D, Yong K. Multiple myeloma. BMJ. 2013 Jun 26;346:f3863. doi: 
10.1136/bmj.f3863. Review. 
Smith D, Yong K. Multiple Myeloma. BMJ 2013;346:f3863 doi: 10.1136/bmj.f3863. 
Society AC. Cancer Facts and Figures, 2017. Atlanta, George, USA: American Cancer 
Society; 2017. 
Strasser A, Cory S, and Adams JM. Deciphering the rules of programmed cell death to 
improve therapy of cancer and other diseases. Embo j. 2011:30;3667-3683. 
Swerdlow SH, et al. The 2016 revision of the World Health Organization (WHO) 
classification of lymphoid neoplasms. Blood. 2016 
Thall P, Simon R, Estey E. “Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes”, Statistics in Medicine, vol 14, 357-379 (1995). 
Thomas RL, Roberts DJ, Kubli DA et al.  Loss of MCL-1 leads to impaired autophagy 
and rapid development of heart failure.  Genes Devel.  2013;27:1365-1377. 
Tilly H, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):116-125. 
van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-
2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer 
Cell. 2006;10:389-399. 
Wang X, Bathina M, Lynch J, et al.  Deletion of MCL-1 causes lethal cardiac failure and 
mitochondrial dysfunction.  Genes Devel.  2013;27:1351-1364. 
Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is 
regulated by MCL1 and FBW7. Nature. 2011:471:110-114. 
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Witzig TE, et al. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin 
lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leuk 
Lymphoma. 2008;49(6):1074-1080. 
Xiang Z, Luo H, Payton J E, Cain J, Ley T J, Opferman J T, Tomasson M H. Mcl1 
haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin 
Investigation;2010;120(6):2109-2118. 
Youle, R. J. and A. Strasser. "The BCL-2 protein family: opposing activities that mediate 
cell death." Nat Rev Mol Cell Biol 2008; 9(1): 47-59. 
Zelenetz AD, et al. Non-Hodgkin’s Lymphomas, Version I.2016', National 
Comprehensive Cancer Network Guidelines.  
Ziepert M, et al. Standard International prognostic index remains a valid predictor of 
outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin 
Oncol. 2010;28(14):2373-2380. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE Version 4.03 is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm. 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.7 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.7.1 and Section 6.7.2 or who experience AST or ALT elevations > 3 x ULN or 
2-fold increase above baseline values for subjects with evaluated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
• 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
Complete blood count (CBC) with differential to assess for eosinophilia 
− 
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
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− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
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Appendix B.  eSerious Event Contingency Form 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
  
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Appendix D.  Operating Characteristics for 2-Parameter BLRM Design 
The operating characteristics of the two-parameter BLRM design were evaluated via 
simulation.  The cohort size was fixed to 2 or 4 subjects. The initial multiple subject dose 
level is 80 mg and subsequent doses were selected based on the following rules: 
After each cohort, the next dose is the one with the highest probability of the target TPI, 
subject to the overdose control limits.  
Dose escalation was stopped given 1 or more of the following conditions: 
• 
There have been at least 6 subjects treated at the dose recommended by the model. 
• 
A maximum number of 30 subjects are evaluated  
A total of 6 dose levels (unit:  mg) were considered:  80, 160, 240, 320, 480, 640 in 
these simulations of the multiple subject cohorts (80, 160, 320 and 640 are planned 
dose levels with 240 and 480 possible intermediate dose levels). 
The design was evaluated for 3 possible dose-response scenarios:  “Low”, “Mid”, and 
“High” MTD.  Table 1 shows the dose level and true probability of DLT for each scenario 
used in the simulated studies estimating the MTD. Table 2 and Table 3 report the 
operating characteristics from 1,000 simulated studies estimating the MTD when the 
target TPI is (0.20, 0.33]; Table 2 reports characteristics when the overdose control limit 
is 0.40 probability of an excessive or unacceptable TPI while Table 3 reports a limit of 
0.25 probability of an excessive or unacceptable TPI.  
Table 1.  True Probability of DLT by Scenario for Simulated Studies 
Estimating MTD 
Dose Level 
80 
160 
240 
320 
480 
640 
MTD Scenario 
 
 
 
 
 
 
High 
0.04 
0.08 
0.11 
0.18 
0.25 
0.33 
Mid 
0.06 
0.11 
0.18 
0.25 
0.33 
0.45 
Low 
0.09 
0.18 
0.25 
0.33 
0.45 
0.55 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
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Table 2.  Operating Characteristics by Scenario for Simulated Studies Estimating 
the MTD When the Target TPI is (0.20, 0.33) 
Overdose Control Limit is 0.40 Probability of an Excessive or Unacceptable TPI 
MTD Scenario 
High 
Mid 
Low 
 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
Number of Subjects 
 Median (IQR) 
24 
(20 to 28) 
16 
(12 to 18) 
24 
(20 to 28) 
16 
(14 to 18) 
24 
(20 to 28) 
16 
(14 to 18) 
Number of DLTs 
 Median (IQR) 
4 
(3 to 5) 
3 
(2 to 4) 
5 
(4 to 6) 
4 
(3 to 5) 
6 
(4 to 7) 
4 
(3 to 6) 
Proportion of DLT (%) 
 Median (IQR) 
18 
(13 to 21) 
19 
(14 to 25) 
21 
(19 to 25) 
25 
(19 to 29) 
25 
(21 to 30) 
29 
(25 to 33) 
Percentage of studies recommending dose with DLT probability of: 
 ≤ 10%  
2.7 
3.3 
4.2 
4.5 
9.3 
12.2 
 > 10% and ≤ 20% 
23.4 
19.7 
12 
10.7 
17.5 
13.5 
 > 20% and ≤ 33% 
73.9 
77.0 
72.4 
66.7 
57.2 
50.7 
 > 33% 
0 
0 
11.4 
18.1 
16.0 
23.6 
Probability of 
identifying MTD to 
have 15% to 33% DLT 
probability 
94.8 
95.0 
80.3 
72.6 
74.7 
64.2 
DLT = dose-limiting toxicity; IQR = interquartile range; MTD = maximum tolerated dose; TPI = toxicity 
probability interval. 
EAST version 6.4 software used to generate 1,000 simulated clinical trials for each scenario. 
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Table 3.  Operating Characteristics by Scenario for Simulated Studies Estimating 
the MTD When the Target TPI is (0.20, 0.33) 
Overdose Control Limit is 0.25 Probability of an Excessive or Unacceptable TPI 
MTD Scenario 
High 
Mid 
Low 
 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
4 subjects 
per cohort 
2 subjects 
per cohort 
Number of Subjects 
 Median (IQR) 
24 
(20 to 28) 
14 
(12 to 16) 
24 
(20 to 28) 
14 
(12 to 18) 
20 
(16 to 24) 
14 
(10 to 18) 
Number of DLTs 
 Median (IQR) 
4 
(3 to 5) 
3 
(2 to 3) 
4 
(3 to 6) 
3 
(2 to 4) 
5 
(4 to 6) 
3 
(2 to 5) 
Proportion of DLT (%) 
 Median (IQR) 
17 
(13 to 21) 
19 
(14 to 25) 
20 
(17 to 25) 
22 
(18 to 29) 
25 
(20 to 29) 
28 
(22 to 36) 
Percentage of studies recommending dose with DLT probability of: 
 ≤ 10%  
4.7 
10.7 
5.3 
15.5 
16.9 
28.9 
 > 10% and ≤ 20% 
34.0 
30.7 
14.8 
11.7 
18.8 
14.2 
 > 20% and ≤ 33% 
61.3 
58.6 
72.2 
67.7 
54.5 
42.7 
 > 33% 
0 
0 
7.7 
5.1 
9.8 
14.2 
Probability of identifying 
MTD to have 15% to 33% 
DLT probability 
93.5 
87.9 
79.9 
72.9 
73.3 
56.9 
DLT = dose-limiting toxicity; IQR = interquartile range; MTD = maximum tolerated dose; TPI = toxicity 
probability interval. 
EAST version 6.4 software used to generate 1,000 simulated clinical trials for each scenario. 
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Appendix E.  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 measureable, and serum free light 
assay is also not measureable, ≥ 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 
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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 
2.65mmol/L) that can be attributed solely to the plasma cell proliferative 
disorder 
Page 2 of 2 
Source: Durie 2006; Rajkumar 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; 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 κ/λ ratio.  An abnormal κ/λ 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 κ/λ 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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Appendix F.  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 
1. Class I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea. 
2. Class II 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea. 
3. Class III 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation or dyspnea. 
4. 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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Appendix G.  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 for patients with Multiple Myeloma requires any one or more of 
the following: 
• 
Increase of ≥ 25% from lowest response value in any of the following 
o 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) 
o 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 patients with AML is defined as: 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute 
blast counts in the blood: 
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• 
> 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/uL], 
and/or platelet count to > 50 x 109/L [50,000/uL] nontransfused); or 
• 
>50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L 
(>25,000/uL) (in the absence of differentiation syndrome)†; or 
• 
New extramedullary disease 
Relapse after complete remission for patients 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 acute 
myeloid leukemia in adults: Recommendations from an international expert panel, on 
behalf of the European Leukemia Net" (Döhner et al, 2010). 
The criteria for progressive disease were suggested in the 2017 ELN recommendations 
(Döhner et al, 2017). 
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Appendix H.  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. Patients with APML are not eligible for this study.  
First, AML should be classified as AML with recurrent cytogenetic abnormalities. If this is 
not applicable the leukemia is classified as AML with multilineage dysplasia or therapy 
related and if this subtype is also not applicable as AML not otherwise categorized.  
Acute Myeloid Leukemia and Related Precursor Neoplasms, and Acute Leukemias of 
Ambiguous Lineage (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 
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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 
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. 
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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Appendix I.  Response Assessment per the Lugano Classification for NHL 
 
 
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Appendix J.  European Leukemia Network (ELN) Response Criteria in AML (2017) 
Category 
Definition 
Comment 
Response 
  
  
• CR without minimal residual 
disease (CRMRD-) 
If studied pretreatment, CR with negativity for a genetic marker 
Sensitivities vary by marker tested, and by method used; 
therefore, 
  
by RT-qPCR, or CR with negativity by MFC 
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 
MRD+ or unknown 
  
blasts with Auer rods; absence of extramedullary disease; 
  
  
ANC ≥ 1.0 x 109/L (1000/uL); platelet count  ≥ 100 x 109/L 
  
  
(100,000/uL) 
  
• CR with incomplete 
All CR criteria except for residual neutropenia (<1.0 x 109/L 
hematologic recovery (CRi) 
[1000/uL]) or thrombocytopenia (<100 x 109/L [100,000/uL]) 
• Morphologic leukemia-free 
Bone marrow blasts <5%; absence of blasts with Auer rods; 
Marrow should not merely be “aplastic”; at least 200 
state (MLFS) 
absence of extramedullary disease; no hematologic recovery 
cells should be enumerated or cellularity should be at least 10% 
  
required 
• Partial remission (PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
Especially important in the context of phase 1-2 clinical 
  
percentage to 5% to 25%; and decrease of pretreatment 
trials 
  
bone marrow blast percentage by at least 50% 
  
Treatment failure 
  
  
• Primary refractory disease 
No CR or CRi after 2 courses of intensive induction treatment; 
Regimens containing higher doses of cytarabine  
  
excluding patients with death in aplasia or death due to 
are generally considered as the best option for patients not 
  
indeterminate cause 
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 
Deaths occurring before completion of therapy, or < 7 d 
  
cause 
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 
  
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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 
Period of stable disease should last at least 3 mo 
  
not met 
  
• Progressive disease (PD)*,† 
Evidence for an increase in bone marrow blast percentage 
Category mainly applies for older patient given low intensity 
  
and/or increase of absolute blast counts in the blood: 
or single-agent “targeted therapies” in clinical trials. 
  
• >50% increase in marrow blasts over baseline (a minimum 
In general, at least 2 cycles of a novel agent should be 
administered. 
  
15% point increase is required in cases with < 30% blasts at 
Some protocols may require blast increase in 2 consecutive 
marrow 
  
baseline; or persistent marrow blast percentage of > 70% 
assessments at least 4 wk apart; the date of progression should 
  
over at least 3 mo; without at least a 100% improvement in 
then be defined as of the first observation date. 
  
ANC to an absolute level (> 0.5 x 109/L [500/uL], and/or 
  
platelet count to > 50 x 109/L [50,000/uL] nontransfused); or 
Some protocols may allow transient addition of hydroxyurea to 
  
• > 50% increase in peripheral blasts (WBC x % blasts) to 
lower blast counts. 
  
> 25 x 109/L (>25,000/uL) (in the absence of differentiation 
“Progressive disease” is usually accompanied by a decline in 
ANC 
  
syndrome)†; or 
and platelets and increased transfusion requirement 
  
• New extramedullary disease 
and decline in performance status or increase in symptoms. 
Relapse 
  
  
• Hematologic relapse 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the 
  
(after CRMRD-, CR, CRi) 
blood; or development of extramedullary disease 
  
• Molecular relapse 
If studied pretreatment, reoccurrence of MRD as assessed by 
Test applied, sensitivity of the assay, and cutoff values used 
must be 
(after CRMRD-) 
RT-qPCR or by MFC 
reported; analyses should be done in experienced laboratories 
  
  
(centralized diagnostics) 
Page 2 of 2 
ANC, absolute neutrophil count; IDH, isocitrate dehydrogenase; MLFS, morphologic leukemia-free state; WBC, white blood cell. 
* The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing the various definitions used in different clinical 
trials. 
† Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the 
percentage of bone marrow blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily 
indicate PD. 
 
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Appendix K.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
 
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Appendix L.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
 
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Amendment 1 
Protocol Title:  A Phase 1 Open-label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With 
Selected Relapsed or Refractory Hematological Malignancies 
AMG 397 
Amgen Protocol Number AMG 397 20170173 
 
Amendment Date: 
28 March 2018 
Rationale: 
The following updates were made to the protocol, dated 28 March 2018: 
• 
Addressed the following changes requested by FDA: 
o Changes to inclusion/exclusion criteria 
o Definition of DLT and criteria for DLT 
o Extended DLT window from 21 days to 28 days 
o Added safety monitoring assessments including: 
o Cardiac echocardiogram, imaging and assessments if any clinical signs 
or symptoms of cardiomyopathy or cardiac compromise are noted 
o Inclusion of an MRI/CT at baseline to check for CNS lymphoma or uncontrolled 
CNS disease 
• 
Begin enrollment of Cohort 1B (AML) at the same time as Cohort 1A at the same 
doses 
• 
Implement measures to mitigate the risk and manage tumor lysis syndrome including 
below:  
o Every subject will receive mandatory prophylaxis for tumor lysis syndrome 
(TLS) prior to the first dose of AMG 397 and prior to at all subsequent dose 
escalations 
o Allopurinol 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 PI discretion and the Institutional guidelines. 
o Upon admission, 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 and as needed per 
Investigator discretion.  
Approved 
 
 


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CONFIDENTIAL 
 
 
o 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.  
o Nephrology (or other acute dialysis service) consultation should be 
considered upon admission per institutional standards at investigators' 
discretion to ensure emergency dialysis is available and the appropriate staff 
is aware and prepared 
• 
Typographical errors and inconsistencies between sections throughout the protocol 
were corrected. 
Approved 
 
 


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Description of Changes: 
1. Title Page 
Removed strikethrough text, Added text in BOLD 
 
 
2. Investigator’s Agreement, page 2 
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3. Protocol Synopsis; Primary Objectives, Exploratory Objectives 
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4. Protocol Synopsis; Study Design; 4th paragraph,  
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5. Protocol Synopsis; Study Design and Treatment Schema 
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Replaced Figure with Below: 
 
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6. Protocol Synopsis; Study Design and Treatment Schema 
Added Figure 2: 
 
7. Section 2.1.1 Multiple Myeloma Background, full Section 
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8. Section 2.1.2 Non-Hodgkin’s Lymphoma Background, first paragraph 
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9. Section 2.2.3 Pharmacokinetics, second paragraph 
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10. Section 2.2.4 AMG 397 Preclinical Toxicology, last paragraph 
Added text in BOLD 
 
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11. Section 3.1 Study Design; Dose Escalation – Part 1  
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12. Section 3.2; Number of Sites 
 
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13. Section 3.4; Replacement of Subjects 
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14. Section 4.1; Inclusion Criteria 
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15. Section 4.1 Inclusion Criteria; Additional criteria for Part 2 – Dose Expansion 
Subjects 
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16. Section 4.2 Exclusion Criteria 
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17. Section 4.2 Exclusion Criteria; pages 45-47 
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18. Section 6.2.1.1 Dosage, Administration and Schedule 
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19. Section 6.2.1.1.1 Lead-in Dosing  
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20. Section 6.2.1.2 Dose-cohort Study Escalation and Stopping Rules  
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21. Section 6.2.1.3, Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation  
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22. Section 6.3.1; Pre-dosing requirements for AMG 397 
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23. Section 6.4; Dose Limiting Toxicities 
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24. Section 6.5.7; Tumor Lysis Syndrome (TLS)
Added below text
Prophylaxis and Management of TLS
Tumor lysis syndrome prophylaxis must be initiated in all subjects prior to the first dose 
of AMG 397 and prior to every dose escalation. 
The management recommendations below focus on the minimum initial responses 
required. If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be conducted per institutional protocols 
(Coiffier et al, 2008; Cairo et al, 2004).

Initiate allopurinol or equivalent 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 PI discretion. Dosing per institutional guidelines.

All subjects will be hospitalized for intensive monitoring: 
o
For the first 2 doses received, beginning 24 hours prior to first dosing day 
(Day -1) until 24 hours post the second dose
o
Once lead-in dosing is initiated (see Section 6.2.1.1.1):

For the first 2 doses received (Lead-in dosing), beginning at least 
24 hours prior to first dosing day (Day -1) until 24 hours post the 
second dose

Each time an additional week of lead-in dosing is instituted 
(Section 6.2.1.1.1)

For the first 2 doses received after the dose is escalated (target 
dose) beginning at least 24 hours prior to dosing day (usually 
day 7) until 24 hours post the second dose 

During hospitalization, intensive safety laboratory monitoring per designated 
timepoints per Table 4 and/or 5 to identify and prompt management of any 
metabolic changes.

Pre-treatment serum chemistry and hematology laboratory samples must 
be drawn within 24 hours prior to first dose, and electrolyte values 
(ie, potassium, uric acid, inorganic phosphorus, calcium) must be 
reviewed and within normal range prior to AMG 397 dosing. The 
investigator's decision to proceed with AMG 397 treatment initiation may 
be based on these laboratory values. These labs must be reviewed in real 
time by the investigator. 
NOTE: 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, dosing can be resumed following review of 
laboratory values and agreement between the Amgen medical monitor 
and investigator.
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
Prophylactic reductions of potassium, inorganic phosphorus and/or uric 
acid above of normal range prior to dosing are recommended per PI 
discretion.

Day 2 dosing of AMG 397 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.

Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria (Appendix L) are met, no additional AMG 397 doses should be 
administered until resolution. A rapidly rising serum potassium is a medical
emergency. 

Upon admission, 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 and as needed per Investigator discretion. 

Monitor for signs and symptoms of TLS (eg, fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion and seizures). If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour. 

Nephrology (or other acute dialysis service) consultation should be considered 
upon admission per institutional standards at investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared.

Management recommendations of laboratory abnormalities as stated below: 
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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):2767-78. 
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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25. Section 6.8; Concomitant Therapy 
Added text in BOLD: 
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. For subjects 
with AML hydroxyurea for 7 days at a dose of 1 – 10 g/day is allowed prior to the 
first cycle of AMG 397 treatment for subjects with high WBC (> 25,000 cells/ul) and 
during the first cycle but not on dosing days at a dose of up to 5 g/day. 
26. Section 6.10; Excluded Treatments and Procedures During Study Period  
Removed strikethrough text, Added text in BOLD 
 
 
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27. Section 7.1, Schedule of Assessments 
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28. Section 7.1, Schedule of Assessments 
Added Table 5 
Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose
 Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation 
(1)  
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
Vital signs (T, BP, 
HR, RR)  
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
12-lead ECG (2) 
X 
X 
X 
(2)  
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 
Echocardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization (3) 
 
 
 
 
 
 
 
 
 
TLS prophylaxis (4) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 397 dosing 
(5) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X (5) 
Dosing diary review 
(5) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X X 
AE Reporting 
 
 
 
 
 
 
SAE Reporting 
 
 
Prior /concomitant 
medication(s) 
 
 
Page 1 of 4  
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Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after
D2 
dose
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose 
 
 
LAB ASSESSMENTS 
 
 
 
AMG 397 PK  (7) 
 
 
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 
 
 
CBC with diff (8) 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Chemistry (9) 
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 
Coagulation  
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X X 
Pregnancy test (10) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample 
collection (11) 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
Hepatitis serology, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER and DISEASE ASSESSMENTS 
 
 
 
Bone marrow 
aspirate (12) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood Na/Hep 
(13) 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
Cytochex (14) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Plasma 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cell Pellet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 4  
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Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after 
D2 
dose
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose 
 
 
BIOMARKER and DISEASE ASSESSMENTS 
 
 
 
MM SUBJECTS ONLY 
SPEP/UPEP/ 
Immunofixation (15)  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SFLC (16) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2 
microglobulin  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative Ig (17) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasmacytoma (19) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey (20) X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 4  
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Table 5.  Schedule of Assessments (Cycle 1 ONLY After Lead-in Dosing is Implemented) 
CYCLE 
 
 
 
CYCLE 1 ONLY 
DAY(S) 
-
21 
to 
 -2 
-1 
1 
2 
3 
4 
7 
8 
9 
10 
11 
15 22 
HOUR(S) (relative 
to time of dosing) 
 
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 
0 
1 
2 
3 
5 
8 
12 
24h 
after 
D2 
dose 
48h 
after
D2 
dose
 
Pre-
dose 0 
1 
2 
3 
5 
8 
12 Pre-
dose 0 
1 
2 
3 
5 
8 
12 
24h 
after 
D9 
dose 
48h 
after 
D9 
dose 
 
 
NHL SUBJECTS ONLY 
Lymph Node 
Biopsy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
plasma  
(Dose expansion 
only)  (21) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy (22) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT and CECT 
Imaging (23) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Brain (24) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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29. Section 7.1, Footnotes for Table 4 and Table 5 
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30. Section 7.2.8, Echocardiogram (ECHO) / Multigated Acquisition (MUGA) Scan  
Removed strikethrough text, Added text in BOLD 
 
31. Section 7.2.9 Dosing Diary Review 
Added text in BOLD 
 
32. Section 7.2.11.1 Imaging and Disease assessments, 2nd paragraph 
Added text in BOLD 
PET-CT and CECT scans required in this protocol will be performed according to 
the Imaging Manual provided by the central vendor.  However, depending on 
scanner types and availability, as well as local regulations, institutional guidelines 
may be followed upon consultation with, and approval by, the central vendor.  
Combined PET-CT whole body scans will be acquired from base of skull to 
mid-thigh, with the CT portion of the scan used only for attenuation correction.  
CECT anatomical coverage includes the chest, abdomen, and pelvis (and neck, if 
not visualized with chest), and the acquisition of separate CECT scans is strongly 
recommended for staging evaluation.  Refer to the Imaging Manual for complete 
details about PET-CT and CECT scanning procedures and instructions. 
PET-CT images should be converted to standardized uptake values (SUV) maps to 
support comparison across timepoints and to standardize viewing conditions. 
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If PET-CT and CECT are acquired on the same day, it is strongly recommended 
that PET-CT is performed prior to CECT.  If acquired separately, every attempt 
should be made to complete PET-CT and CECT within 3 days of each other.   
Refer to the Imaging Manual for additional details. Findings will be recorded per 
eCRF guidelines. 
33. Section 7.2.11.2 MRI Brain 
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34. Section 7.2.14 Blood Samples , Tables 6, 7, and 8  
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35. Section 7.3.1 Blood Samples , Tables 6, 7, and 8  
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36. Section 7.4.1 Screening 
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37. Section 7.4.2 Treatment 
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38. Section 7.4.3 End of Treatment Visit 
Removed strikethrough text, Added text in BOLD 
 
Approved 
 
 


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39. Section 10.4, Adaptive Design, 3rd paragraph 
Removed strikethrough text, Added text in BOLD, Added Table 10 and 11 
 
Approved 
 
 


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40. Section 13, References 
Added text in BOLD, Removed strikethrough text 
 
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41. Added Appendix K. Cairo-Bishop Clinical Tumor Lysis Syndrome Definition 
and Grading  
 
42. Added Appendix L. Cairo-Bishop Definition of Laboratory Tumor Lysis 
Syndrome 
 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 397 
Protocol Number:  20170173 
Date:  10 March 2021 
Page 1 of 32 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1 Open-label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics and Efficacy of 
AMG 397 in Subjects With Selected Relapsed or 
Refractory Hematological Malignancies 
Short Protocol Title: 
A Phase 1 Open-label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics and Efficacy of 
AMG 397 
Protocol Number: 
20170173 
NCT Number: 
 NCT03465540 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive                                         
Thousand Oaks, CA 91320-1799 
Tel: +1-805-447-1000 
SAP Date: 
Document Version 
Date 
Amendment 1 (v2) 
10 March 2021 


Product:  AMG 397 
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Version Number 
Date 
Summary of Changes, including 
rationale for changes 
Original (v1.0) 
21DEC2018 
 
Amendment 1 
(v2.0) 
10MAR2021 
 
Updates made as per protocol 
amendment 4  
o 
Study design: Closed 
enrollment for Parts 
1A and 1B and added 
Parts 2A, 2B, 2C, 3A, 
3B, and 3C. 
o 
Sample size section 
 
Removed the definitions not 
related to analysis; updated 
the definitions (DOR, 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 the imputation rules for 
non-pharmacokinetic 
measurements above or below 
the upper quantification limits. 
 
Added the analyses for 
subjects proceed to a higher 
dose or crossover from 
monotherapy to a combination 
therapy cohort. 
 
Updated statistical methods of 
analysis (section 9)  
 
Updated appendix A for 
imputation of start and stop 
dates 
 
Updated appendix B for code 
fragment 
 


Product:  AMG 397 
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Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................. 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 13 
3.3 
Adaptive Design ........................................................................................ 13 
4. 
Covariates and Subgroups ................................................................................... 15 
5. 
Definitions ............................................................................................................. 15 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
Full Analysis Set........................................................................................ 18 
6.2 
DLT Evaluable Analysis Set ...................................................................... 18 
6.3 
Pharmacokinetic Analysis Set ................................................................... 18 
7. 
Planned Analyses ................................................................................................. 19 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 19 
7.2 
Primary Analysis ....................................................................................... 19 
7.3 
Final Analysis ............................................................................................ 19 
8. 
Data Screening and Acceptance ........................................................................... 19 
8.1 
General Principles ..................................................................................... 19 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 19 
8.3 
Handling of Missing and Incomplete Data ................................................. 19 
8.4 
Detection of Bias ....................................................................................... 20 
8.5 
Outliers ..................................................................................................... 20 
8.6 
Distributional Characteristics ..................................................................... 20 
8.7 
Validation of Statistical Analyses ............................................................... 20 
9. 
Statistical Methods of Analysis.............................................................................. 20 
9.1 
General Considerations ............................................................................. 20 
9.2 
Subject Accountability ............................................................................... 21 
9.3 
Important Protocol Deviations ................................................................... 21 
9.4 
Demographic and Baseline Characteristics ............................................... 21 
9.5 
Efficacy Analyses ...................................................................................... 21 
9.6 
Safety Analyses ........................................................................................ 22 
9.6.1 
Adverse Events ......................................................................... 22 
9.6.2 
Laboratory Test Results ............................................................ 22 
9.6.3 
Vital Signs ................................................................................. 22 


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9.6.4 
Physical Measurements ............................................................ 23 
9.6.5 
Electrocardiogram ..................................................................... 23 
9.6.6 
Antibody Formation ................................................................... 23 
9.6.7 
Exposure to Investigational Product .......................................... 24 
9.6.8 
Exposure to Other Protocol-required Therapy ........................... 24 
9.6.9 
Exposure to Concomitant Medication ........................................ 24 
9.7 
Analyses of Exploratory Endpoints ............................................................ 24 
9.8 
Other Analyses ......................................................................................... 24 
9.8.1 
Analyses of Pharmacokinetic Endpoints .................................... 24 
9.8.2 
Analyses of Biomarker Endpoints .............................................. 25 
10. 
Changes From Protocol-specified Analyses.......................................................... 25 
11. 
Literature Citations / References ........................................................................... 26 
12. 
Prioritization of Analyses....................................................................................... 27 
13. 
Data Not Covered by This Plan............................................................................. 27 
14. 
Appendices ........................................................................................................... 28 
Appendix A.  Imputation Rules .............................................................................. 29 
Appendix B.  Code Fragments .............................................................................. 31 
Appendix C.  Reference Values/Toxicity Grades .................................................. 32 
 
List of Figures 
Figure 1.  Part 1 Study Design and Treatment Schema (CLOSED TO 
ENROLLMENT) ...................................................................................... 12 
Figure 2.  Parts 2A, 2C, and 3 Study Design and Treatment Schema (Dose 
Escalation and Dose Expansion) ............................................................ 12 
Figure 3.  Part 2B Study Design and Treatment Schema (AML Subjects in 
Japan) .................................................................................................... 13 
List of Tables 
Table 1.  Guidelines for Dose Level Decisions for Parts 2A and 2C and Part 3 ............. 15 
Table 2.  Efficacy Endpoints .......................................................................................... 21 
 


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List of Abbreviations and Definition of Terms 
Enter List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event  
ALT 
Alanine aminotransferase (SGPT) 
ALP 
Alkaline phosphatase 
AML 
Acute myeloid leukemia 
AST 
aspartate aminotransferase (SGOT) 
AUC 
Area under the concentration-time curve 
CI 
Confidence interval  
CL 
Clearance 
Cmax 
Maximum observed concentration 
CRF 
Case report form  
CTCAE 
Common terminology criteria for adverse events 
DLRT 
Dose level review team 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
ELN 
European LeukemiaNet 
FIH 
First in human 
GSO-DM 
Global study operations-data management 
IMWG 
International myeloma working group  
IPD 
Important protocol deviation 
IWG 
International working group 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligrams 
MM 
Multiple myeloma 
MRD 
Minimal residual disease  
MTD 
Maximum tolerated dose 
NHL 
Non-Hodgkin’s lymphoma 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic 
 


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Abbreviation or Term 
Definition/Explanation 
PFS 
Progression free survival 
PR  
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 
PK 
Pharmacokinetic 
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 
RP2D 
Recommended phase 2 dose  
RR 
Relapsed or Refractory 
t1/2 
Half-life 
tmax 
Time of maximum observed serum concentration 
TPI 
Toxicity probability interval 
TTR 
Time to response 
WHO 
World health organization 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 4 for Study 20170173 -  
AMG 397 dated 09 December 2020. The scope of this plan includes the interim analysis, 
the primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Bio-statistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
 
Indications: Relapsed or Refractory (RR) Multiple Myeloma (MM), Non-Hodgkin’s 
Lymphoma (NHL), Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia 
(AML). 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
Part 1 QD2 Monotherapy (MM, NHL, AML) – CLOSED TO ENROLLMENT  
 
Evaluate the safety and tolerability 
of AMG 397 QD2 monotherapy  
 
Estimate the maximum tolerated 
doses (MTDs) and/or biologically 
active doses (eg, recommended 
phase 2 doses [RP2Ds]) of AMG 
397  
 
Incidence of dose-limiting 
toxicities (DLTs), 
treatment-emergent adverse 
events, treatment-related adverse 
events and clinically-significant 
changes in vital signs, physical 
examinations, electrocardiogram 
(ECGs) and clinical laboratory 
tests  
Part 2A QW Monotherapy (MDS, AML)  
 
Evaluate the safety and tolerability 
of AMG 397 QW monotherapy in 
subjects with MDS or AML  
 
Incidence of DLTs, 
treatment-emergent adverse 
events, treatment-related adverse 
events and clinically-significant 
changes in vital signs, physical 
examinations, ECGs, and clinical 
laboratory tests  
Part 2B QW Monotherapy in Japan (AML) 
 
Evaluate the safety and tolerability 
of AMG 397 QW monotherapy in 
subjects in Japan with relapsed or 
refractory AML  
 
Evaluate the PK of AMG 397 
when administered as 
monotherapy (QW) in Japan  
 
Incidence of DLTs, 
treatment-related, 
treatment-emergent adverse 
events and clinically significant 
changes in vital signs, physical 
examinations, ECGs, and clinical 
laboratory tests 
 
PK parameters for AMG 397 
including, but not limited to Cmax, 
AUC, CL, and t1/2  


Product:  AMG 397 
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Part 2C QW Monotherapy (MM)  
 
Evaluate the safety and tolerability 
of AMG 397 QW monotherapy in 
subjects with MM  
 
Incidence of DLTs, 
treatment-emergent adverse 
events, treatment-related adverse 
events and clinically-significant 
changes in vital signs, physical 
examinations, ECGs, and clinical 
laboratory tests  
Part 3 QW Combination Therapy (MDS, AML, MM) 
 
Evaluate the safety and tolerability 
of AMG 397 combination therapy  
 
MDS/AML: AMG 397 + 
azacitidine  
 
MM: AMG 397 + 
dexamethasone  
 
Incidence of DLTs, 
treatment-emergent adverse 
events, treatment-related adverse 
events and clinically-significant 
changes in vital signs, physical 
examinations, ECGs, and clinical 
laboratory tests  
 
Estimate the maximum tolerated 
or recommended combination 
dose (MTCD) and/or 
recommended phase 2 
combination doses (RP2CD) of 
AMG 397  
 
Secondary 
Part 1 QD2 Monotherapy (MM, NHL, AML) – CLOSED TO ENROLLMENT  
 
Evaluate the preliminary efficacy 
of AMG 397 monotherapy  
 
Overall response rate (ORR) 
using response criteria per the 
following:  
 
International Myeloma 
Working Group – Uniform 
Response Criteria 
(IMWG-URC) for MM 
subjects  
 
Lugano Classification for 
NHL subjects  
 
Revised International 
Working Group (IWG) for 
AML subjects  
 
Revised IWG for MDS 
subjects  
 
progression-free survival (PFS)  
 
overall survival (OS)  
 
time to response  
 
duration of response (DOR)  


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 
Evaluate the pharmacokinetics 
(PK) of AMG 397  
 
AMG 397 PK parameters 
including, but not limited to, 
maximum observed concentration 
(Cmax), time of maximum observed 
concentration (Tmax), area under 
the concentration time curve 
(AUC), clearance (CL) and half-life 
(t1/2)  
Part 2A QW Monotherapy (MDS, AML), Part 2B QW Monotherapy (AML), and Part 
2C QW Monotherapy (MM)  
 
Evaluate the preliminary efficacy 
of AMG 397 monotherapy (For 
Part 2B: Japan subjects only)  
 
 
ORR using response criteria per the 
following:  
 
Revised IWG for AML subjects  
 
Revised IWG for MDS subjects  
 
IMWG-URC for MM subjects  
 
PFS  
 
OS  
 
time to response  
 
DOR  
 
Evaluate the PK of AMG 397  
 
AMG 397 PK parameters 
including, but not limited to, Cmax, 
Tmax, AUC, CL, and t1/2  
Part 3 QW Combination Therapy (MDS, AML, MM)  
 
Evaluate the preliminary efficacy 
of AMG 397 combination therapy  
 
OR based on investigator 
assessment per:  
 
Revised IWG for MDS 
subjects  
 
2017 European 
LeukemiaNet (ELN) criteria 
in AML subjects 
 
IMWG-URC for MM 
subjects  
 
PFS 
 
OS  
 
time to response  
 
DOR  
 
Evaluate the PK of AMG 397 and 
azacitidine (Parts 3A and 3B) or 
dexamethasone (Part 3C) when 
administered in combination  
 
PK parameters for the combination 
including, but not limited to Cmax, 
AUC, CL, and t1/2  


Product:  AMG 397 
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Page 10 of 32 
CONFIDENTIAL 
 
 
Exploratory 
Parts 1, 2 and 3 
 
Explore pharmacokinetic/ 
pharmacodynamic (PK/PD) 
relationships for safety and/or 
efficacy endpoints  
 
AMG 397 exposure/efficacy and 
exposure/safety relationships  
 
Demonstrate AMG 397 
inactivation of myeloid cell 
leukemia sequence 1 (MCL1) by 
the activation of BAX and caspase 
3 in circulating monocytes or blast 
cells, and/or the decrease of 
circulating monocytes or blast cells 
 
Expression of BAX and Caspase 3 
in monocytes or blast cells, 
circulating monocyte counts, 
circulating blast counts 
 
Evaluate the correlation of clinical 
responses to disease-specific 
features in tumor cells  
 
Clinical response measures, 
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  
 
Evaluate changes to immune cell 
subsets in peripheral blood due to 
MCL1 inactivation  
 
Immune cell subset frequencies, 
absolute counts and MFIs in 
peripheral blood  
 
Parts 3B and C only: Evaluate 
additional measures of efficacy via 
minimal residual disease negative 
(MRD[-]) status with patient 
response  
 
MRD[-] status at the time of 
complete response (CR)  
  
2.2 
Hypotheses and/or Estimations 
No formal hypothesis testing will be performed. The point estimates and corresponding 
2-sided 95% exact CI will be presented on ORR. 
3. 
Study Overview 
3.1 
Study Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study 
evaluating AMG 397 administered orally in adult subjects with selected RR 
hematological malignancies. 
Part 1 of the study was designed to investigate AMG 397 as monotherapy on a twice 
weekly dosing schedule (ie, once daily for 2 consecutive days followed by 5 days break 
at a weekly interval [QD2]) in subjects with MM, NHL, and AML (Figure 1). In July 2019, 
reports of troponin elevations occurring at the highest dose level investigated of 


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Page 11 of 32 
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320 mg/m2 resulted in the clinical trial being placed on hold.  In 2020, the study was 
redesigned to investigate low weekly doses of AMG 397 including Part 2 (Figure 2, 
Figure 3) and Part 3 (Figure 2) as follows: 
 
Parts 2A will enroll subjects with MDS or AML (monotherapy [QW]) for dose 
escalation and subjects with only MDS for dose expansion 
 
Parts 2B will enroll subjects with AML in Japan (monotherapy [QW]) 
 
Parts 2C will enroll subjects with 1q21 amp MM (monotherapy [QW]) 
 
Parts 3A will enroll subjects with MDS (AMG 397 + azacitidine) for dose escalation 
and dose expansion 
 
Parts 3B will enroll subjects with AML (AMG 397 + azacitidine) for dose escalation 
and dose expansion 
 
Parts 3C will enroll subjects with 1q21 amp MM (AMG 397 + dexamethasone) for 
dose escalation and dose expansion 


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Study Design and Treatment Schema 
Figure 1.  Part 1 Study Design and Treatment Schema (CLOSED TO 
ENROLLMENT) 
 
 
Figure 2.  Parts 2A, 2C, and 3 Study Design and Treatment Schema (Dose 
Escalation and Dose Expansion) 
 


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Figure 3.  Part 2B Study Design and Treatment Schema (AML Subjects in Japan) 
 
3.2 
Sample Size 
Up to 240 subjects will be enrolled in the study. A total of 24 subjects were 
enrolled during Part 1 dose escalation (12 in both Part 1A and Part 1B). Up to 
26 evaluable subjects will be enrolled into Parts 2A and 2C monotherapy dose 
escalation part and up to 20 evaluable subjects into Part 2A (MDS only) dose 
expansion. Up to 6 subjects will be enrolled into Part 2B. Up to 78 evaluable 
subjects will be enrolled into each of the combination therapy dose escalation 
parts (up to 26 each for Parts 3A, 3B, and 3C) and up to 60 evaluable subjects (up 
to 20 subjects each for 3A, 3B, and 3C) in dose expansion.  
The sample sizes are based on practical considerations and it is consistent with 
conventional oncology studies with the objective to identify the MTCD. With 
10 subjects, there is a 40% to 65% probability of observing at least 1 adverse 
event if the true event rate is 5% to 10%. Exact 95% binomial CI will be provided 
for ORR. With the 20 subjects in each dose expansion group and a 20% ORR, the 
2-sided 95% exact CI would be 6% to 44%. 
3.3 
Adaptive Design 
Part 1 
A two-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
escalation. The maximum tolerated dose (MTD) target Toxicity Probability Interval (TPI) 
for dose-limiting toxicity (DLT) is (0.20, 0.33] and TPIs of (0.33, 0.60] and (0.60, 1.00] 
are defined as excessive and unacceptable, respectively. The design seeks to identify a 
dose most likely to have a DLT rate in the target TPI, but with overdose control that limits 


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Page 14 of 32 
CONFIDENTIAL 
 
 
the possibility the dose has an excessive or unacceptable DLT rate (Babb et al, 1998). 
The overdose control limit is defined as less than a 0.40 probability of an excessive or 
unacceptable TPI. Based on accumulating safety data, the DLRT may implement an 
overdose control limit of less than a 0.25 probability of an excessive or unacceptable 
TPI. The probability of a DLT at dose level di is assumed to follow a Bernoulli distribution 
with probability pi where the logit of pi increases linearly with the log of the standardized 
dose in the following 2-parameter logistic model: 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
Where a and b are random variables and dref is one of the planned doses selected as 
the reference dose. 
A bi-variate normal prior distribution (Neuenschwander et al, 2008) is used for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose of 80 mg is 0.90 and the probability the true DLT rate is ≤ 0.05 at the 
reference dose of 640 mg is 0.05. These values are selected such that pi is 0.05 for the 
starting dose and 0.25 for the reference dose. Model sensitivity to the prior will also be 
investigated and in particular the BLRM will be examined using a prior having a lower 
reference dose (eg, 320 mg). 
Part 2 and Part 3 
Each dose cohort will initially enroll 2-4 subjects in Parts 2A and 2C and 3-4 
subjects in Part 3; and up to 10 subjects at the highest dose level or MTD/MTCD 
may be enrolled.  After reviewing all available safety and tolerability data, dose 
level decisions will be made by the DLRT using a mTPI model based on all 
evaluable 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, MTCD has not been defined and 
no DLTs occur at any dose level.   
 
An MTD or MTCD is identified. 
At least 6 evaluable subjects need to be treated at the dose level of MTCD. 
Guidelines for dose level decisions can be found in Table 1.  Please note one 
exception to the guidelines provided in Table 1, a single grade 3 treatment related 
troponin elevation will result in dose de-escalation regardless of number of 
subjects treated at current dose. 


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Table 1.  Guidelines for Dose Level Decisions for Parts 2A and 2C and Part 3 
 
Number of DLTs 
No. of DLT-evaluablea 
subjects treated at 
current dose 
Escalate 
Stay at current dose 
De-escalateb 
1 
0 
- 
1 
2 
0 
- 
≥ 1 
3 
0 
1 
≥ 2 
4 
0 
1 
≥ 2 
5 
0 
1 
≥ 2 
6 
0-1 
- 
≥ 2 
7 
0-1 
2 
≥ 3 
8 
0-1 
2 
≥ 3 
9 
0-1 
2 
≥ 3 
10c 
0-1 
2-3 
≥ 4 
DLT = dose-limiting toxicity. 
a See Section 6 for definition of DLT evaluable. 
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 MTCD is defined as the highest dose with a probability of DLT lower than or 
close to a targeted toxicity probability of 0.2. 
4. 
Covariates and Subgroups 
There are no planned covariates in this study. 
If appropriate the following baseline variables may be used to evaluate efficacy 
endpoints in subgroup analysis: Age at baseline (< 65, ≥ 65), sex, race, prior lines of 
anti-cancer therapy (1, 2, >2). 
5. 
Definitions 
Age at Enrollment  
Subject age at enrollment will be determined using the age in years reported in the 
clinical database.  
Baseline  
Unless otherwise specified, baseline will be defined as the last assessment before the 
first dose of investigational product (AMG 397). 


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Baseline and Post-Baseline Electrocardiogram (ECG) Values in Triplicate  
For the three baseline triplicate ECG, the mean of values in a triplicate should be 
calculated before taking the mean of the three baseline 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 within that assessment visit 
will be averaged for that time point. 
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec):  QTcB=QT/(RR/1000)1/2 
Best Overall Response (BOR)  
Best overall response for a subject is the best observed post-baseline disease 
response based on investigator assessment. Response criteria are as follows: 
 
IMWG-URC for MM  
 
2017 ELN criteria for AML  
 
Revised IWG for MDS 
 
Lugano Classification for NHL 
Dose Limiting Toxicity (DLT) 
Unless otherwise specified, investigators determine whether an adverse event 
qualifies as a DLT per the definition described in the protocol. 
DLT Observation Period 
The DLT observation period is defined as, at minimum, 28 days after the initial 
dose of AMG 397.  If lead-in dosing period is initiated, the DLT-observation period 
is defined as the amount of time for subject(s) for each dose cohort to receive at 
least 1 week of lead-in dose and 3 weeks of target dose. 
Duration of Response (DOR) 
Duration of response is calculated for subjects who have achieved response (PR 
or better). It is defined as time from the first observation indicating a response to 
the subsequent date of disease progression or death, whichever is earlier.  


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CONFIDENTIAL 
 
 
DOR time in months: (date of disease progression or death - date of the first 
observation of response +1)/30.4  
Subjects without disease progression or death until the analysis data cut-off date 
will be censored at the last adequate disease assessment date. 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec):  QTcF=QT/(RR/1000)1/3 
Investigational Product (IP) 
IP is used in reference to AMG 397. 
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. 
Progression-free survival (PFS) 
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: (date of disease progression or death - 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 adequate disease assessment date. If no post-baseline 
disease assessment, censoring is at the first dose of IP date. 
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  
Patients without event will be censored at their last date known to be alive.   
Study Day 
Post study day 1: study day = (date –Study Day 1) + 1 
Pre study day 1: study day = (date –Study Day 1) 


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Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Day -1. 
Treatment-Emergent Adverse Event (TEAE) 
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. 
Time to Response (TTR) 
Time to response is defined as the time from the first dose of IP until the first 
documentation of objective response. Only subjects who have achieved objective 
response will be evaluated for TTR. 
TTR time in months: (date of the first observation of response - first dose of IP 
date +1)/30.4 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
Full Analysis Set defined as all subjects that are enrolled and receive at least 1 
dose of AMG 397.  The analysis of all endpoints, unless noted otherwise, will be 
conducted on the Full Analysis Set. 
6.2 
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 397 
 
in Parts 3A/3B:  and received at least 85% of the planned dose of 
azacitidine 
 
in Part 3C:  and received at least 75% of the planned dose of 
dexamethasone 
 
experienced a DLT 
6.3 
Pharmacokinetic Analysis Set 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
AMG 397 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 


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significant protocol deviations have affected the data, or if key dosing or sampling 
information is missing. 
7. 
Planned Analyses 
 The planned analyses are described in following sections. 
7.1 
Interim Analysis and Early Stopping Guidelines 
No formal interim efficacy analysis is planned. Safety data will be reviewed on an 
ongoing basis. Interim safety analyses will be performed for each dose level of each 
cohort to support the evaluation of safety by the DLRT.  After reviewing all available 
safety data and reviewing the dose recommendation from mTPI, the DLRT will make all 
dose level and dosing schedule decisions. 
Upon the completion of each cohort or each part, interim analyses can be performed to 
evaluate safety and efficacy data. 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or withdraws from the study. 
7.3 
Final Analysis 
The final analysis will occur after all subjects have ended the study. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation of missing values will be done:  
Incomplete adverse event, concomitant medication dates and dates used for the 
derivation of time to efficacy endpoints will be imputed as per Appendix A.  
Non-pharmacokinetic measurements that are above or below the quantification 
limits will be considered equal to the upper or lower limit of quantification for all 
analyses unless explicitly noted otherwise. 


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8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by listing important protocol violations by cohort and site. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
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,  


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efficacy and safety data will be summarized per their initial assigned dose level. 
9.2 
Subject Accountability 
The number and percent of subjects who are enrolled (including the dates for the 
first subject enrolled and last subject completed study), receive investigational 
product, complete investigational product, discontinue from investigational 
product (including reasons for discontinuing), complete study, discontinue the 
study (including reasons for discontinuing) will be summarized by cohort.   
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol.  IPDs and eligibility deviation will be summarized. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced: Demographic (ie, age, age groups [18 < 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 Eastern Cooperative Oncology 
Group [ECOG] Performance Status) will be summarized using descriptive statistics. If 
multiple races have been reported for a subject, the subject will be categorized as 
multiple. 
9.5 
Efficacy Analyses 
Table 2.  Efficacy Endpoints 
Endpoint 
Statistical Analysis Methods 
Overall response rate 
The proportion of subjects with response to 
treatment 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 B for code fragment. 
DOR, PFS, and OS 
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. 
MRD[-] status at CR (Parts 3B 
and 3C only) 
Proportion of MRD[-] at CR will be provided for 
subjects with CR. 


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For time to event endpoints (including DOR, TTR, OS, 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 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. The severity of each adverse event will be graded using (CTCAE) 
version 4.03 (Appendix C). 
Subject incidence of all treatment-emergent adverse events, serious adverse 
events, 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.  
Subject incidence of DLTs will be summarized by dose level and preferred term 
using the DLT Evaluable Analysis Set. 
9.6.2 
Laboratory Test Results 
The analyses of safety laboratory data will include summary statistics at the 
scheduled time points by dose cohort. 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, total 
neutrophils) will be tabulated by dose cohort. 
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 for baseline and on study assessed within 
7 days.   
Subject incidence of troponin elevation will be summarized. 
9.6.3 
Vital Signs 
Vital signs (systolic / diastolic blood pressure, heart rate) over time and change 
from baseline will be summarized. 


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9.6.4 
Physical Measurements 
The physical measurement to each scheduled assessment time point will be provided. 
9.6.5 
Electrocardiogram 
All on-study ECG data including PR, QRS, QT, RR, QTcB, and QTcF interval will be 
summarized. 
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 QTcB and 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 397 and change from 
baseline in QTcF may be explored graphically. 
Analysis of the relationship between AMG 397 serum concentrations and change from 
baseline in QTcF will be conducted and plots of the relationship between AMG 397 
serum concentrations and change from baseline in QTcF will be provided.  
9.6.6 
Antibody Formation 
The incidence of subjects who develop anti-AMG 397 antibodies at any time will 
be tabulated. 


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9.6.7 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to AMG 397 by 
dosing schedule. Number of cycles initiated, number of doses, duration of 
treatment, average dose delivered per day, average dose delivered per treated 
week and cumulative dose will be summarized. Subject incidence of dose 
modification along with the reason for dose modification will be summarized. 
A listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided.  
9.6.8 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be provided to describe the exposure to azacytidine and 
dexamethasone. 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. 
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term as coded by the World Health Organization Drug 
(WHO DRUG) dictionary. 
9.7 
Analyses of Exploratory Endpoints 
Analyses of exploratory endpoints may include, but not limited to, biomarkers, 
pharmacodynamics biomarker measurements, and genomic aberrations.  
Identification of metabolite(s) of AMG 397 in plasma and the relationships between 
PK/PD for safety and efficacy may also be explored. 
Details of the exploratory analysis will be provided in a supplemental analysis 
plan.  
9.8 
Other Analyses 
9.8.1 
Analyses of Pharmacokinetic Endpoints 
PK parameters will include, but are not limited to, Cmax, Tmax, AUC, CL and t1/2. These 
parameters will be estimated using standard non-compartmental PK methods and 
summarized by dose groups using n, means, standard deviations, medians, coefficients 
of variation, geometric mean, minimums and maximums. 


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PK analyses will be provided by the Department of Clinical Pharmacology, Modeling & 
Simulation (CPMS). Details regarding the analyses will be provided in a separate 
analysis plan by CPMS. 
9.8.2 
Analyses of Biomarker Endpoints 
The analysis of biomarker will be described and performed by Clinical Biomarker 
Group. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


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11. 
Literature Citations / References 
Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometricka.  1934;26:404-413. 


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12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
The analyses of PK and biomarkers are not covered by this plan. 
 


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14. 
Appendices 


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Appendix A.  Imputation Rules 
Imputation Rules for Partial or Missing Dates for Adverse Events and Concomitant 
Medications 
Imputation Rules for Partial or Missing Start Dates 
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.  
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. 
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.  


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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. 
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. 
 


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


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Appendix C.  Reference Values/Toxicity Grades 
Adverse Event Grading Scale  
The CTCAE is available at the following location:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm