Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Relapsed Multiple Myeloma Refractory Multiple Myeloma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 42
Healthy volunteers: no

Brief summary:
This is a first in human phase 1 multicenter open label study in subjects with relapsed or refractory multiple myeloma.

Detailed description:
This is a first in human phase 1 multicenter open label study to evaluate the safety and tolerability of AMG 224 in subjects with relapsed or refractory multiple myeloma. The study will be conducted in 2 parts. Part 1 is the dose-exploration and part 2 is the dose-expansion. Study medication will be administered once every 3 weeks by intravenous (IV) infusion.

Arms:
arm 1: Participants were administered AMG 224 Dose A as an intravenous (IV) infusion once every 3 weeks (Q3W) on Day 1 of each cycle, where each cycle is 3 weeks. arm 2: Participants were administered AMG 224 Dose B as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 3: Participants were administered AMG 224 Dose C as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 4: Participants were administered AMG 224 Dose D as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 5: Participants were administered AMG 224 Dose E as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 6: Participants were administered AMG 224 Dose F as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 7: Participants were administered AMG 224 Dose G as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 8: Participants who had prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the maximum tolerated dose \[MTD\] based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks. arm 9: Participants who had no prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the MTD based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.

Interventions: intervention 1: AMG 224
Intervention descriptions: intervention 1: Administered as an IV infusion.

Protocol document:
Prot_000.pdf: 
Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 1 of 105 
CONFIDENTIAL 
Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects With Relapsed 
or Refractory Multiple Myeloma 
Amgen Protocol Number 20130314 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1-805-447-1000 
Key Sponsor Contacts: 
, MD, PhD 
Medical Monitor  
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: 
Email: 
Clinical Research Study Manager 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Email: 
Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
09 June 2015 
07 October 2015 
12 July 2017 
02 March 2018 
16 July 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:  1- 800-77-AMGEN. For all other study-related 
questions, please contact the Key Sponsor Contact. 
Approved
NCT Number: NCT02561962
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov
Note added in posting: Discrepant dates in some headers are from a clerical error in the 
original protocol.  For correct dates please refer to  this cover page.


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 2 of 105 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects 
with Relapsed or Refractory Multiple Myeloma, dated 16 July 2018, and agree to abide 
by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonization (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) at the start of the study and for up to 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 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 3 of 105 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 224 in Subjects with Relapsed or Refractory Multiple Myeloma 
Study Phase: 1  
Indication:  Multiple Myeloma 
Primary Objectives:   
 
Evaluate the safety and tolerability of AMG 224 monotherapy in subjects with relapsed or 
refractory multiple myeloma 
 
Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose 
(RP2D) of AMG 224, if possible 
Secondary Objectives:   
 
Characterize the pharmacokinetics (PK) of AMG 224 when administered intravenously 
(IV) once every 3 weeks (Q3W) 
 
Evaluate preliminary efficacy of AMG 224 when given as monotherapy in relapsed or 
refractory multiple myeloma according to International Myeloma Working Group (IMWG) 
uniform response criteria. 
 
Evaluate the preliminary rate of conversion to minimal residual disease (MRD) negativity 
 
Evaluate the incidence of anti-AMG 224 antibody formation. 
Exploratory Objectives:   
 
Correlate clinical response with B-cell maturation antigen (BCMA) expression in pre-dose 
bone marrow biopsies and/or bone-marrow aspirates  
 
Evaluate gene expression profiling by sequencing in pre-dose biopsies/plasma to identify 
gene signatures for response 
 
Determine prognostic and predictive value of serum BCMA and BCMA ligands, a 
proliferation inducing ligand (APRIL)/B-cell activating factor (BAFF), from multiple 
myeloma serum samples 
 
Assessment of multiple myeloma samples for relevant circulating tumor cells 
Hypotheses:   
 
AMG 224 administered by IV infusion at (or one dose level below) the preliminary MTD 
identified during the dose exploration part of the study is expected to achieve acceptable 
safety and tolerability in subjects with relapsed or refractory multiple myeloma. A 
favorable PK profile will be achieved with AMG 224 administered by IV infusion Q3W. 
 
Objective responses by IMWG uniform response criteria will be observed at a dose level 
that achieves acceptable safety and tolerability  
Primary Endpoints:   
 
Safety: Incidence of dose limiting toxicities (DLTs), treatment-related, treatment-emergent 
adverse events, and clinically significant changes in vital signs, physical examinations, 
electrocardiograms (ECG)s and clinical laboratory tests  
Secondary Endpoints:   
 
PK profile: PK parameters for AMG 224 conjugated antibody (anti-BCMA antibody with at 
least one DM1 molecule conjugated to the antibody), total anti-BCMA antibody (sum of 
unconjugated anti-BCMA antibody and AMG 224 conjugated antibody), and DM1 (total 
unconjugated DM1) including, but not limited to maximum observed concentration (Cmax), 
minimum observed concentration (Cmin), area under the concentration-time curve (AUC), 
clearance (CL), and if feasible half-life (t1/2) 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 4 of 105 
CONFIDENTIAL 
 
 
 
Overall response according to International Myeloma Working Group (IMWG) uniform 
response criteria, relative reduction in M-component, time to progression (TTP), duration 
of response (DOR) 
 
Conversion to MRD negativity 
 
Incidence of anti-AMG 224 antibody formation 
Exploratory Endpoints:   
 
Quantification of BCMA expression in pre-dose bone marrow biopsy and bone-marrow 
aspirates 
 
Pre-dose bone marrow biopsy and/or plasma DNA gene expression profiles 
 
Serum level of BCMA, BCMA ligands, APRIL and BAFF  
 
Quantification of circulating tumor cells, plasma cells and/or BCMA specific tumor cells 
Study Design:    
This is a phase 1, first-in-human, multicenter; non-randomized, open-label, dose-exploration and 
dose-expansion study of AMG 224 administered by IV infusion Q3W in subjects with relapsed or 
refractory multiple myeloma.  The study will be conducted in two parts: Part 1 - Dose Exploration 
to define the MTD and/or RP2D followed by Part 2 - Dose Expansion to obtain further safety and 
efficacy data.  Eligible subjects enrolled in the study will receive AMG 224 by IV infusion Q3W 
beginning at study Day 1.  During the initial DLT window (Day 1 through Day 28), subjects will be 
assessed for DLTs (see Section 6.2.1.6 for DLT definition).  Dosing with AMG 224 may continue 
Q3W unless there is evidence of progressive disease (PD) defined by IMWG, the subject 
becomes intolerant to the study medication, signs and symptoms of clinical progression are 
evident as determined by the principal investigator or the subject withdraws consent.  
Part 1 – Dose Exploration:   
In Part 1 for the first dose level and at each new higher dose level, the first enrolled subject will be 
treated, and then after a period of 24 hours, subsequent subjects will be treated, provided that 
there are no safety concerns relating to the treatment of the first subject.  The dose-exploration 
cohorts will define the preliminary MTD, safety, tolerability, PK, and PD of AMG 224.  A standard 
3+3 design will be used to make a preliminary estimate of MTD.  The preliminary MTD is defined 
as the maximum dose at which fewer than one-third of subjects experience a DLT.  A final 
estimate of the MTD will be made using data from Dose Exploration and Dose Expansion.  
Planned dose levels for the dose-exploration cohorts are as follows: 30, 
 
 mg of AMG 224 (IV; Q3W).   
Part 2 – Dose Expansion: 
In Part 2 of the study, up to 20 subjects with relapsed or refractory multiple myeloma will be 
treated.  Subjects will be divided into the following 2 groups based on the status of prior treatment 
with CD38 targeting antibody (eg, Daratumumab): 
 
Group A will consist of subjects who had prior treatment with a CD38 targeting antibody (at 
least 10 subjects). 
 
Group B will consist of subjects who is naïve to CD38 targeting antibody treatment 
(approximately 10 subjects). 
In the Part 1 of the study, a fixed dosing (ie, dose not adjusted for individual subject’s body 
weight) will be evaluated and in Part 2 of study body weight-based dosing will be evaluated.  
Subjects will be treated with preliminary MTD identified from the Dose Exploration part of the 
study 
 adjusted for their body weight.  Subjects with grade 2 thrombocytopenia at 
baseline (ie, platelet count < 75 to 50 x 109/L) should be started at a reduce dose of 
.  
The subsequent doses of AMG 224 could be further reduced to 
 if the criteria for dose 
reduction for thrombocytopenia are met as per sections 6.2.5.1 and 6.3.1.  For therapeutic 
monoclonal antibody based therapies a full assessment of body weight effect on the PK/PD 
should be conducted to determine the optimal dosing approach prior to conducting the 
registration trial and a recommendation for adjustment or lack of adjustment of dose based on 
body weight be made once sufficient clinical data is available (Bai, 2012 and Wang, 2009).  When 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 5 of 105 
CONFIDENTIAL 
 
 
sufficient AMG 224 clinical data becomes available, a full assessment of body size effect on 
PK/PD will be conducted to determine the optimal dosing approach prior to conducting the 
registration trial for AMG 224 in multiple myeloma patients. 
During dose-expansion, after 5 subjects have enrolled (combining Group A and B subjects) and 
completed 28 days on study, a toxicity probability interval (TPI) Bayesian model utilizing all 
current DLT-evaluable subjects will be fit to evaluate the appropriateness of the preliminary MTD 
from dose exploration.  The subsequent subjects to be enrolled in dose expansion may be dosed 
with the updated dose level.  A final estimate of the MTD will be made based on a toxicity 
probability interval (TPI) Bayesian model utilizing all DLT evaluable subjects from the dose 
exploration and dose expansion cohorts. 
An end of study (EOS) visit will be performed 30 to 37 days after the last dose of AMG 224.   
Sample Size:  It is anticipated that approximately 60 subjects will be enrolled in this study.  
Approximately 40 subjects will be enrolled in the dose exploration cohorts and up to 20 additional 
subjects will be enrolled in the dose expansion cohort. 
The sample size in the dose exploration is based on practical consideration and it is consistent 
with conventional oncology studies with the objective to identify the MTD.  With 3 subjects per 
cohort, there is a 27 to 70% probability of observing at least one DLT if the true DLT rate is 10 to 
33% and with 6 subjects per cohort, there is a 47 to 91% probability. 
In the dose expansion cohort, a subject number of 20 will provide a 64% probability of observing 
at least one adverse event with 5% incidence rate and 88% probability of observing at least one 
adverse event with 10% incidence rate.  An exact 80% binomial confidence interval (CI) will be 
provided for overall response rate (ORR).  With the 20 subjects and 20% ORR, the 80% CI would 
be 9% to 36%. 
Summary of Subject Eligibility Criteria:   
Subjects ≥ 18 years of age with pathologically documented, definitively diagnosed, multiple 
myeloma relapse or refractory progressive disease after at least 3 lines of therapy for multiple 
myeloma.  Once consented to the study, subjects will undergo safety tests and provide a medical 
history to confirm they meet all requirements of the study.  For a full list of eligibility criteria, 
please refer to Section 4.1 and Section 4.2. 
Amgen Investigational Product Dosage and Administration:  
AMG 224 will be supplied as 5 mL deliverable volume in a single use 8cc glass vial stored at 
liquid temperatures of 
 at 10 mg/mL protein concentration formulated with 
 mM 
sodium acetate, 
 (w/v) sucrose, 
 (w/v) polysorbate 20, pH 
. 
AMG 224 will be administered as an IV infusion given over 60 ± 10 minutes once Q3W in the first 
2 cycles.  The dose of AMG 224 will vary by study part: 
 
Part 1 – Dose Exploration: The doses range from 30 to 300 mg   
 
Part 2 Dose Expansion: The starting dose is 
.  Subjects with grade 2 
thrombocytopenia at baseline (ie, platelet count < 75 to 50 x 109/L) should be started at a 
reduced dose of 
  The subsequent doses of AMG 224 could be further reduced to 
 if the criteria for dose reduction for thrombocytopenia are met as per 
sections 6.2.5.1 and 6.3.1.  
During the Dose Expansion Phase all doses are to be based on the subject’s actual body weight 
on the day of dosing (Day 1 of each cycle).  For cycles 2 and beyond, weight should be 
re-checked, and dosing adjusted accordingly, unless body weight is changed by 5% or less 
compared to the cycle 1 weight.  The dose of AMG 224 should not exceed 
 (based on 
available nonclinical toxicology information on maximum sucrose allowance limit). 
For each subject, the infusion time may be shortened to 30 ± 5 minutes in the later cycles if 
subjects experience no infusion reaction or lengthened up to 120 ± 10 minutes if subjects 
experience an infusion reaction. 
Control Group:   
The study does not incorporate a control group. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2018 
Page 6 of 105 
CONFIDENTIAL 
Procedures:
After written informed consent has been obtained, all screening tests and procedures will be 
performed within 14 days of administration of the first dose of AMG 224 (day 1), unless otherwise 
noted.  Subjects will be seen in clinic where critical clinical safety and study evaluations will be 
performed including physical examination, vital signs, clinical laboratory tests, ECGs, PK, and 
biomarker sample collections. 
For a full list of study procedures, including the timing of each procedure and the Schedule of 
Assessments, please refer to Section 7. 
Statistical Considerations:
All subjects who are enrolled and receive at least one administration of the investigational product 
(AMG 224) will be included in the analysis, unless otherwise specified.  The primary analysis will 
occur when target enrollment is complete and each subject either completes 6 months on study 
or withdraws from the study.  Descriptive statistics will be provided for selected demographics, 
safety, PK, PD and biomarker data by dose, dose schedule, and time as appropriate.  Descriptive 
statistics on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  The number and 
percentage of subjects reporting any treatment-emergent adverse events will be tabulated.  
Summaries of positive anti-AMG 224 antibody test results over time will be provided.  The 
preliminary estimate of the MTD will be identified using the 3+3 design.  A final estimate of the 
MTD will be made based on a toxicity probability interval (TPI) Bayesian model utilizing all DLT 
evaluable subjects from the dose exploration and dose expansion cohorts.  
The proportion of subjects with objective response (PR or better) per IMWG criteria with 
corresponding exact 80% CI will be calculated using the Clopper-Person method and tabulated 
for subjects treated at the MTD.  
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:  Amgen Inc.
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 7 of 105 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Enrollment 
End of Treatment 
End of Study 
30 mg Q3W 
 Q3W 
 Q3W 
 Q3W 
 Q3W 
 Q3W 
Part 1 - DOSE EXPLORATION 
Part 2 - DOSE EXPANSION 
Screening 
Enrollment 
End of Treatment 
End of Study 
Body Weight Based Dosing will be 
explored (Dose = Preliminary MTD 
identified from Part 1 adjusted for 
subject’s body weight) 
 
Group A: Prior CD38 targeting antibody 
(n= at least 10) 
Group B: No prior CD38 targeting antibody 
(n=~10) 
 
 Q3W 
 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 8 of 105 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADC 
antibody drug conjugates 
AE 
adverse event  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
APRIL 
A proliferation inducing ligand 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
BAFF 
B-cell activating factor 
BAFF-R 
B-cell activating factor receptor 
BCMA 
B-cell maturation antigen 
BP 
blood pressure 
CBC 
complete blood count 
CI 
confidence interval  
CL 
clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CR 
complete response  
CRF 
case report form  
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DAR 
drug-to-antibody ratio 
DILI 
drug-induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 9 of 105 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject. 
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 (end of trial) defined as when the last subject completes the safety follow-up 
assessments (30 to 37 days after last dose of AMG 224)  
End of Safety Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
eSAE 
electronic serious adverse event 
ESR 
erythrocyte sedimentation rate 
FIH 
first in human 
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 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
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 
intravenous or roman numeral 4 
LVEF 
left ventricular ejection fraction  
MAD 
maximum administered dose 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 10 of 105 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligrams 
MM 
multiple myeloma  
MR 
minor response 
MRD 
minimal residual disease  
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition scan 
N, n 
number 
ORR 
overall response rate 
PD 
pharmacodynamics or progressive disease 
PG 
pharmacogenetic 
PK 
pharmacokinetics 
PKDM 
pharmacokinetics and data management 
Pre 
pre-dose 
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 
Q3W 
once every 3 weeks 
QD 
once daily 
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 
RBC 
red blood cells 
RF 
rheumatoid factor 
RP2D 
recommended phase 2 dose  
sCR 
stringent complete response 
SD 
standard deviation 
SFLC 
serum free light chain 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 11 of 105 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
SPEP 
serum protein electrophoresis 
T1/2 
half-life 
TACI 
trans-membrane activator and calcium modulator 
TBL 
total bilirubin 
tmax 
time of maximum observed serum concentration 
TPI 
toxicity probability interval 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
w/v 
weight/volume  
WBC 
White blood cell 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 12 of 105 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 7 
Study Glossary ................................................................................................................ 8 
1. 
OBJECTIVES ....................................................................................................... 17 
1.1 
Primary ..................................................................................................... 17 
1.2 
Secondary ................................................................................................. 17 
1.3 
Exploratory ................................................................................................ 17 
2. 
BACKGROUND AND RATIONALE ...................................................................... 17 
2.1 
Multiple Myeloma Background .................................................................. 17 
2.2 
AMG 224 Background ............................................................................... 19 
2.2.1 
AMG 224 Preclinical Pharmacology .......................................... 20 
2.2.2 
Pharmacokinetics ...................................................................... 21 
2.2.3 
AMG 224 Preclinical Toxicology ................................................ 22 
2.3 
Risk Assessment ....................................................................................... 22 
2.4 
Rationale ................................................................................................... 23 
2.4.1 
Target Rationale ........................................................................ 23 
2.4.2 
Dose Selection Rationale .......................................................... 24 
2.5 
Clinical Hypotheses ................................................................................... 28 
3. 
EXPERIMENTAL PLAN ........................................................................................ 28 
3.1 
Study Design ............................................................................................. 28 
3.2 
Number of Sites ........................................................................................ 30 
3.3 
Number of Subjects ................................................................................... 31 
3.4 
Replacement of Subjects .......................................................................... 31 
3.5 
Estimated Study Duration .......................................................................... 31 
3.5.1 
Study Duration for Subjects ....................................................... 31 
3.5.2 
End of Study .............................................................................. 31 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 32 
4.1 
Inclusion Criteria ....................................................................................... 32 
4.2 
Exclusion Criteria ...................................................................................... 33 
5. 
SUBJECT ENROLLMENT .................................................................................... 35 
5.1 
Treatment Assignment .............................................................................. 36 
6. 
TREATMENT PROCEDURES .............................................................................. 37 
6.1 
Classification of Product ............................................................................ 37 
6.2 
Investigational Product .............................................................................. 37 
6.2.1 
AMG 224 Investigational Product .............................................. 37 
6.2.1.1 
Dosage, Administration, and Schedule .................... 37 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 13 of 105 
CONFIDENTIAL 
 
 
6.2.1.2 
Study Dose Exploration and Stopping 
Rules ....................................................................... 39 
6.2.1.3 
Study Dose Expansion and Stopping 
Rules ....................................................................... 41 
6.2.1.4 
Other Stopping Rules During Enrollment ................. 41 
6.2.1.5 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 42 
6.2.1.6 
Dosage Limiting Toxicities ....................................... 44 
6.3 
Management of Adverse Events ............................................................... 45 
6.3.1 
Management of Thrombocytopenia ........................................... 45 
6.3.2 
Management of Anemia ............................................................ 47 
6.3.3 
Management of Infections ......................................................... 47 
6.3.4 
Management of Peripheral Neuropathy ..................................... 48 
6.3.5 
Management of Cardiac Arrhythmia .......................................... 48 
6.3.6 
Management of Renal Toxicities ................................................ 48 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 49 
6.4.1 
Criteria for Permanent Withholding of AMG 224 due to 
Potential Hepatotoxicity ............................................................. 49 
6.4.2 
Criteria for Conditional Withholding of AMG 224 due to 
Potential Hepatotoxicity ............................................................. 50 
6.4.3 
Criteria for Rechallenge of AMG 224 After Potential 
Hepatotoxicity............................................................................ 50 
6.5 
Concomitant Therapy ................................................................................ 51 
6.6 
Product Complaints ................................................................................... 51 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period .................................................................................. 51 
7. 
STUDY PROCEDURES ....................................................................................... 52 
7.1 
Schedule of Assessments Dose Exploration and Dose 
Expansion ................................................................................................. 52 
7.2 
General Study Procedures ........................................................................ 57 
7.2.1 
Informed Consent ...................................................................... 57 
7.2.2 
Medical History .......................................................................... 57 
7.2.3 
Prior Therapy ............................................................................. 57 
7.2.4 
Physical Examinations ............................................................... 57 
7.2.5 
Peripheral Neuropathy Assessment .......................................... 57 
7.2.6 
Height Measurements ............................................................... 57 
7.2.7 
Weight Measurements ............................................................... 58 
7.2.8 
Vital Signs ................................................................................. 58 
7.2.9 
Eastern Cooperative Oncology Group Performance 
Status ........................................................................................ 58 
7.2.10 
Electrocardiogram Performed in Triplicate ................................. 58 
7.2.11 
Echocardiogram (ECHO) / Multi-gated Acquisition 
(MUGA) Scan ............................................................................ 59 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 14 of 105 
CONFIDENTIAL 
 
 
7.2.12 
Tumor Assessments .................................................................. 59 
7.2.13 
Serum Free Light Chain ............................................................ 59 
7.2.14 
Quantitative Immunoglobulin ..................................................... 59 
7.2.15 
Beta-2 Microglobulin .................................................................. 60 
7.2.16 
Skeletal Survey ......................................................................... 60 
7.2.17 
Pharmacokinetic Blood Sampling .............................................. 60 
7.2.18 
Blood Samples .......................................................................... 60 
7.2.19 
Clinical Laboratory Assessments ............................................... 61 
7.2.20 
Screening .................................................................................. 61 
7.2.21 
Screening Procedures to Determine Eligibility ........................... 62 
7.2.22 
Treatment .................................................................................. 63 
7.2.23 
End of Treatment ....................................................................... 64 
7.2.24 
End of Study Visit ...................................................................... 65 
7.3 
Antibody Testing Procedures .................................................................... 66 
7.4 
Biomarker Development ............................................................................ 66 
7.5 
Bone Marrow ............................................................................................. 67 
7.6 
Pharmacogenetic Studies ......................................................................... 67 
7.7 
Sample Storage and Destruction ............................................................... 67 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 68 
8.1 
Subjects’ Decision to Withdraw ................................................................. 68 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 69 
8.3 
Reasons for Removal From Treatment or Study ....................................... 69 
8.3.1 
Reasons for Removal From Treatment ...................................... 69 
8.3.2 
Reasons for Removal From Study ............................................. 70 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 70 
9.1 
Definition of Safety Events ........................................................................ 70 
9.1.1 
Adverse Events ......................................................................... 70 
9.1.2 
Serious Adverse Events ............................................................ 71 
9.2 
Safety Event Reporting Procedures .......................................................... 71 
9.2.1 
Adverse Events ......................................................................... 71 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 71 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 72 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 73 
9.3 
Pregnancy and Lactation Reporting .......................................................... 74 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 75 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 75 
10.1.1 
Study Endpoints ........................................................................ 75 
10.1.2 
Analysis Sets ............................................................................. 75 
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10.1.3 
Covariates and Subgroups ........................................................ 76 
10.2 
Sample Size Considerations ..................................................................... 76 
10.3 
Planned Analyses ..................................................................................... 76 
10.3.1 
Interim Analyses ........................................................................ 76 
10.3.2 
Data Monitoring Committee (DMC), Data Review 
Team (DRT) or Dose Level Review Team (DLRT) .................... 77 
10.3.3 
Primary Analysis ........................................................................ 77 
10.3.4 
Final Analysis ............................................................................ 77 
10.4 
Planned Methods of Analysis .................................................................... 77 
10.4.1 
General Considerations ............................................................. 77 
10.4.2 
Primary Endpoints ..................................................................... 78 
10.4.2.1 
Safety Endpoints ..................................................... 78 
10.4.2.2 
Adverse Events ....................................................... 78 
10.4.2.3 
Dose Limiting Toxicities ........................................... 78 
10.4.2.4 
Clinical Laboratory Tests ......................................... 78 
10.4.2.5 
Vital Signs ............................................................... 79 
10.4.2.6 
Electrocardiograms ................................................. 79 
10.4.3 
Pharmacokinetic Endpoints ....................................................... 79 
10.4.4 
Secondary Endpoint(s) .............................................................. 80 
10.4.4.1 
Efficacy Endpoint Analyses ..................................... 80 
10.4.4.2 
Anti-AMG 224 Antibodies ........................................ 80 
10.4.5 
Exploratory Endpoints ............................................................... 80 
11. 
REGULATORY OBLIGATIONS ............................................................................ 80 
11.1 
Informed Consent ...................................................................................... 80 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 81 
11.3 
Subject Confidentiality ............................................................................... 82 
11.4 
Investigator Signatory Obligations ............................................................. 82 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 83 
12.1 
Protocol Amendments and Study Termination .......................................... 83 
12.2 
Study Documentation and Archive ............................................................ 83 
12.3 
Study Monitoring and Data Collection ....................................................... 84 
12.4 
Investigator Responsibilities for Data Collection ........................................ 85 
12.5 
Language .................................................................................................. 85 
12.6 
Publication Policy ...................................................................................... 86 
12.7 
Compensation ........................................................................................... 86 
13. 
REFERENCES ..................................................................................................... 87 
14. 
APPENDICES ...................................................................................................... 90 
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List of Tables 
Table 1.  3+3 Dose Level Decision Rules ...................................................................... 29 
Table 2.  Cohort and Dose Exploration Schema ............................................................ 41 
Table 3.  Dose Reduction of AMG 224 for Toxicity (Only in Dose Expansion) ............... 42 
Table 4.  Dosing Guideline Based on Platelet Count After 2nd Cycle .............................. 46 
Table 5.  Schedule of Assessments – Dose Exploration and Dose Expansion .............. 53 
Table 6.  Approximate Blood Volumes for Part 1 and Part 2 .......................................... 60 
Table 7.  Clinical Laboratory Assessments .................................................................... 61 
List of Figures 
Figure 1.  Preliminary Serum Concentration-time Profiles of AMG 224 
Conjugated Antibody, Total Anti-BCMA Antibody, and DM1 in 
Subjects With Relapsed or Refractory Multiple Myeloma 
Following Q3W Administration of AMG 224 as IV Infusion ...................... 25 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 91 
Appendix B.  Sample Serious Adverse Event Form ....................................................... 93 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 96 
Appendix D.  International Myeloma Working Group Uniform Response 
Criteria for Multiple Myeloma (IMWG-URC) ............................................ 98 
Appendix E.  ECOG Performance Status and NYHA Classification ............................. 100 
Appendix F.  Medications That May Cause QTc Prolongation ..................................... 101 
Appendix G.  Definition of Relapsed or Refractory Disease and Line of 
Therapies ............................................................................................. 104 
Appendix H.  Peripheral Neuropathy Assessment ....................................................... 105 
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1. 
OBJECTIVES 
1.1 
Primary 
 
Evaluate the safety and tolerability of AMG 224 monotherapy in subjects with 
relapsed or refractory multiple myeloma. 
 
Determine the maximum tolerated dose (MTD) and/or recommended phase 2 
dose (RP2D) of AMG 224, if possible. 
1.2 
Secondary 
 
Characterize the pharmacokinetics (PK) of AMG 224 when administered 
intravenously (IV) once every 3 weeks (Q3W). 
 
Evaluate preliminary efficacy of AMG 224 when given as monotherapy in 
relapsed and refractory multiple myeloma according to International Myeloma 
Working Group (IMWG) uniform response criteria (Durie, 2006 and 
Rajkumar 2011). 
 
Evaluate the preliminary rate of conversion to minimal residual disease (MRD) 
negativity. 
 
Evaluate the incidence of anti-AMG 224 antibody formation. 
1.3 
Exploratory 
 
Correlate clinical response with B-cell maturation antigen (BCMA) expression in 
pre-dose bone marrow biopsies. 
 
Evaluate gene expression profiling by sequencing in pre-dose biopsies/plasma to 
identify gene signatures for response. 
 
Determine prognostic and predictive value of serum BCMA and BCMA ligands a 
proliferation inducing ligand (APRIL)/B-cell activation factor (BAFF) from multiple 
myeloma serum samples. 
 
Assess multiple myeloma blood samples for the relevant circulating tumor cell. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Multiple Myeloma Background 
Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal 
proliferation of malignant plasma cells in the bone marrow microenvironment, 
monoclonal protein in the blood or urine and associated organ dysfunction 
(Palumbo and Anderson, 2011).  Multiple myeloma accounts for almost 2% of all 
cancers and 20% of hematologic malignancies.  The disease is slightly more common in 
males and African Americans (Siegel, 2015).  Multiple myeloma remains an incurable 
cancer, although recent improved understanding of pathogenesis of myeloma has led to 
the development of new treatments and improved survival (Smith and Yong, 2013).  
Myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma 
cells that are derived from post–germinal-center B cells.  Multistep genetic and 
micro-environmental changes lead to the transformation of these cells into a malignant 
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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 only clinical observation, since early treatment with 
conventional chemotherapy has shown no benefit.  Investigational trials are currently 
evaluating the ability of immunomodulatory drugs to delay the progression from 
asymptomatic to symptomatic myeloma.  The treatment strategy is mainly related to age.  
Current data would support the initiation of induction therapy with thalidomide, 
lenalidomide, or bortezomib plus hematopoietic stem-cell transplantation for patients 
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 patients or those with coexisting conditions.  
Conventional therapy combined with thalidomide, lenalidomide, or bortezomib should be 
administered in patients older than 65 years of age.  Less intensive approaches that limit 
toxic effects or prevent treatment interruption that would reduce the intended treatment 
effect should be considered in patients over 75 years of age or in younger patients with 
coexisting conditions.  Biologic age, which may differ from chronologic age and the 
presence of coexisting conditions should determine treatment choice and drug dose 
(Palumbo and Anderson, 2011).  
Treatment of relapsed or refractory multiple myeloma (RRMM) presents a special 
therapeutic challenge, due to the heterogeneity of disease at relapse and the absence of 
clear biological based recommendations regarding the choice of salvage therapies at 
various time points of disease progression.  With increasing recognition of the inherent 
clonal heterogeneity and genomic instability of the plasma cells influencing both inherent 
and acquired therapeutic resistance, the identification of the optimal choice and 
sequence of therapies has become critical.  Several new agents and targets are 
currently under development and show considerable promise.  Besides Carfilzomib and 
Pomalidomide that were granted approval by US FDA in 2012 and 2013 respectively for 
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RRMM, the next generation proteasome inhibitors (PIs) (ixazomib, marizomib and 
oprozomib), other molecularly targeted therapies directed at specific cell signaling 
pathways (including histone deacetylase inhibitors, PI3K/AKT/mTOR inhibitors, 
Hsp90 inhibitors, cell cycle inhibitors, kinesin spindle protein inhibitors) are currently in 
development.  
The first monoclonal antibodies targeting SLAMF7 (elotuzumab) and 
CD38 (daratumumab) have recently been granted approval.  Emplicity™ (elotuzumab) is 
indicated in combination with lenalidomide and dexamethasone for the treatment of 
patients with multiple myeloma who have received one to three prior therapies.  The 
1 and 2-year rates of PFS for elotuzumab in combination with lenalidomide and 
dexamethasone treatment were 68% and 41%, respectively, compared with 57% and 
27%, respectively, for lenalidomide and dexamethasone treatment in the corresponding 
phase 3 trial (Lonial et al, 2015).  Darzalex® (daratumumab) approval was based on the 
pivotal phase III POLLUX and CASTOR clinical studies.  Daratumumab in combination 
with lenalidomide and dexamethasone, or bortezomib and dexamethasone, substantially 
improved progression-free survival and overall response rates for previously treated 
patients with multiple myeloma, regardless of prior treatment exposure or cytogenetic 
risk.  Daratumumab with lenalidomide and dexamethasone lowered the risk of disease 
progression or death by 64 percent, compared with lenalidomide and dexamethasone 
alone, in patients with multiple myeloma who had received 1 to 3 prior lines of therapy.  
Daratumumab with bortezomib and dexamethasone reduced the risk of disease 
progression or death by 61 percent in similar patients, compared with bortezomib and 
dexamethasone alone (Dimopoulos et al, 2016; Palumbo et al, 2016).  Even newer 
approaches such as chimeric antigen-receptor (CAR) T-cells, antibody-drug conjugates 
and bispecific antibodies targeting BCMA have also demonstrated first promising 
anti-myeloma activity (Cohen, 2016; Berdeja, 2016; Panowski, 2016).  
Despite advances in the management of multiple myeloma as described, relapse is 
inevitable in almost all patients.  Recurrence of myeloma is typically more aggressive 
with each relapse, leading to the development of treatment-refractory disease, which is 
associated with a shorter survival (Dimopoulos, 2014).  More treatment options are still 
warranted. 
2.2 
AMG 224 Background 
AMG 224 is an antibody drug conjugate (ADC) comprised of anti-BCMA-MCC-DM1 
where anti-BCMA is an anti-human BCMA IgG1 antibody; MCC is the non-cleavable 
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linker 4-[N-maleimidomethyl] cyclohexane-1-carboxylate conjugated to lysine residues in 
the antibody; and DM1 is a semi-synthetic derivative of the ansamycin antibiotic, 
maytansine conjugated to MCC.  There is an average of 3.5 DM1 molecules per 
antibody. 
The antibody portion of AMG 224 consists of anti-human BCMA Xenomouse 
IgG1 antibody that selectively binds to native BCMA, does not cross-react to B-cell 
activating factor receptor (BAFF-R) or Trans-membrane activator and calcium modulator 
(TACI), and is internalized rapidly into BCMA-expressing myeloma cell lines. 
The anti-tubulin warhead is a maytansinoid.  Maytansine, an ansamycin antibiotic, was 
originally isolated from an Ethiopian shrub, Maytenus serrata.  DM1 is reported to bind to 
tubulin in the vinca alkaloid binding site and to inhibit tubulin polymerization 
(Sackett, 1995). 
Upon internalization of an antibody drug conjugate, with a “non-cleavable” linker, the 
antibody was catabolized into individual amino acids, including amino acids with 
warhead still attached (Erickson, 2006).  The amino acid-linker-drug, Lysine-MCC-DM1, 
was identified in the cytoplasm of cells.  Once internalized, this warhead was capable of 
killing target-expressing tumor cells in vitro and in vivo.  The amino acid-linker-drug is 
considerably less potent on cells than the free warhead.  The highly restricted normal 
tissue BCMA expression, the robust antibody internalization of BCMA specific antibodies 
into BCMA expressing tumor cells and the ability of the anti BCMA conjugated to DM1 
with a non-cleavable linker to deliver a level of warhead capable of mediating tumor cell 
kill combine to create a promising impactful therapy for BCMA-expressing malignancies. 
2.2.1 
AMG 224 Preclinical Pharmacology 
Amgen pre-clinical pharmacology studies have shown that AMG 224 binds with high 
affinity to human BCMA.  Flow cytometry indicates that anti-BCMA antibody binds to 
recombinant BCMA from cynomolgus monkey and humans with similar affinity, but does 
not bind to rat BCMA. 
The activity of AMG 224 against human multiple myeloma cells has been investigated 
both in vitro and in vivo.  Upon binding to BCMA-expressing H929 or KMS26 human 
multiple myeloma cells in culture, AMG 224 has been shown to internalize into the cells 
where it is catabolized into its individual amino acids, thereby releasing the 
lysine-MCC-DM1 warhead into the cytoplasm.  It can then associate with tubulin during 
mitosis thereby inhibiting cell division resulting in cell death. 
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The activity in animals was investigated using KMS26 (express 3,000 BCMA sites/cell 
on average) human multiple myeloma tumors grown as orthotopic xenografts in murine 
model.  In the KMS26 model, significant anti-tumor activity was still observed at a single 
dose of AMG 224 as low as 62.5 μg/kg DM1 equivalents.  KMS26 tumors that grew back 
post initial low dose AMG 224 therapy maintained their sensitivity to AMG 224 upon 
re-treatment.  Administration of AMG 224 at 62.5, 150 and 250g DM1/kg resulted in a 
protection against KMS26-luc mediated osteolytic bone lesions.   
2.2.2 
Pharmacokinetics 
The pharmacokinetics (PK) of AMG 224 was characterized in cynomolgus monkeys 
following single dose intravenous (IV) administration and following multiple-dose 
IV administration.  
Single dose IV PK of AMG 224 was studied at 
 and 
 dose levels.  After 
single dose IV administration of AMG 224 the plasma exposures for AMG 224 
conjugated antibody (anti-BCMA antibody with at least one DM1 molecule conjugated to 
the antibody), total anti-BCMA antibody (sum of unconjugated anti-BCMA antibody and 
AMG 224 conjugated antibody), and DM1 (total unconjugated DM1) increased in an 
approximately dose proportional manner over the studied doses 
) in 
cynomolgus monkeys.  Relatively similar plasma concentration profiles for AMG 224 
conjugated antibody and total anti-BCMA antibody were observed indicating low plasma 
exposure for unconjugated antibody.  In addition, low plasma exposures were observed 
for DM1.  
The multiple-dose PK of AMG 224 was characterized in the GLP toxicology study 
following multiple once every 2 weeks (Q2W) IV administration of AMG 224 at 
, 
 and 
 dose levels in cynomolgus monkeys.  Following multiple dosing 
the plasma exposures for AMG 224 conjugated antibody, total anti-BCMA antibody, and 
DM1 increased in an approximately dose proportional manner over the studied dose 
range (
).  No significant plasma accumulation (accumulation ratio < 2) was 
observed for any of the PK analytes upon multiple Q2W dosing with AMG 224 in 
cynomolgus monkeys.  Following multiple dosing relatively similar plasma concentration 
profiles for AMG 224 conjugated antibody and total anti-BCMA antibody were observed 
indicating low plasma exposure for unconjugated antibody.  In addition, low plasma 
exposures were observed for DM1.  
A 2-compartment model best described the PK of AMG 224 conjugated antibody in 
cynomolgus monkey.  The half-life of AMG 224 conjugated antibody in cynomolgus 
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monkey from this model was estimated to be approximately 8 days.  A 2-compartment 
model identical in structure to the one used to fit the cynomolgus monkey PK data was 
used to simulate human PK for AMG 224 conjugated antibody.  Human PK parameters 
were predicted allometrically from the cynomolgus monkey PK parameters.  The 
predicted half-life of AMG 224 conjugated antibody in humans is approximately 15 days. 
2.2.3 
AMG 224 Preclinical Toxicology 
The potential toxicity of AMG 224 was evaluated in a 28-day intravenous study in the 
cynomolgus monkey at 
 administered every 2 weeks for a total of 
3 doses.  Scheduled necropsy was on Day 36, one week after the last dose.  One 
animal at 
 was euthanized on Day 35 after being found in a moribund condition 
that was attributed to bacteremia secondary to marked bone marrow hypocellularity of all 
cell lineages.  Heart rate was increased at 
 at the end of the study.  Clinical 
pathology changes included decreased lymphocytes, platelets and red cell mass, 
increased liver enzymes, and indicators of an acute phase response.  Light microscopic 
changes attributed to expected DM1 pharmacology included degeneration/regeneration 
in epithelial cells of the choroid plexus, liver, adrenal gland and salivary gland, axonal 
degeneration of the spinal cord and sciatic nerve, and lymphocyte depletion of lymphoid 
organs.  The effects in this study were largely consistent with those of other ADC’s 
containing the same DM1 warhead (Poon, 2013, Saber and Leighton, 2015) and are 
expected to be reversible.  Based on the AMG 224-related decreased bone marrow 
cellularity with secondary bacteremia that resulted in the early euthanasia of one animal 
at 
, the highest non-severely toxic dose (HNSTD) was 
   
2.3 
Risk Assessment 
The target cell populations of AMG 224 are plasma cells, mature and activated B cells 
shown to express BCMA; hence the potential on-target toxicity is depletion of these 
hematologic cell types and depleting immunoglobulin level which could result in an 
increased risk of infection.  In a recent review of antibody-drug conjugates by the FDA, it 
was revealed that the small molecule appears to dictate the dose limiting adverse 
events.  For ADCs sharing the small molecule (SM) drug, the same linker, and the same 
SM:Ab ratio, available prior clinical data can inform the design of a safe yet efficient 
Phase 1 clinical trial design (Saber, 2015).  Based on experiences with an approved 
ADC Trastuzumab emtansine (T-DM1 [Kadcyla®]) and Amgen past experiences 
(AMG 595) with antibody drug conjugates utilizing MCC-DM1 as a linker warhead and 
the same drug-to-antibody ratio (DAR), the anticipated toxicities include 
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thrombocytopenia and hepatotoxicity.  Clinical signs and symptoms of infection, bleeding 
and liver dysfunction, platelet counts and liver enzymes, along with other safety labs, will 
be monitored during the study and at the appropriate time points to ensure subjects’ 
safety.  Refer to the Investigator’s Brochure for the full details of the potential and 
identified risks of AMG 224. 
2.4 
Rationale 
2.4.1 
Target Rationale 
B-cell Maturation Antigen (BCMA, TNFRSF17, CD269) is a TNF receptor superfamily 
member and a type III integral membrane protein (Madry, 1998).  BCMA expression on 
normal tissues is highly restricted to the B-cell lineage where it is predominately 
expressed in the secondary follicle/germinal center of tonsils/lymph nodes (Chiu, 2007), 
on plasmablasts (Avery, 2003) and on differentiated plasma cells (O’Connor, 2004).  
Analysis of BCMA mRNA and protein expression in human tissues indicated that, except 
for plasma cells, BCMA is not detectably expressed in normal human tissues 
(Carpenter, 2013).  The biological function of BCMA, promoting the survival of plasma 
cells, is mediated via binding to its ligands APRIL and BAFF (Yu et al, 2000).  In addition 
to BCMA, APRIL binds to Trans-membrane activator and calcium modulator (TACI) and 
BAFF binds to B-cell activating factor receptor (BAFF-R) (Gross, 2000) and 
(Thompson, 2001).  Both APRIL and BAFF are expressed predominately by 
myeloid-derived cells including macrophages, DCs and neutrophils that form part of the 
bone marrow stroma and also reside in lymphoid organs.  Disruption of the 
BCMA/BAFF-APRIL interaction in mice deficient for BCMA results in decreased survival 
of long-lived plasma cells (Avery, 2003).  
BCMA is expressed at relatively higher levels on malignant plasma cells (multiple 
myeloma) than the level observed on normal plasma cells (Zhao et al, 2008).  Multiple 
independent analyses of mRNA in primary human MM samples indicate that all MM 
patients’ samples have high levels of BCMA (Moreaux, 2004 and Tai et al, 2006).  The 
high prevalence of BCMA expression in MM has been confirmed at the protein level by 
immunohistochemistry or flow cytometry, which demonstrated cell-surface BCMA 
expression in neoplastic plasma cells from all MM patients tested (Novak, 2004 and 
Carpenter, 2013).   
For this phase I trial, relapsed or refractory multiple myeloma has been chosen as the 
indication to pursue with the anti BCMA ADC because of the near 100% incidence of 
BCMA expression in this patient population. 
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2.4.2 
Dose Selection Rationale 
Dose Exploration Phase (Part 1) 
In this first-in-human (FIH) study of AMG 224 in subjects with relapsed or refractory 
multiple myeloma the dose exploration phase dose levels 30, 
 
 administered intravenously (IV) once every 3 week (Q3W) are selected 
based on toxicology, pharmacology, and pharmacokinetic (PK) data of AMG 224 as well 
as prior clinical safety and tolerability experience in cancer patients following 
administration of antibody drug conjugates (ADCs) with same cytotoxin, linker, and 
drug-to-antibody ratio (DAR) as AMG 224. 
ADCs AMG 595 and Trastuzumab emtansine (T-DM1 [Kadcyla®]) share with AMG 224 
the same cytotoxin (DM1), the same linker (MCC), and the same DAR (~3.5).  Based on 
a retrospective analysis of ADCs, prior clinical data from ADCs sharing the same 
cytotoxin, linker, and DAR can be used to inform the design of FIH study of a new ADC 
with the same cytotoxin, linker, and DAR (Saber and Leighton, 2015).  Accordingly, a 
dosing interval of Q3W has been selected for AMG 224 based on the recovery profile 
observed from the primary safety concern thrombocytopenia, following administration of 
ADCs like AMG 595 and T-DM1 to cancer patients as single agents.  
The AMG 224 starting dose of 30 mg is based on the ICH S9 guidance for the maximum 
recommended starting dose in patients for novel therapeutics for advanced cancer 
indications.  A retrospective analysis of ADCs also indicates that this approach provides 
a safe FIH starting dose for ADCs (Saber and Leighton, 2015).  For AMG 224 in the 
repeat-dose GLP toxicology study in cynomolgus monkey the HNSTD was 
 
1/6th of the HNSTD and scaling for difference in body surface area between cynomolgus 
monkeys and humans yields a dose of 32 mg for humans.  Accordingly, a conservative 
estimate of 30 mg has been selected as the starting dose.  The planned dose 
exploration steps at lower dose levels are followed by more conservative dose 
exploration steps at higher dose levels in the study.  The planned dose explorations and 
planned nominal highest dose for AMG 224 are also based on the thrombocytopenia 
dose limiting toxicity for ADCs like T-DM1 in cancer patients and will be guided by 
observed safety and tolerability of AMG 224.   
Preliminary PK results of AMG 224 following administration as an IV infusion Q3W to 
adult subjects with relapsed or refractory multiple myeloma in ongoing FIH study are 
available for 12 subjects after the first dose of 30 mg (3 subjects), 
 (3 subjects), 
 (3 subjects), and 
 (3 subjects).  Mean serum concentration-time profiles 
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Product:  AMG 224 
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for AMG 224 conjugated antibody, total anti-BCMA antibody, and DM1 are shown in 
Figure 1. 
Figure 1.  Preliminary Serum Concentration-time Profiles of AMG 224 Conjugated 
Antibody, Total Anti-BCMA Antibody, and DM1 in Subjects With Relapsed or 
Refractory Multiple Myeloma Following Q3W Administration of AMG 224 as 
IV Infusion 
 
Ab = antibody; BCMA = B cell maturation antigen; IV = intravenous(ly); LLOQ = lower limit of quantitation; 
Q3W = once every 3 weeks 
Mean (+ SD) concentration-time profiles:  n = 3 subjects each dose cohort (30 mg Q3W, 
 Q3W; 
 
Q3W; 
 Q3W 
Analytes: 
 
AMG 224 conjugated Ab = anti-BCMA Ab with at least 1 DM1 molecule conjugated to the Ab 
 
Total anti-BCMA Ab = sum of unconjugated anti-BCMA Ab plus AMG 224 conjugated Ab 
 
DM1 = unconjugated total DM1 
DM1 LLOQ 0.25 ng/mL:  DM1 levels following administration of 30 mg and 
 doses were below LLOQ. 
IC90KMS26:  AMG 224 conjugated Ab concentration expected to result in 90% killing of tumor cells 
estimated from the pharmacokinetic/pharmacodynamic modeling of AMG 224-mediated tumor burden 
reduction observed in orthotopic xenograft (BCMA-expressing human multiple myeloma [KMS26]) mice. 
Source:  Pharsight Knowledgebase Server: http://uslv-pweb-pks02/pks/WebUI Study: 
20130314_BSMLIMSPLUS_Clinical_v1 
Following Q3W IV administration of AMG 224 to subjects with relapsed or refractory 
multiple myeloma, similar pharmacokinetic profiles were observed over the 3-week 
dosing interval for AMG 224 (anti-BCMA antibody with at least 1 DM1 molecule 
conjugated to the antibody) and total anti-BCMA antibody (sum of AMG 224 plus 
unconjugated anti-BCMA antibody), indicating low levels of circulating unconjugated 
antibody.  In addition, low plasma levels were observed for DM1 (total unconjugated 
DM1).  The DM1 levels following administration of AMG 224 30 mg or 
 doses were 
below the lower limit of quantitation (LLOQ) (0.25 ng/mL); and following administration of 
0
1 6 8
3 3 6
5 0 4
0 .1
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
3 0 ; A M G  2 2 4  co n ju g a te d  A b
T im e (h)
S erum  conc., n g/m L (M ea n +  S D )
IC 90 K M S26
3 0; T otal an ti-B C M A  A b
A M G  2 2 4  co n ju g a te d  A b
 A M G  2 2 4  co n ju g a te d  A b
T otal an ti-B C M A  A b
DM 1
  T otal an ti-B C M A  A b
D M 1 LLO Q  0.25 ng/m L
A M G  2 2 4  co n ju g a te d  A b
T otal anti-B C M A  A b
 D M 1
D o se  (m g , Q 3 W ); A n a lyte
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 26 of 105 
CONFIDENTIAL 
 
 
 dose were close to the LLOQ, with mean maximum observed 
concentrations of 0.31 ng/mL and 0.52 ng/mL, respectively. 
Based on preliminary observed PK profile for AMG 224 conjugated antibody (Figure 1), 
trough serum concentrations following AMG 224 doses ≥ 30 mg Q3W exceed the 
90% tumor cell killing concentration (IC90) estimated from the pharmacokinetic/ 
pharmacodynamic modeling of AMG 224-mediated tumor burden reduction observed in 
orthotopic xenograft (BCMA-expressing human multiple myeloma [KMS26]) in mice. 
Hence, AMG 224 doses ≥ 30 mg Q3W are expected to be potentially efficacious, which 
is in line with preliminary response observed at AMG 224 doses ≥ 30 mg Q3W doses in 
the ongoing FIH study.  The starting dose of 30 mg Q3W is selected not only to be a 
safe starting dose (as per the ICH S9 guidance for novel therapeutics for advanced 
cancer indications) but also potentially efficacious.  Also higher trough concentrations in 
patients have been associated with improved efficacy based on a recent 
exposure-response analysis by the FDA for the ADC T-DM1 (Wang, 2014).  Accordingly, 
the design of the dose selection strategy for the AMG 224 FIH study is to minimize 
treating subjects with relapsed or refractory multiple myeloma in the study with 
sub-efficacious doses of AMG 224.  
Preliminary pharmacokinetics results indicated dose-related increase in serum exposure 
for AMG 224 conjugated antibody and lack of any significant accumulation upon multiple 
dosing following the Q3W dosing regimen with mean serum accumulation ratio of 
≤ 1.4 for AMG 224 conjugated antibody following the Day 22 dose.  
Safety margins were calculated based on the observed exposures for the AMG 224 
conjugated antibody in subjects with relapsed or refractory multiple myeloma and at the 
HNSTD in cynomolgus monkey from the GLP toxicology study.  At the starting dose of 
30 mg the observed safety margins were 24 and 21 based on the maximum plasma 
concentration (Cmax) and area under the plasma concentration time curve over the 
dosing interval of 3 weeks (AUC0-3 week), respectively relative to observed exposure at the 
HNSTD in cynomolgus monkey.  At the proposed highest planned dose of 
 safety 
margins are expected to be approximately 2.8 and 2.7 based on Cmax and AUC0-3week, 
respectively relative to observed exposure at the HNSTD in cynomolgus monkey.  
Overall, preliminary results indicate that AMG 224 exhibits a favorable PK profile in its 
target patient population of subjects with relapsed or refractory multiple myeloma.  The 
primary safety concern thrombocytopenia is monitor-able and expected to be reversible, 
and the safety and tolerability data from prior dose levels will guide the dose escalations 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 27 of 105 
CONFIDENTIAL 
 
 
and the planned top dose for AMG 224 in the dose exploration phase 
(see Section 6.2.1.2 Study Dose Exploration and Stopping Rules).     
Dose Expansion Phase (Part 2) 
In the Part 1 of the study a fixed dosing (ie, dose not adjusted for individual subject’s 
body weight) will be evaluated and in the Part 2 of study body weight based dosing will 
be evaluated. Subjects will be treated with preliminary MTD identified from the Dose 
Exploration part of the study adjusted for their body weight, which is 
 Q3W. An 
integrated preliminary analysis of dose exploration phase data for the primary safety 
concern of thrombocytopenia indicates that a dose of 
 Q3W is not associated 
with concerning platelet count decreases (greater than Grade 3) during the DLT 
evaluation period. A dose of 
 is also expected to be efficacious based on 
patients’ serum trough coverage of the projected efficacious exposures (90% tumor cell 
killing concentration (IC90)) estimated from the pharmacokinetic/pharmacodynamics 
modeling of AMG 224-mediated tumor burden reduction observed in orthotopic 
xenograft (BCMA-expressing human multiple myeloma [KMS26]) in mice, which is also 
in line with preliminary response observed in the study. Additionally, higher trough 
concentrations in patients have been associated with improved efficacy based on a 
recent exposure-response analysis by the FDA for the ADC T-DM1 (Wang, 2014), with 
same cytotoxin, linker and DAR as AMG 224. Hence, a dose of 
 is expected to 
be well tolerated, as well as efficacious, and is recommended for the dose expansion 
phase.  For therapeutic monoclonal antibody-based therapies a full assessment of body 
weight effect on the PK/PD should be conducted to determine the optimal dosing 
approach prior to conducting the registration trial and a recommendation for adjustment 
or lack of adjustment of dose based on body weight be made once sufficient clinical data 
is available (Bai, 2012 and Wang, 2009).  When sufficient AMG 224 clinical data 
becomes available, a full assessment of body size effect on PK/PD will be conducted to 
determine the optimal dosing approach prior to conducting the registration trial for 
AMG 224 in multiple myeloma patients. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 28 of 105 
CONFIDENTIAL 
 
 
2.5 
Clinical Hypotheses 
 
 AMG 224 administered by IV infusion at (or one dose level below) the 
preliminary MTD identified during the dose exploration part of the study is 
expected to achieve acceptable safety and tolerability in subjects with relapsed 
or refractory multiple myeloma. 
 
A favorable PK profile will be achieved with AMG 224 administered by IV infusion 
Q3W. 
 
Objective responses by IMWG uniform response criteria will be observed at a 
dose level that achieves acceptable safety and tolerability.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 1, first-in-human, multicenter; non-randomized, open-label, 
dose-exploration and dose expansion study of AMG 224 IV Q3W for subjects with 
relapsed or refractory multiple myeloma.  The study will be conducted in two parts: 
Part 1 - Dose Exploration and Part 2 - Dose Expansion.   
Eligible subjects enrolled in the study will receive AMG 224 IV once Q3W beginning at 
study Day 1.  During the initial DLT window (Day 1 through Day 28) subjects will be 
assessed for DLT.  DLTs are defined in Section 6.2.1.6.  Dosing with AMG 224 may 
continue Q3W unless there is evidence of progressive disease (PD) defined by IMWG, 
the subject becomes intolerant to the study medication, signs and symptoms of clinical 
progression are evident as determined by the principal investigator, or the subject 
withdraws consent.  
Part 1 – Dose Exploration 
In Part 1 for the first dose level and at each new higher dose level, the first enrolled 
subject will be treated, and then after a period of 24 hours, subsequent subjects will be 
treated, provided that there are no safety concerns relating to the treatment of the first 
subject.   
The dose-exploration cohorts will define the preliminary MTD, safety, tolerability, PK, 
and PD of AMG 224.  A 3+3 design will be used to make a preliminary estimate of MTD.  
The preliminary MTD is defined as the maximum dose at which fewer than 33% of 
subjects experience a DLT.  A final estimate of the MTD will be made using data from 
Dose Exploration and Dose Expansion.  Planned dose levels for the dose-exploration 
cohorts are as follows: 30, 
 of AMG 224 
(IV; Q3W).   
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 29 of 105 
CONFIDENTIAL 
 
 
Dose exploration decisions will be made by the Dose Level Review Team (DLRT).  All 
cumulative safety and laboratory data will be reviewed prior to making dose exploration 
decisions.  Safety data from all enrolled subjects in preceding cohorts and dose levels 
will also be considered.  Additionally, the DLRT may stop enrollment into a cohort at any 
time to evaluate safety. 
3+3 Design: 
Dose escalation decisions will be made in accordance with a 3+3 design modified to 
allow flexibility in the initial cohort size (decision rules noted in Table 1).  Dose escalation 
will occur at the planned dose levels until the MTD is determined or until the highest 
dose level is tested.  The MTD is defined as the highest dose level with an observed 
incidence of DLT in < 33% of subjects enrolled in a cohort dose level.  At least 6 subjects 
will be treated at the MTD or highest tested dose.  
Table 1.  3+3 Dose Level Decision Rules 
#Subjectsa 
#Subjects with DLT 
Decision 
3-4 
1 
Enroll 2-3 additional subjects at same dose 
level  
3-4 
0 
Escalateb 
3-4 
≥ 2 
De-escalatec 
6 
1 
Escalateb 
6 
≥ 2 
De-escalatec 
a Subjects who are not DLT-evaluable (see Section 3.4) are excluded from the count of subjects 
b If final dose level has been reached, accrual will be suspended. 
c If 6 subjects already entered at next lower dose level, the estimated MTD has been established. 
Part 2 – Dose Expansion: 
In the Part 2 of the study up to 20 subjects with relapsed or refractory multiple myeloma 
will be treated.  Subjects will be divided into the following 2 groups based on the status 
of prior treatment with CD38 targeting antibody (eg, Daratumumab): 
 
Group A will consist of subjects who had prior treatment with a CD38 targeting 
antibody (at least 10 subjects). 
 
Group B will consist of subjects who are naïve to CD38 targeting antibody treatment 
(approximately 10 subjects). 
A body weight-based dosing will be evaluated in the Dose Expansion part of the study.  
Subjects will be treated with preliminary MTD identified from the Dose Exploration part of 
the study 
 adjusted for their body weight. Subjects with grade 2 
thrombocytopenia at baseline (ie, platelet count < 75 to 50 x 109/L) should be started at 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 30 of 105 
CONFIDENTIAL 
 
 
a reduced dose of 
.  The subsequent doses of AMG 224 could be further 
reduced to 
 if the criteria for dose reduction for thrombocytopenia are met as 
per sections 6.2.1.5 and 6.3.1.  For therapeutic monoclonal antibody-based therapies a 
full assessment of body weight effect on the PK/PD should be conducted to determine 
the optimal dosing approach prior to conducting the registration trial and a 
recommendation for adjustment or lack of adjustment of dose based on body weight be 
made once sufficient clinical data is available (Bai, 2012 and Wang, 2009).  In the Part 1 
of the study a fixed dosing (ie, dose not adjusted for individual subject’s body weight) will 
be evaluated and in the Part 2 of study body weight-based dosing will be evaluated. 
When sufficient AMG 224 clinical data becomes available, a full assessment of body 
size effect on PK/PD will be conducted to determine the optimal dosing approach prior to 
conducting the registration trial for AMG 224 in multiple myeloma patients. 
During dose-expansion, after 5 subjects have enrolled (combining Group A and 
B subjects) and completed 28 days on study.  A toxicity probability interval (TPI) 
Bayesian model utilizing all current DLT-evaluable subjects will be fit to evaluate the 
appropriateness of the preliminary MTD from dose exploration.  The subsequent 
subjects to be enrolled in dose expansion may be dosed with the updated dose level.  A 
final estimate of the MTD will be made based on a toxicity probability interval (TPI) 
Bayesian model utilizing all DLT evaluable subjects from the dose exploration and dose 
expansion cohorts. 
The DLRT will review safety after 5 subjects have enrolled and completed 28 days on 
study.  The review will include all available safety data.  If concerns arise from either 
planned or unplanned safety reviews, the DLRT may request additional review or 
recommend modifying or suspending the study  
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
The study will be conducted at approximately 4 to 6 sites in the United States and 
Australia.  Sites that do not enroll subjects into an open cohort within 4 months of site 
initiation may be terminated and replaced.  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 31 of 105 
CONFIDENTIAL 
 
 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Subjects with 
relapsed or refractory multiple myeloma is eligible for this study.  Up to 60 evaluable 
subjects will be enrolled at approximately 4-6 clinical centers in the US and Australia.  In 
the dose exploration cohorts, approximately 40 subjects will be enrolled.  Up to 
6 subjects will be enrolled at the MTD or highest tested dose to gain additional safety 
and PK information.  In the expansion cohorts, up to 20 subjects will be enrolled and 
treated with MTD or highest tested dose of AMG 224.  The rationale for the number of 
subjects required is detailed in Section 10. 
3.4 
Replacement of Subjects 
During dose exploration, subjects that are not DLT-evaluable will be replaced.  A subject 
is not DLT-evaluable if the subject discontinues treatment for any reason other than a 
DLT prior to completing the first 28 days of AMG 224 treatment or does not receive 
2 doses of AMG 224 during the 28-day DLT window.  Additional subjects may be 
enrolled if Amgen’s medical monitor determines that the minimum required numbers of 
subjects with evaluable tissue samples have not been enrolled. 
3.5 
Estimated Study Duration 
The duration of the study will be approximately 30 months which includes 24 months of 
enrollment and 6 months of protocol treatment period.   
3.5.1 
Study Duration for Subjects 
It is anticipated that each subject will be on study for approximately 2 weeks for 
screening and 6 months of treatment period.  Approximately 30 to 37 days after the last 
dose of AMG 224, the subject will return to the clinic for a safety follow-up (EOS) visit.  
The estimated study duration for participant is 7.5 months but this may be longer or 
shorter depending on the subject’s disease, ability to tolerate AMG 224 and/or 
willingness to participate in the study. 
3.5.2 
End of Study 
The end of study occurs when a subject discontinues treatment with AMG 224 and 
completes the EOS visit.  The date the final safety assessment or procedure is 
performed is considered the end of study.  The safety follow-up or EOS visit will occur 
30 to 37 days after the last administration of AMG 224. 
Primary Completion is defined as the time when the last subject is assessed or receives 
an intervention for the purposes of final collection of data for the primary analysis.  The 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 32 of 105 
CONFIDENTIAL 
 
 
primary analysis will occur when target enrollment is complete and each subject either 
completes 6 months on study or withdraws from the study.  Subjects who are still active 
at the time of the primary analysis may continue on study until disease progression, 
study withdrawal, death, or investigational product intolerance is observed  
End of Trial is defined as the time when the last subject is assessed or receives an 
intervention for evaluation in the study.  Once achieved, the final analysis will occur.   
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  Before any study-specific procedure, the appropriate written informed 
consent must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Age > 18 years old at the time of signing the informed consent. 
103 
Subject must have a pathologically documented, definitively diagnosed, multiple 
myeloma relapsed or refractory progressive disease after at least 3 lines of 
therapy for multiple myeloma (see Appendix D and Appendix G for further 
details).  Prior therapeutic treatment or regimens must include proteasome 
inhibitors (eg, bortezomib) and immunomodulatory drugs (eg, lenalidomide).   
a. For group A expansion cohort prior therapy for multiple myeloma must 
include a CD38 targeting antibody. 
b. For group B expansion cohort prior therapy for multiple myeloma must not 
include a CD38 targeting antibody. 
104 
Subject must be willing and able to undergo bone marrow aspirate per protocol 
(with or without bone marrow biopsy per institutional guidelines). 
105 
Measurable disease per the IMWG response criteria (assessed within 28 days 
prior to day 1), as indicated by one or more of the following: 
 
Serum M-protein ≥ 1 g/dL 
 
Urine M-protein ≥ 200 mg/24 hours  
 
Subjects who do not meet 1 of the 2 prior criteria: serum Free Light Chain 
(sFLC) ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (< 0.26 or 
> 1.65) as per the IMWG response criteria 
106 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
107 
Life expectancy of > 3 months, in the opinion of the investigator.  
108 
Hematological function, as follows, without transfusion support:  
 
Absolute neutrophil count ≥ 1.0 X 109/L,  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 33 of 105 
CONFIDENTIAL 
 
 
 
Platelet count ≥ 75 X 109/L (in patients with < 50% of bone marrow 
nucleated cells were plasma cells) or ≥ 50 X 109/L (in patients with ≥ 50% 
of bone marrow nucleated cells were plasma cells) without transfusion or 
growth factor support 
 
Hemoglobin > 8 g/dL (> 80 g/L) 
109 
Coagulation function, as follows: PT/INR and PTT < 1.5 x Institutional Upper 
Limit of Normal (ULN). 
110 
Renal function as follows; estimated Glomerular filtration rate based on MDRD 
(Modification of Diet in Renal Disease) calculation > 45 mL/min/1.73 m2 
111 
Hepatic function, as follows; AST and ALT < 3 x ULN, Total bilirubin < 1.5 x ULN 
(except subjects with Gilbert’s syndrome) 
112 
Cardiac function, as follows; left ventricular ejection fraction (LVEF) > 50%.  
2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation.  
Multi-gated Acquisition Scan (MUGA) is acceptable if ECHO is not available.  
4.2 
Exclusion Criteria 
201 
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days since ending treatment on another investigational device or 
drug study(s).   
202 
Previously received an allogeneic stem cell transplant and the occurrence of one 
or more of the following: 
 
received the transplant within 1 year prior to study day 1 
 
received immunosuppressive therapy within the last 3 months prior to 
study day 1  
 
having signs or symptoms of acute or chronic graft-versus-host disease 
203 
Autologous stem cell transplant less than 90 days prior to study day 1 
204 
Multiple myeloma with IgM subtype  
205 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes).  
206 
Plasma cell leukemia (>2.0 X109/L circulating plasma cells by standard 
differential). 
207 
Waldenstrom’s macroglobulinemia 
208 
Amyloidosis 
209 
Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior 
to study day 1. 
210 
History of other malignancy, except:  
 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 2 years before study day 1 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 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 34 of 105 
CONFIDENTIAL 
 
 
 
Adequately treated cervical carcinoma in situ without evidence of disease 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer 
 
Adequately treated urothelial papillary noninvasive carcinoma or 
carcinoma in situ   
211 
Evidence of a bleeding diathesis 
212 
Current use of anticoagulationagents.  Note: Use of therapeutic anti-coagulation 
agents may be permitted if there is no bleeding and in the opinion of the 
investigator and in consultation with Amgen’s medical monitor the use of these 
agents is medically necessary. Subjects with thrombocytopenia (platelet count 
< 100 x 109/L) and on anti-coagulant treatment should be closely monitored 
during treatment with AMG 224. 
213 
Myocardial infarction within 6 months of study day 1, symptomatic congestive 
heart failure (New York Heart Association > class II).  
214 
History of arterial thrombosis (eg, stroke or transient ischemic attack) within 
6 months prior to study day 1. 
215 
Infection requiring intravenous anti-infective treatments within 1 week of study 
day 1. 
216 
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  
217 
Known positive results for Human Immunodeficiency Virus (HIV) 
218 
Unresolved toxicities from prior anti-tumor therapy, defined as not having 
resolved to Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 grade 1, or to levels dictated in the eligibility criteria with the 
exception of grade 2 peripheral neuropathy, alopecia or toxicities from prior 
anti-tumor therapy that are considered irreversible (defined as having been 
present and stable for >4 weeks may be allowed if they are not otherwise 
described in the exclusion criteria AND there is agreement to allow by both the 
investigator and Amgen medical monitor). 
219 
Treatment with medications known to cause QTc interval prolongation 
(see Appendix F) within 7 days of study day 1 unless approved by the Amgen 
medical monitor. 
220 
A baseline ECG QTcF > 470 msec 
221 
Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, 
or investigational agent) within 28 days prior to study day 1. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 35 of 105 
CONFIDENTIAL 
 
 
222 
Prior systemic radiation therapy must have been completed at least 28 days 
before study day 1.  Prior focal radiotherapy completed at least 14 days before 
study day 1. 
223 
Major surgery within 28 days prior to study day 1. 
224 
Male and female of reproductive potential who are unwilling to practice a highly 
effective method(s) of birth control while on study through 3 months (female) or 
6 months (male) after receiving the last dose of study drug.  Acceptable highly 
effective methods of birth control are defined as those which result in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly such 
as implants, injectables, combined oral contraceptives, intrauterine devices 
(IUDs), sexual abstinence or vasectomized partner.  Barrier methods of 
contraception are acceptable if a condom with spermicide (male) is used in 
combination with diaphragm, cervical cap or cervical sponge (female). 
225 
Female who are breastfeeding or who plan to breastfeed while on study through 
3 months after receiving the last dose of study drug. 
226 
Female with a positive pregnancy test. 
227 
Female planning to become pregnant while on study through 3 months after 
receiving the last dose of study drug. 
228 
Subject has known sensitivity to any components of the investigational product. 
229 
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 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific 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 (see Section 11.2).   
All subjects must personally sign and date the IRB/IEC approved ICF before 
commencement of study-specific procedures.  Each subject who signs the inform 
consent enters into the screening period for the study and 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 study identification number will consist of 11 digits.  The first 3 digits will 
represent the last 3 digits of the protocol number (eg, 314).  The next 5 digits will 
represent the country code and site number (eg, 66001) and will be identical for all 
subjects at the site.  The next 3 digits will be assigned in sequential order as subjects 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 36 of 105 
CONFIDENTIAL 
 
 
are screened (eg, 001, 002, 003).  For example, the first subject to enter screening at 
site 66001 will receive the number 31466001001, and the second subject at the same 
site will be 31466001002.The subject identification number must remain constant 
throughout the entire clinical study; it must not be changed after initial assignment, 
including if a subject is rescreened.   
All screening tests and procedures should be performed within 14 days prior to study 
day 1, unless otherwise indicated.  All blood and urine samples collected for screening 
assessments will be submitted and analyzed by the local laboratory.  Time permitting, 
screening laboratory assessments used to determine subject eligibility may be repeated 
once (up to a total of 2 times during the 14-day screening period), if necessary.  
Subjects who do not meet eligibility criteria within the 14-day screening period will not be 
eligible for enrollment.  Subjects may be re-screened up to 2 additional times at the 
discretion of the Investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside of the 14-day screening period.  Subjects who are deemed 
ineligible will be documented as screen failures. 
Subjects may be eligible to enroll once all screening tests and procedures are completed 
and results indicate that all eligibility criteria are met.  A site representative will complete 
and send the enrollment eligibility worksheet to Amgen along with the lab results and 
any requested supporting documentation for review of eligibility criteria.  The Eligibility 
Worksheet should be completed and emailed to the Amgen representative at least 
3 days prior to the planned day of first dose.  The Amgen representative will 
acknowledge receipt of the paperwork and send confirmation of the cohort and dose 
level assignment for the subject. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in the enrollment eCRF. 
5.1 
Treatment Assignment 
An Amgen representative will notify the site in writing when a cohort is open to screen 
and enroll subjects.  The notification will include the cohort number and dose level in 
which subjects will be enrolled.  The treatment assignment date is to be documented in 
the subject’s medical record and on the enrollment eCRF.  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 37 of 105 
CONFIDENTIAL 
 
 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product   
The Amgen Investigational Product used in this study is AMG 224.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 224.  
6.2 
Investigational Product 
All investigational products will be administered at the research facility by a qualified staff 
member.  A physician must be available at the time of administration of Investigational 
Product. 
6.2.1 
AMG 224 Investigational Product  
AMG 224 will be manufactured by BSP Pharmaceuticals, Italy and packaged by Amgen 
Inc. and distributed using Amgen clinical study drug distribution procedures.  AMG 224 
will be presented as 10 mg/mL protein concentration formulated with 
 mM sodium 
acetate, 
 % (w/v) sucrose,
% (w/v) polysorbate 20, pH 
.  AMG 224 will be 
supplied as 5 mL deliverable volume in a single use 8cc glass vial stored at liquid 
temperatures of
C to
°C.  AMG 224 will be administrated as an IV infusion. 
6.2.1.1 
Dosage, Administration, and Schedule 
AMG 224 will be administered as an intravenous (IV) infusion Q3W.  In Part 1 of the 
study, the pre-specified nominal AMG 224 (mg) doses are 30, 
 
 (non-weight-based dosing).  
In part 2 of the study, AMG 224 will be also administered as per weight-based dosing at 
 with a cap of 
 based on available nonclinical toxicology information on 
maximum sucrose allowance limit.  It is estimated that 3 g sucrose (
 AMG 224) 
per injection with a total dose not exceeding 1.8 g/dose/week is safe. 
AMG 224 will be administered as an IV infusion given over 60 ± 10 minutes Q3W in the 
first 2 cycles.  The dose of AMG 224 will vary by study part: 
 
Part 1 - Dose Exploration:  The doses range from 30 to 300 mg. 
 
Part 2 - Dose Expansion: The starting dose is 
. Subjects with grade 2 
thrombocytopenia at baseline (ie, platelet count < 75 to 50 x 109/L) should be started 
at a reduced dose of 
.  The subsequent doses of AMG 224 could be further 
reduced to 
 if the criteria for dose reduction for thrombocytopenia are met 
as per sections 6.2.1.5 and 6.3.1. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 38 of 105 
CONFIDENTIAL 
 
 
The dose of AMG 224 should not exceed 
 (based on available nonclinical 
toxicology information on maximum sucrose allowance limit).  
During the Dose Expansion Phase all doses are to be based on the subject’s actual 
body weight on the day of dosing (Day 1 of each cycle).  For cycles 2 and beyond, 
weight should be re-checked and dosing adjusted accordingly, unless body weight is 
changed by 5% or less compared to the cycle 1 weight.  The dose of AMG 224 should 
not exceed 
 (based on available nonclinical toxicology information on maximum 
sucrose allowance limit).  
For each subject, the infusion time may be shortened to 30 minutes ± 5 in the later 
cycles if the subject did not experience an infusion reaction or lengthened up to 
120 ± 10 minutes if the subject experienced an infusion reaction.  The dose, start 
date/time, stop date/time and lot number is to be recorded for each subject in the eCRF.  
No other investigational product will be used or provided in this study. 
The effects of overdose of this product are not known.   
Pre-medication for AMG 224 
No routine pre-medication should be administered prior to the first AMG 224 infusion.  If 
a subject develops an infusion reaction, subjects should acutely be treated according to 
best clinical practice.  The infusion should be either interrupted or slowed depending 
upon the severity of the symptoms.  Reduce the infusion rate by 50% in subjects who 
experience Grade 1 or 2 AMG 224-related infusion reaction.  Terminate the infusion in 
subjects who experience ≥ Grade 3 AMG 224-related infusion reaction.  Medication may 
be administered as deemed appropriate by the investigator to control any infusion 
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 an infusion reaction of Grade 3 
or greater severity. 
Premedication with antihistamines and/or corticosteroids may be considered for 
subsequent doses in subjects who experience an infusion reaction, at the discretion of 
the investigator.  Any subject experiencing ≥ Grade 2 bronchospasm or generalized 
urticaria, significant hypotension and/or wheezing despite maximal medical management 
should receive no additional doses of AMG 224. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 39 of 105 
CONFIDENTIAL 
 
 
6.2.1.2 
Study Dose Exploration and Stopping Rules 
For the dose exploration, a 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 the Investigators, 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, Global Safety Officer or designee, and study investigators.  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; or determination of RP2D. 
All available study data, including data collected after the initial DLT window, and 
including demographics, IP administration, medical history, concomitant medications, 
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 decisions will be made in accordance with a modified 3+3 design using 
the rules noted below (refer to Table 1) and in Section 3.1. 
o If no dose limiting toxicity (DLT) is observed within the DLT window in the initial 
3-4 subjects of a cohort, then dose escalation to the next higher dose level cohort 
will occur. 
o If 1 DLT is observed within the DLT window in the initial 3-4 subjects of a cohort, 
then the cohort will be expanded to 6 subjects.  If no further DLT(s) are observed 
in the 6 subjects, then dose escalation to the next higher dose level cohort will 
occur.  If ≥ 2 subjects among the initial 3-4 evaluable subject or among the 
expanded cohort of 6 evaluable subjects experience a DLT in a cohort, then the 
dose will be declared not safe and enrollment will be stopped. 
o If a subject permanently ended the study treatment before completion of DLT 
evaluation period for a reason other than experiencing a DLT, then another 
subject will be recruited to replace this subject for the evaluation of the MTD.  
Dose escalation will occur at the planned dose levels until the MTD is determined or until 
the highest dose level is tested.  The MTD is defined as the highest dose level with an 
observed incidence of DLT in < 33% of subjects enrolled in a cohort dose level.  At least 
6 subjects will be treated at the MTD or highest tested dose.  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 40 of 105 
CONFIDENTIAL 
 
 
A DLT will be defined as any of the events described under (Section 6.2.1.6), occurring 
in a subject during the DLT window, and regarded by the investigators and/or Amgen 
medical monitor to be related to AMG 224.  The DLT window will be the initial 28 days of 
treatment with AMG 224.  The DLT window may also be extended to assess events 
starting within the window in case the DLT definition is time dependent (neutropenia or 
thrombocytopenia, see below).  Any adverse event occurring outside the DLT window 
that is determined by the investigator to be possibly related to the investigational 
product, which is seen more frequently or is more severe than expected or is persistent 
despite appropriate management, can be determined to be a DLT upon unanimous 
decision by the DLRT after review of the adverse event and all available safety data.  
The CTCAE version 4.0 will be used to assess the severity of toxicities/adverse events.   
The DLRT may request additional reviews or recommend modifying or suspending the 
study if safety concerns arise during the study.  In the event that a need to modify or 
suspend the study is identified, this information will be communicated to investigators 
immediately, in accordance with Amgen procedures, and in compliance with prevailing 
guidance, including EMEA/CHMP/SWP/28367/07 (Guideline on strategies to identify and 
mitigate risks for first-in-human clinical trials with investigational medicinal products).  
Refer to Section 10.3.2 for additional details regarding the DLRT. 
Dose Exploration Stopping Rules 
The DLRT may consider part 1 dose exploration complete if one of the following rules is 
met: 
 
The highest planned dose level is evaluated, MTD has not been defined and no 
DLTs occur at any dose level, in this case the maximum administrated dose 
(MAD) may be used for part 2. 
 
A total of 40 DLT-evaluable subjects have been enrolled.  
 
An MTD is identified. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 41 of 105 
CONFIDENTIAL 
 
 
Table 2.  Cohort and Dose Exploration Schema 
Dose Exploration Schema 
Cohort 
Number of Subjects 
Dose IV Q3W 
1 
3-6 
30 mg 
2 
3-6 
3 
3-6 
4 
3-6 
5 
3-6 
6 
3-6 
7 
3-6 
8 
3-6 
6.2.1.3 
Study Dose Expansion and Stopping Rules 
For the dose-expansion phase, a safety review will be held after 5 subjects have 
enrolled and completed 2 cycles of therapy regardless of group. 
The dosing schedule is described in schema in the protocol synopsis. 
6.2.1.4 
Other Stopping Rules During Enrollment 
Enrollment will be held at any time during the study if any of the following events occurs: 
 
DLTs in the first 2 subjects in cohort 1 
 
Any other study drug-related Grade 5 toxicity  
In this case, enrollment and dosing at that particular dose level will be discontinued 
immediately. Subjects in that dosing cohort will have their treatment dose immediately 
reduced to the next lower dose level or have study treatment discontinued if the event 
occurs in Cohort 1 at the starting dose level. 
The investigator must discuss the safety findings with all ongoing subjects before 
continuing AMG 224 to ensure that the subjects understand the risks of continuing 
AMG 224 therapy. 
The sponsor will discuss such cases with the DLRT, Regulatory Authority and the study 
Investigators as appropriate to decide whether to resume enrollment. IRBs/IEs will be 
notified by the Investigators of all cases and decisions regarding continued enrollment. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 42 of 105 
CONFIDENTIAL 
 
 
6.2.1.5 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dosage Adjustments 
The subject should continue on the same dose of AMG 224 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  (ie Dose 
Level -1 as outlined in Table 3 or a further lower dose level (ie Dose Level -2 as 
outlined in Table 3). 
 
The study drug can be resumed once the adverse events recover to baseline or 
Grade 1 and the reintroduction of AMG 224 is deemed safe by the Investigator, 
Amgen’s Medical Monitor, and Global Safety Officer.  
 
Subjects must be informed of the risk of continuing on therapy.  Each subject is 
only allowed a single dose reduction. 
 
For subjects experiencing thrombocytopenia after the DLT-window, there will be 
an option to reduce the dose to the immediate next lower dose level (ie, Dose 
Level -1 as outlined in Table 3) or a further lower dose level (ie Dose Level -2 as 
outlined in Table 3 in the dose expansion part of the study (as described in 
section 6.3.1).  
The investigator should notify Amgen immediately before administration of the lower 
dose of AMG 224. 
Subject who have been dose-reduced will have an option to receive the higher dose 
(ie, Dose Level -1 or Dose Level 1) at the next planned cycle if the adverse event 
resolves to ≤ grade 1 or baseline and the reintroduction of AMG 224 at the higher 
dose is deemed safe by the Investigator. 
For dose reduction level, refer to Table 3: 
Table 3.  Dose Reduction of AMG 224 for Toxicity (Only in Dose Expansion) 
Dose level 
Dose IV Q3W 
Dose Level 1 
Dose Level -1  
Dose Level -2 
Subjects should not be rechallenged with AMG 224 if the following AMG 224-related 
adverse events occur: 
o Any life-threatening adverse events 
o DILI (Drug Induced Liver Injury) meeting Hy’s law  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 43 of 105 
CONFIDENTIAL 
 
 
o Persistent grade 3 adverse events that do not recover to baseline or Grade 1 
within 4 weeks.  Any treatment-related adverse event meeting DLT-criteria 
that recurs 
Dosage Delays  
During the DLT-window, if the dosing is delayed for more than 7 days the subject will be 
removed from the study and will be replaced.  After DLT-window, if the dosing is delayed 
for ≤ 3 weeks, the subject should resume the treatment as soon as possible if deemed 
safe by the investigator.  The investigator should inform the Amgen Clinical team as 
soon as the unexpected dosing interruption occurs.  If the dosing of AMG 224 is delayed 
more than 3 weeks (missing 1 cycle) due to treatment-related adverse events, the 
subject will be removed from the study.  If the dosing delay occurred under conditions 
other than those associated with AMG 224 related toxicities, the case will be reviewed 
by Amgen medical monitor to determine whether the subject will be allowed to resume 
AMG 224 treatment. 
Rules for Withholding or Restarting 
AMG 224 should be withheld for any of the following: 
 
Suspected DLT (including AE that meet DLT definition outside DLT window) 
 
Grade 3 thrombocytopenia (follow the thrombocytopenia management in 
Section 6.3.1) 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater 
than 3x ULN or total bilirubin greater than 1.5x ULN 
AMG 224 dosing can be resumed if the toxicities resolve to grade ≤ 1 or return to 
subjects’ baseline values.  The restarting of therapy should be deemed safe by the 
investigators and Amgen’s medical monitor.  
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 224 treatment and will 
be treated as deemed appropriate by the investigator or treating physician.  
Except for: 
o Subjects showing evidence of response or subjects who in the opinion of 
the investigator may be responding to AMG 224, may have the option to 
continue therapy once the adverse events recover to baseline or Grade 1 
and the re-introduction of AMG 224 is deemed safe by the investigator, 
Amgen’s medical monitor, and Global Safety Officer.  The subject should 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 44 of 105 
CONFIDENTIAL 
 
 
restart at a reduced dose (see Section 6.2.1.4) subsection Dose 
Adjustments). 
 
Intolerability of the study treatment 
 
The dosing is delayed > 3 weeks due to AMG 224-related adverse events  
 
Disease progression according to IMWG response criteria 
 
Clinical significant deterioration of health status  
 
Withdrawal of informed consent 
 
Subjects become pregnant or is breastfeeding 
6.2.1.6 
Dosage Limiting Toxicities  
The grading of adverse events will be based on the guidelines provided in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (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 4.0.  The relationship of an adverse event to investigational product will 
be determined by the Investigator.  An event should be considered related to treatment 
if, in the Investigator’s medical judgment, there is a reasonable possibility that the event 
may have been caused by AMG 224. 
A DLT is defined as a Grade 3 or higher non-hematological or a Grade 4 hematologic 
adverse event that occurs during the DLT window (day 1 through day 28 after the 
administration of the first dose of AMG 224) in Part 1 Dose Exploration unless clearly 
attributable to causes other than AMG 224 treatment.  DLT toxicities do not include 
fatigue, nausea, diarrhea, vomiting, neutropenia, anemia, thrombocytopenia and 
lymphopenia, increased serum creatinine or electrolytes abnormalities that are not 
clinically significant and require no treatment unless the following criteria are met:  
Hematological toxicity:   
o Grade 4 neutropenia lasting > 7 days  
o Grade 3 or 4 neutropenia with fever > 38.5°C 
o Grade 3 thrombocytopenia with ≥ Grade 2 hemorrhage   
o Grade 4 thrombocytopenia lasting > 7 days  
o Grade 3 anemia with symptoms or required intervention (eg, transfusion) 
o Grade 4 anemia   
o Lymphopenia of any grade is not considered a DLT  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 45 of 105 
CONFIDENTIAL 
 
 
Non-hematological toxicity:  
o ≥ Grade 3 nausea, vomiting or diarrhea persisting more than 3 days despite 
optimal medical support 
o Grade 3 fatigue persisting > 7 days 
o ≥ Grade 3 acute kidney injury (creatinine >3 X baseline or > 4.0 mg/dL) 
lasting > 3 days 
o Elevation of either AST or ALT according to the following criteria: 
- 
> 8x ULN; 
- 
> 5x ULN but < 8x ULN for ≥ 2 weeks; 
- 
> 5x ULN but < 8x ULN and unable to adhere to enhanced monitoring 
schedule; or 
- 
> 3x ULN with clinical signs or symptoms that is consistent with hepatitis 
(such as right upper quadrant pain/tenderness, fever, nausea, vomiting, 
jaundice, rash or eosinophilia (> 5%). 
o TBIL > 3x ULN 
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 6.4 for hepatotoxicity management 
and Appendix A for further explanation of Hy’s law case and Management of Hepatic 
Function). 
6.3 
Management of Adverse Events 
6.3.1 
Management of Thrombocytopenia 
Increased monitoring should be implemented in subjects whose platelet counts are 
< 100 x 109/L and subjects on anti-coagulant or anti-platelet treatment.  Hematology 
panels should be repeated on days 5, 6, or 7, or as clinically indicated, following each 
dose, if platelet counts are < 75 x 109/L, until platelet counts are ≥ 75 x 109/L (Grade 1). 
Subjects should not receive anti-coagulant therapy or anti-platelet therapy while treated 
with AMG 224 unless in the opinion of the investigator and in consultation with Amgen’s 
medical monitor the use of these agents is medically necessary.  Use caution with these 
agents and consider additional monitoring as described above when concomitant of 
these agents is medically necessary. 
Details of dose modification based on pre-dose platelet count are described in Table 4. 
The investigator should notify Amgen immediately before administration of the lower 
dose of AMG 224. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 46 of 105 
CONFIDENTIAL 
 
 
Subjects who have been dose-reduced will have an option to receive the higher dose (ie 
Dose Level -1 or Dose Level 1 as outlined in Table 3, Section 6.2.1.5) at the next 
planned cycle if the adverse event resolves ≤ grade 1 or baseline and the reintroduction 
of AMG 224 at the higher dose is deemed safe by the Investigator.  The investigator 
should notify Amgen immediately before administration of the higher dose of AMG 224. 
  Treatment for thrombocytopenia should be initiated per standard of care as clinically 
indicated.  Any subject who experiences a Grade 3 or 4 thrombocytopenia that cannot 
be managed per standard of care, will be permanently discontinued from AMG 224 
treatment. 
Table 4.  Dosing Guideline Based on Platelet Count After 2nd Cycle  
Grade of 
Platelet Count 
Decrease 
Withhold 
Dose 
Previous dose 
 
Previous dose 
 
Dose 
Discontinuation 
Grade 0 or 1 
(PLT LLN 
to ≥ 75 109/L) 
No 
Continue to 
administer 
AMG 224 at 
Dose Level 1 
 
Q3W) 
Escalate to one 
higher Dose Level 
(
 
Q3W) 
N/A 
Grade 2 (PLT 
75 to ≥ 50 109/L) 
No 
Continue to 
administer 
AMG 224 at 
Dose Level 1 
 
Q3W) 
Continue to 
administer 
AMG 224 at the 
same dose level 
N/A 
Grade 3 (PLT 
<50 to 
≥ 25 109/L) 
Yes, don’t 
administer 
AMG 224 
until platelet 
count 
recovers to 
≤ Grade 2 
(≥ 50K) 
Upon 
recovery, 
administer 
AMG 224 at 
Dose Level 1 
(
 
Q3W)  
Upon recovery, 
administer 
AMG 224 at the 
same dose level  
Yes, if grade 3 
platelet count 
decrease did not 
recover to at least 
grade 2  
Grade 4 (PLT 
< 25 109/L) and 
last ≤ 7 days 
Yes, don’t 
administer 
AMG 224 
until platelet 
count 
recovers to 
≤ Grade 2 
(≥ 50K) 
Upon 
recovery, 
administer 
AMG 224 at 
Dose Level -1 
(
 
Q3W) if 
deemed safe 
by the 
investigator  
Upon recovery, 
administer 
AMG 224 at one 
lower Dose Level 
(minimum 
Q3W) if 
deemed safe by 
the investigator 
Yes, if grade 4 
platelet count 
decrease did not 
recover to at least 
grade 2 OR 
subsequent drops in 
platelet count to 
Grade 4 after dose 
reduction 
Page 1 of 2 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 47 of 105 
CONFIDENTIAL 
 
 
Table 4.  Dosing Guideline Based on Platelet Count After 2nd Cycle 
Grade of 
Platelet Count 
Decrease 
Withhold 
Dose 
Previous dose 
 
Previous dose 
 
Dose 
Discontinuation 
Grade 3 or 
4 PLT count 
decreased 
associated with 
< grade 2 
bleeding 
Yes, don’t 
administer 
AMG 224 
until platelet 
count 
recovers to 
≤ Grade 2 
(≥ 50K) and 
bleeding is 
controlled 
Upon 
recovery, 
administer 
AMG 224 at  
Dose Level -1 
(
 
Q3W) if 
deemed safe 
by the 
investigator 
Upon recovery, 
administer 
AMG 224 at one 
lower Dose Level 
(minimum 
Q3W) if 
deemed safe by 
the investigator 
Yes, if grade 3 or 
4 platelet count 
decrease did not 
recover to at least 
grade 2 and 
bleeding is not 
controlled OR 
subsequent episode 
of Grade 3 or 
4 thrombocytopenia 
associated with 
< grade 2 bleeding 
Grade 4 (PLT 
< 25 109/L) and 
last > 7 days or 
Grade 3 or 4 
(PLT<50 109/L) 
with ≥G2 
bleeding 
N/A 
N/A 
N/A 
Yes 
Page 2 of 2 
6.3.2 
Management of Anemia 
Anemia is one of the multiple myeloma-related organ/tissue dysfunction and is generally 
related to bone marrow infiltration or renal dysfunction.  Subject should be monitored for 
changes in hemoglobin as described in the schedule of assessments (see Table 5.).  
Increased monitoring should be implemented in subjects whose hemoglobin < 8 g/dL.  
Subjects should have anemia corrected in accordance with the local practice and 
institutional guidelines.  Hemoglobin parameters of grade 3 but not considered as 
clinically relevant (ie, without symptoms of anemia and not leading to a clinical 
intervention including withdrawal of investigational product treatment, transfusion, or 
significant additional concomitant therapy) will not require discontinuation of AMG 224.  
However, treatment should be discontinued for persistent (ie, ongoing > 3 weeks after 
the end of a treatment cycle) grade 3 or 4 anemia in the absence of detectable multiple 
myeloma which may reflect a prolonged marrow toxic effect of AMG 224. 
6.3.3 
Management of Infections 
Subjects with evidence of existing infection should be closely monitored while being 
treated with AMG 224.  Subjects with active systemic infections requiring IV antibiotics, 
antivirals, or antifungals should not be dosed with AMG 224 until infection has resolved 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 48 of 105 
CONFIDENTIAL 
 
 
and if being treated with an anti-infectious therapy, the course of such therapy should 
have been completed.  Management should be tailored to the appropriate prophylaxis 
and/or treatment for the underlying infection according to the local standard of care and 
institutional guidelines. 
6.3.4 
Management of Peripheral Neuropathy 
Peripheral neuropathy is a common side effect of multiple myeloma standard of care 
therapy.  Thorough assessment of baseline peripheral neuropathy is required at 
screening (see Appendix H).  Subjects should be clinically monitored on ongoing basis 
for signs and symptoms of peripheral neurotoxicity according to the schedule of 
assessments (see Table 5.).  AMG 224 should be temporarily withheld in subjects 
experiencing Grade 3 or 4 peripheral neuropathy until resolution to grade 1 or baseline.  
Peripheral neuropathy should be managed according to the local standard of care and 
institutional guidelines. 
6.3.5 
Management of Cardiac Arrhythmia 
Subjects with risk factors for, or evidence of, existing heart disease should be closely 
monitored throughout their treatment with AMG 224.  Subjects should be clinically 
monitored on ongoing basis for cardiac function (blood pressure, heart rate, and ECG) 
according to the schedule of assessments (see Table 5.).  The administration of 
AMG 224 should be withheld if grade 3 or 4 arrhythmias (including tachycardia) develop 
or appear to be exacerbated by AMG 224 treatment.  Treatment may be resumed once 
the signs and symptoms resolve to baseline value or grade 1.  Management should be 
tailored to the appropriate treatment for the underlying cardiac disorder according to the 
local standard of care and institutional guidelines. 
6.3.6 
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 224.  Serum 
chemistry values, including BUN, serum creatinine, and urine for urinalysis and 
microscopic exam (microscopic exam only needed for positive dipstick), must be 
obtained and reviewed prior to each dose of AMG 224 per the schedule of assessments 
(see Table 5.).  AMG 224 must be held for subjects with CrCl or eGFR 
<30 ml/min/1.73m2 or any other grade 3 or 4 renal toxicity any time during study 
treatment participation.  Management should be tailored to the appropriate treatment for 
the underlying renal disorder according to the local standard of care and institutional 
guidelines. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 49 of 105 
CONFIDENTIAL 
 
 
6.4 
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 Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009). 
6.4.1 
Criteria for Permanent Withholding of AMG 224 due to Potential 
Hepatotoxicity 
AMG 224 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 > 2 x ULN or INR > 1.5 
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: 
o Hepatobilliary tract disease  
o Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
Cytomegalovirus, Herpes Simplex Virus, Varicella, Toxoplasmosis, and 
Parvovirus) 
o Right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia  
o Exposure to hepatotoxic agents/drugs including herbal and dietary 
supplements, plants, and mushrooms  
o Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir)  
o Alpha-one antitrypsin deficiency 
o Alcoholic hepatitis 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 50 of 105 
CONFIDENTIAL 
 
 
o Autoimmune hepatitis 
o Wilson’s disease and hemochromatosis 
o Nonalcoholic Steatohepatitis (NASH) or other “fatty liver disease” 
o Non-hepatic causes (eg, rhabdomyolisis, hemolysis) 
6.4.2 
Criteria for Conditional Withholding of AMG 224 due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent withholding of AMG 224 outline 
above and with 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 conditional 
withholding of AMG 224 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 is consistent with hepatitis (such as right 
upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice, rash or 
eosinophilia (> 5%). 
o OR: TBIL > 3x ULN at any time 
o OR: ALP > 8x ULN at any time 
AMG 224 should be withheld pending investigation into alternative causes of DILI.  If 
investigational product 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.  
6.4.3 
Criteria for Rechallenge of AMG 224 After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, Principal Investigator, and Amgen.  Subjects who clearly 
meet the criteria for permanent discontinuation (ie, no definite alternative cause for the 
laboratory abnormalities was discovered) (as described in Section 6.2.1.4) should never 
be rechallenged.  If signs or symptoms recur with rechallenge, then AMG 224 should be 
permanently discontinued. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 51 of 105 
CONFIDENTIAL 
 
 
6.5 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments, including red blood cell (RBC) and platelet transfusions as deemed 
necessary to provide adequate supportive care except for those listed in Appendix F. 
Concomitant therapies are to be collected from informed consent through the EOS. 
Collect therapy name, indication, dose, unit, frequency, route, start date, and stop date. 
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drugs or devices after it is released for distribution to market or clinic 
by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drugs or devices provisioned and/or repackaged/modified by 
Amgen.  Drugs or devices includes investigational product.   
Any product complaint(s) associated with an investigational supplied by Amgen are to be 
reported according to the instructions provided in the IPIM. 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period  
The following medications and/or therapies should not be administered within the 
timeframes specified prior to enrollment or during the study (unless otherwise specified 
below): 
 
Treatment with immune modulators including, but not limited to, 
immunosuppressive dose of corticosteroid (>10 mg/day prednisone or 
equivalent), cyclosporine, and tacrolimus  
 
Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, 
or investigational agent); concurrent use of bisphosphonates or denosumab for 
bone loss are permitted   
 
Treatment with medications known to cause QTc interval prolongation unless 
approved by the Amgen Medical Team  
 
Concurrent use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors 
unless agreed upon by Amgen and investigator (eg, use of agents such as 
low-dose aspirin and low-dose warfarin may be allowed) 
 
Any live vaccine therapies used for the prevention of infectious disease  
 
Any surgery or radiotherapy unless agree upon by Amgen and investigator 
There are no prohibited therapies and procedures during the post-treatment follow-up.  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 52 of 105 
CONFIDENTIAL 
 
 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments Dose Exploration and Dose Expansion 
 
Approved 
 
 


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Hours (relative to start 
of dosing) 
 
Pre-
dose 
0 
0.
5 
EOI 
4 
2
4 
96 
168 
336 
Pre-
dose 
0 
0.5 
EOI 
4 
24 
96 
168 
336 
Pre-dose 
0 
0.5 
EOI 
 
 
*(1(5$/$1'6$)(7<$66(660(17 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation (1) 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
Vital signs (2) 
x 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
12-lead ECG (3) 
x1 
3x
3 
 
 
x3 
x3 
x
3 
x3 
x3 
x3 
x3 
 
 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
 
x3 
x3 
x3 
x3 
Echocardiogram (4) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Neuropathy 
Assessment (5) 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Prior/concomitant 
medication review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
/$%25$725<$66(660(176$1''26,1* 
AMG 224 dosing (6) 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
AMG 224 PK (7) (9)  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
DM1 PK (8) (9) 
 
x 
 
x 
x 
x 
x 
x 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Anti-AMG 224 antibody 
collection 
(Immunogenicity) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 3 
only 
 
 
 
 
 
Safety lab tests (10) 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
Pregnancy test (11) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x (11) 
Hepatitis serology (12) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPEP/UPEP/ 
Immunofixation (13) 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
SFLC (14) 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Quantitative Ig (15) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2 microglobulin 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow, FISH (16) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Bone Marrow 
Biopsy 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Bone Marrow 
Aspirate 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Blood 
Samples collection (17) 
Plasma 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Serum 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Whole Blood CTC 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cell Pellet (PG 
sample) 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
PAXgene RNA (18) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
,0$*,1*$66(660(176 
Plasmacytoma (19) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey (20) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of this table. 
/$%25$725< $66(660(176 $1' '26,1*
 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 54 of 105 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments – Dose Exploration and Dose Expansion 
 
Page 2 of 2 
Footnotes defined on the next page. 
EOT(21)
EOS(21)
Q6W
Q9W
Pre-dose
0
EOI
Pre-dose
Pre-dose
x
x
X
x
x
x
X
x3
x3
x3
x
x
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Biomarker 
Blood 
Sample 
Collection 
(17)
Plasma
x
x
x
Serum
x
x
x
Cell Pellet
x
x
x
x
Treatment
Cycle
V and Beyond
Weeks
Q3W
LABORATORY ASSESSMENTS AND DOSING
Days
Hours (relative to start of dosing)
GENERAL AND SAFETY ASSESSMENT
Informed consent
Clinical evaluation (1)
Vital signs (2)
12-lead ECG (3)
Echocardiogram (4)
Peripheral Neuropathy Assessment (5)
Prior/concomitant medication review
Adverse events review
Bone marrow, FISH (16)
AMG 224 dosing (6)
AMG 224 PK (7) (9)
DM1 PK (8) (9)
Anti-AMG 224 antibody collection (Immunogenicity)
Safety lab tests (10)
Pregnancy test (11)
Hepatitis serology (12)
SPEP/UPEP/Immunofixation (13)
SFLC (14)
Quantitative Ig (15)
Beta-2 microglobulin
Biomarker Bone Marrow Biopsy
Biomarker Bone Marrow Aspirate
IMAGING ASSESSMENTS
Plasmacytoma (19)
Skeletal survey (20)
 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 55 of 105 
CONFIDENTIAL 
 
 
1. 
Clinical evaluation will include: physical exam with a neurologic assessment, ECOG status, and weight.  Screening only - medical and surgical history, weight and 
height. 
2. 
Vitals signs (blood pressure, respiratory rate, heart rate, temperature) will be collected (pre-dose on dosing days) after subject has rested for at least 5 minutes. 
3. 
ECG will be performed after subject has rested for approximately 5 minutes; X1 = single ECG; X3 = triplicate ECG (tracings one minute apart), reporting PR, QRS, 
QT, QTc, RR interval.  If interval prolongation > 480 msec occurs (and is a 30 msec increase above baseline), subject’s serum potassium, magnesium, calcium 
and phosphorus should be measured immediately and replaced if needed.  On day 1 predose only, triplicate ECGs to be completed at approximately 90, 60 and 
30 minutes prior to dosing. 
4. 
Echocardiogram (or MUGA; a consistent method will be used throughout the study) will be performed at screening only. 
5. 
Refer to Appendix H for the evaluation tool and document in the eCRF.  The site will enter the score to each question and the total score will be derived in RAVE. 
6. 
Each complete cycle will be of 3 weeks duration comprising 1 dose administration of AMG 224.  The subsequent cycle will start 3 weeks after the dose 
administration of the prior cycle 
7. 
AMG 224 PK = samples collected and analyzed for AMG 224 conjugated antibody and Total anti-BCMA antibody.  The PK of AMG 224 conjugated antibody and 
total anti-BCMA antibody will be assessed using the same samples.  
8. 
DM1 PK = samples collected and analyzed for Total unconjugated  DM1 PK.  Samples for total DM1 PK will be collected on Day 1: predose, 0.5hr, EOI, 4hr, 24hr 
(Day 2), 96hr (Day 5); Day 22: predose, 0.5hr, EOI , 4hr, 24hr (Day 23), 96hr (Day 26).  Refer to Laboratory Manual for procedure. 
9. 
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 to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations. 
10. Safety lab tests will include: chemistry (sodium, potassium, chloride, bicarbonate, albumin, calcium, magnesium, phosphorus, glucose, total protein, BUN or urea, 
creatinine, total bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, uric acid and LDH (LDH required at Screening only); Hematology includes CBC and 
platelets with differential; coagulation includes PT, PTT and INR; and urinalysis includes specific gravity, pH, blood, leucocyte esterase (WBC), protein, ketones, 
glucose, bilirubin (microscopic is needed only for positive dipstick for the following test): WBC, RBC, epithelial cells, bacteria, casts and crystals.  Abnormal 
electrolytes should be corrected prior to administration of AMG 224 and consideration should be given to monitoring electrolytes (eg, magnesium and potassium) 
in symptomatic subjects (eg, subjects with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).  Day 5, 8 and 15 can be +/- 1 day, CBC, LFT or renal 
function test should be repeated within 24-48 hour if labs if the subject experiences Grade 2 to 3 thrombocytopenia or transaminitis or grade 3 acute kidney injury. 
11. Serum pregnancy test performed at screening; urine or serum pregnancy test at all other timepoints (day 1, week 9 and Q9W thereafter, EOT) for female of child 
bearing potential. 
12. Hepatitis Serology, all subjects will be tested for HBsAg, antiHBcAb, HCVAb.  If HBsAg is negative and HBcAb positive, test HBV DNA by PCR.  If HCVAb 
positive, test HCV RNA by PCR.   
13. 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.   
14. Serum free light chain (SFLC) assay and ratio will be performed at each time point. 
15. 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). 
16. Bone marrow sample will be collected from all subjects during screening to quantify percent myeloma involvement and for fluorescent in situ hybridization (FISH).  
An additional bone marrow sample will only be required to confirm a complete response (CR). 
17. Biomarker samples will be collect at pre-dose for cycle 1 through cycle 5 then every 6 weeks (odd cycles) thereafter, EOT and EOS. 
18.   Signed informed consent specifically allowing pharmacogenetic testing must be obtained ssssbefore obtaining samples. 
 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 56 of 105 
CONFIDENTIAL 
 
 
19. 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 Q9W if clinically indicated ie.; new symptoms (bone pain) arises. Consider obtaining MRI for subjects with bone pain but skeletal 
survey is normal. 
21. In any case of premature treatment discontinuation, the investigator should make every effort to perform all examinations scheduled for the EOT and EOS visits.  
These data should be recorded, as they comprise an essential evaluation that should be performed prior to discharging any subject from the study and to allow for 
the evaluation of the study endpoints.  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.  The end of study (EOS) visit will occur 30 to 37 days after last treatment of AMG 224.  
 
 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 57 of 105 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
A signed and dated IRB-approved informed consent must be obtained before any 
study-specific procedures are performed.  Procedures that are part of routine care are 
not considered study-specific procedures and may be used at screening to determine 
eligibility.  All subjects will be screened for eligibility before enrollment.  Only eligible 
subjects will be enrolled into the study. 
7.2.1 
Informed Consent 
A signed informed consent must be obtained from each subject prior to any study 
mandated procedures. 
7.2.2 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through the time of consent.  Medical history will include 
information on the subject’s concurrent medical health conditions, relevant past medical 
conditions, and surgical history.   
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. 
7.2.3 
Prior Therapy 
The Investigator or designee will collect relevant prior therapy which includes previous 
chemotherapy or radiotherapy, anticancer therapies (eg,stem cell transplant). 
7.2.4 
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).  
7.2.5 
Peripheral Neuropathy Assessment  
The peripheral neuropathy assessment should be done at screening and time points 
specified in the Schedule of Assessments (Section 7.1).  All assessments must be 
reported on the corresponding eCRF page (see Appendix H for peripheral neuropathy 
assessment tool).   
7.2.6 
Height Measurements 
Height (cm) will be measured without shoes at screening. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 58 of 105 
CONFIDENTIAL 
 
 
7.2.7 
Weight Measurements 
Weight (kg) without shoes will be obtained at screening and time points specified in the 
Schedule of Assessments (see Section 7.1).  
7.2.8 
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 designated site physician 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. 
7.2.9 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group Performance Status (Appendix E) assessments 
will occur at time points specified in the Schedule of Assessments (see Section 7.1). 
7.2.10 
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, and run 
consecutively (approximately 1 minute apart), prior to blood draws or other invasive 
procedures.  Each ECG must include the following measurements: QRS, QT, QTc, RR, 
and PR intervals. 
Electrocardiograms will be performed as follows: 
 
Three baseline ECGs will be collected ≥ 30 minutes apart, with each ECG in 
triplicate approximately 30 seconds apart (3 set collected pre-dose on day 1 
[ie, total = 9 ECGs]) 
 
Triplicate ECGs, with each ECG approximately 30 seconds apart, at all other 
time points except for screening when this is only required once 
When ECGs, vital signs, blood for laboratory tests and PK are to be collected at the 
same time points, the ECGs and vital signs will be collected prior to blood collections. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 59 of 105 
CONFIDENTIAL 
 
 
The principal investigator or designated site physician will review all ECGs.  
Electrocardiograms will be transferred electronically to an ECG central reader for 
analysis per Amgen instructions.  Once signed, the original ECG tracing will be retained 
with the subject’s source documents.  At the request of 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 transited to the selected vendor. 
7.2.11 
Echocardiogram (ECHO) / Multi-gated Acquisition (MUGA) Scan 
ECHO or MUGA will be performed to assess cardiac ejection fraction and cardiac valve 
abnormalities and will occur at screening only.  The test can be repeated if clinically 
indicated by the investigator. 
7.2.12 
Tumor Assessments 
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.  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  
Bone marrow sample will be collected from all subjects during the screening to quantify 
percent myeloma involvement and for fluorescent in situ hybridization (FISH); FISH will 
be performed locally.  An additional bone marrow sample will only be required to confirm 
a complete response (CR). 
7.2.13 
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.  
7.2.14 
Quantitative Immunoglobulin 
Quantitative Immunoglobulin (Ig) will be performed at screening.  Quantitative 
Immunoglobulin will be repeated only if clinically indicated, ie, frequent infection despite 
multiple myeloma disease control or deemed clinically indicated by the investigator.  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 60 of 105 
CONFIDENTIAL 
 
 
7.2.15 
Beta-2 Microglobulin 
Beta-2 microglobulin will be performed only at baseline as part of risk stratification. 
7.2.16 
Skeletal Survey 
Skeletal survey will be performed at the time points as specified in the schedule of 
assessments (Table 5.).  Skeletal survey is defined by X-rays or PET/CT scans of 
lateral view of the skull, anteroposterior and lateral views of the spine and 
anteroposterior views of the pelvis, ribs, femora, and humeri. MRI should be performed 
in subjects with bone pain but skeletal survey is normal. 
7.2.17 
Pharmacokinetic Blood Sampling 
For pharmacokinetic assessment blood samples for quantitative determination of 
AMG 224 conjugated antibody, Total anti-BCMA antibody, and DM-1 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.  The pharmacokinetics of AMG 224 conjugated antibody and total anti-BCMA 
antibody will be assessed using the same samples. 
7.2.18 
Blood Samples 
Approximate blood volumes expected to be collected during 6 months for Part 1 and 
Part 2 of study participation are presented in Table 6 
Table 6.  Approximate Blood Volumes for Part 1 and Part 2 
Test 
Volume (mL) 
per Collection 
Approximate 
Number of 
Collection 
Approximate 
Total Volume 
(mL) 
Laboratory safety (chemistry, hematology, 
coagulation) 
15 mL 
17 
255 mL 
Serology 
5 mL 
1 
5 mL 
Quantitative Immunoglobulin 
10 mL 
1 
10 mL 
Serum pregnancy test (female of child bearing 
potential only) 
3 mL 
5 
15 mL 
Blood for Anti-AMG 224 (Immunogenicity) 
5 mL 
4 
20 mL 
Blood samples for PK (DM1) 
3 mL 
16 
48 mL 
 
10 mL 
5 
50 mL 
Blood samples for PK (AMG 224, conjugated 
Antibody and Total anti-BCMA antibody) 
3 mL 
25 
75 mL 
PaxGene RNA sample 
2.5 mL 
1 
2.5 mL 
Total blood volume assumes 6 cycles for study participation plus EOT and 
EOS (if applicable) 
~480.5 mL 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 61 of 105 
CONFIDENTIAL 
 
 
7.2.19 
Clinical Laboratory Assessments 
Blood samples for clinical chemistry, hematology, and urine samples for urinalysis, will 
be collected at screening, and at time points specified in the Schedule of Assessments 
(Table 5.).  All tests (except for PK, antibodies and biomarkers) are to be performed at  
a local laboratory and test results are to be recorded in the eCRF.  Blood samples will be 
obtained by venipuncture before study drug administration.  All laboratory tests must be 
reviewed by the investigator or qualified designee.  Additional safety laboratory 
assessments may be performed if clinically indicated at the discretion of the investigator.  
The following tests listed in Table 7 will be conducted on samples collected by standard 
laboratory procedures.  
Table 7.  Clinical Laboratory Assessments 
Chemistry 
Hematology  
Urinalysis 
Coagulation  
Albumin 
ALP 
ALT 
AST 
Bicarbonate 
BUN or Urea 
Calcium 
Chloride 
Creatinine 
Direct bilirubin 
Glucose 
LDH 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
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 
PTT 
INR 
 
Other Labs: 
Pregnancy 
Hep B surface antigen 
Hep B antibody 
Hep C antibody 
HCV PCR (if applicable) 
HBV PCR (if applicable) 
PK 
Biomarker 
Anti-AMG 224 
Anti-BCMA 
SPEP 
UPEP 
SFLC 
Quantitative 
Immunoglobulin 
Beta-2 microglobulin 
PG  
7.2.20 
Screening 
After obtaining informed consent, all screening procedures and tests establishing 
eligibility will be performed within a period of 28 days before dosing and 14 days for 
laboratory assessments.  If acceptable screening laboratory assessments are within 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 62 of 105 
CONFIDENTIAL 
 
 
48 hours of study day 1, the pre-dose laboratory assessments do not need to be 
obtained.  The following procedures are to be completed during the screening period at 
time points designated in the Schedule of Assessments (Table 5.) (Section 7.1). 
7.2.21 
Screening Procedures to Determine Eligibility 
Confirmation that the Informed Consent Form has been signed and dated  
Review of inclusion and exclusion criteria to determine eligibility 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact biomarker variability and 
pharmacokinetics. 
 
Review of medical and surgical history including: 
 
concomitant medication 
 
documentation of diagnosis including history of current and prior cancers 
 
prior anticancer treatments  
 
Clinical evaluation includes the following: 
 
physical examination with neurological assessment, ECOG performance 
status, height and weight 
 
assessment according to CTCAE version 4.0 for prior and continuing 
diagnosis, disease complications and toxicities  
 
Peripheral neuropathy assessment 
 
Vital signs (blood pressure, respiratory rate, heart rate, temperature) 
 
12-lead ECG 
 
Collected after subject has rested for 5 minutes.  
 
Record QRS, QT, QTc, RR and PR intervals. 
 
Echocardiogram 
 
Safety Laboratory Assessments (locally tested) within 14 days of study day 1 
 
Chemistry 
 
Hematology 
 
Coagulation 
 
Urinalysis 
 
Serum pregnancy test (only females of childbearing-potential) 
 
Determination of HIV status (via medical history) 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 63 of 105 
CONFIDENTIAL 
 
 
 
Determination of HBV and HCV status 
 
HBsAg and total HBc 
o If results are HBc positive and HBsAg positive, no additional testing is 
necessary 
o If results are HBc positive and HBsAg negative, additional testing for 
hepatitis B virus DNA by PCR is necessary 
 
HepCAb  
o If results are HepCAb positive, additional testing for hepatitis C virus 
RNA by PCR is necessary. 
 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis 
(UPEP)  
 
Serum free light chain (SFLC) 
 
Beta-2 macroglobulin 
 
Quantitative Immunoglobulin 
 
Bone marrow, bone marrow biopsy and bone marrow aspirate 
 
Pharmacogenetic blood collection (optional) 
 
Imaging Assessments (plasmacytoma and skeletal survey) 
 
Adverse event assessment is preformed throughout the study at every visit 
 
Serious adverse events are collected from the time the subject signs the ICF 
 
Adverse events are collected from the time the subject is dosed on day 1 
Subjects can be rescreened at the discretion of the investigator after consultation with 
Amgen.  The investigator must provide appropriate rationale prior to repeating any 
screening procedures or tests during the screening period.  A new consent must be 
signed unless it has been < 30 days since the last consent was signed. 
7.2.22 
Treatment 
The following procedures will be completed during each cohort treatment period at the 
times designated in the Schedule of Assessments (Table 5.).  Administration of 
AMG 224 is to be administered after all protocol-specific pre-dose assessments has 
been performed during each visit that it is required. 
Clinical evaluation to include the following: 
 
Physical examination with neurological assessment and ECOG performance status 
 
Peripheral neuropathy assessment 
 
Vital signs (blood pressure, respiratory rate, heart rate, temperature)  
 
12-lead ECG 
 
collected after subject has rested for 5 minutes.  
 
record QRS, QT, QTc, RR and PR intervals.  
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 
Pregnancy test – serum or urine (only females of childbearing-potential) 
 
Safety Laboratory Assessments (locally tested) 
 
Chemistry 
 
Hematology 
 
Coagulation 
 
Urinalysis 
 
Blood collection 
 
PK (DM1 & AMG 224 conjugated antibody and Total anti-BCMA antibody 
PK) 
 
Anti-AMG 224 antibody  
 
Biomarker 
 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis 
(UPEP)  
 
Serum free light chain (SFLC) 
 
Imaging Assessments (plasmacytoma and skeletal survey) 
 
Adverse event assessment is preformed throughout the study at every visit 
 
Serious adverse events are collected from the time the subject signs the 
ICF. 
 
Adverse events are collected from the time the subject is dosed on day 1. 
 
Documentation of concomitant medications 
7.2.23 
End of Treatment 
The end of treatment (EOT) visit will occur after the last dose of AMG 224.  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. 
Clinical evaluation to include the following: 
 
Physical examination with neurological assessment and ECOG performance status 
 
Vital signs (blood pressure, respiratory rate, heart rate, temperature)  
 
Peripheral neuropathy assessment 
 
12-lead ECG 
 
collected after subject has rested for 5 minutes.  
 
record QRS, QT, QTc, RR and PR intervals.  
 
Safety Laboratory Assessments (locally tested) 
 
Chemistry 
 
Hematology 
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 
Coagulation 
 
Urinalysis 
 
Blood collection 
 
Anti-AMG 224 antibody  
 
Biomarker 
 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis 
(UPEP)  
 
Serum free light chain (SFLC) 
 
Adverse event assessment is preformed throughout the study at every visit 
 
Serious adverse events are collected from the time the subject signs the 
ICF. 
 
Adverse events are collected from the time the subject is dosed on day 1. 
 
Documentation of concomitant medications 
7.2.24 
End of Study Visit 
The EOS visit must be performed 30 to 37 days after the last dose of AMG 224.  All 
efforts should be made to conduct this visit.  If it is not possible to conduct the EOS 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 to include the following: 
 
Physical examination with neurological assessment and ECOG performance status 
 
Vital signs (blood pressure, respiratory rate, heart rate, temperature)  
 
Peripheral neuropathy assessment 
 
12-lead ECG 
 
collected after subject has rested for 5 minutes.  
 
record QRS, QT, QTc, RR and PR intervals.  
 
Safety Laboratory Assessments (locally tested) 
 
Chemistry 
 
Hematology 
 
Coagulation 
 
Urinalysis 
 
Blood collection 
 
Biomarker 
 
Anti-AMG 224 antibody  
 
Serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis 
(UPEP)  
 
Serum free light chain (SFLC) 
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 
Adverse event assessment is preformed throughout the study at every visit 
 
Serious adverse events are collected from the time the subject signs the 
ICF. 
 
Adverse events are collected from the time the subject is dosed on day 1. 
 
Documentation of concomitant medications 
7.3 
Antibody Testing Procedures 
Blood samples for anti-drug antibody (ADA) testing are to be collected at the time points 
as specified in the table of assessment (Table 5.).  Samples testing positive for binding 
anti-AMG 224 antibodies may be further characterized for quantity/titer, isotype, affinity 
and presence of immune complexes.  Additional blood samples may be obtained to rule 
out anti-AMG 224 antibodies during the study.  The incidence of binding anti-AMG 224 
antibodies will be reported, and the impact of ADA on pharmacokinetics, 
pharmacodynamics, safety and efficacy will be evaluated. 
Samples testing positive for binding anti-AMG 224 antibodies will be banked and may be 
analyzed in a validated in-vitro neutralizing assay during late-stage clinical development. 
7.4 
Biomarker Development 
In addition to testing the safety and effectiveness of the experimental drug AMG 224 in 
this study, Amgen will attempt to develop tests from blood and/or tumor tissue that will 
identify subjects most likely to benefit from AMG 224.  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 224 or protocol required 
therapies.   
Biomarker development may be pursued by use of advanced biochemical analyses, 
such as proteomic methods or ribonucleic acid transcript profiling.  Some of the 
biomarkers to be explored include but are not limited to, BCMA and BCMA ligand 
expression, mutation status, analysis of BCMA RNA transcripts in tumors, enumeration 
and/or signaling activity of CTCs levels of soluble BCMA and BCMA ligands. 
Blood Samples 
Blood samples are to be collected for biomarker development at the time points as listed 
in the schedule of assessments.  Plasma samples may also be used to explore whether 
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expression or mutation of specific commonly occurring mutations found in tumors tissues 
(and other genes based on emerging data) correlates with response to AMG 224. 
7.5 
Bone Marrow 
During screening, bone marrow sample is required for all subjects.  Samples will be sent 
to the central laboratory along with the corresponding pathology report.  The tumor block 
is to be carefully selected by a pathologist or a skilled experienced histology associate to 
include generous tumor tissue using the Pathology Report as a guide.  In lieu of a block, 
20 unstained sections on charged slides from the same block can be submitted within 
4 weeks of study day 1 to allow time to evaluate the samples, and to ask for additional 
samples if the initial samples are not appropriate.  Analyses of tumor specific mutations 
or epigenetic changes may be performed (eg, somatic mutations) when the samples of 
tumor tissues become available.  Minimal residual disease will be evaluated on the bone 
marrow specimen of the patients that achieve complete remission per IMWG.  
7.6 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be 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 multiple myeloma 
and/or to identify subjects who may have positive or negative response to AMG 224.  No 
additional samples are collected for this part of the study however for subjects who 
consent to this/these analysis/analyses, DNA may be extracted from the blood samples 
collected for the biomarker studies will be used for this purpose. 
7.7 
Sample Storage and Destruction 
Any remaining blood and tumor samples collected according to the Schedule of 
Assessments (Table 5.) can be analyzed for any of the tests outlined in the protocol 
and for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
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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, the dose response and/or prediction of response to AMG 224 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 pharmacogenetic, 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 Amgen with the required study and subject number so that any remaining blood 
or tumor samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
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 
derivative materials gained or produced from the sample.  See Section 11.3 for subject 
confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol required therapies or procedures at any 
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time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 5.) and 
collection of data, including endpoints and adverse events.  The Investigator must 
document the change to the Schedule of Assessments (Table 5.) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or Amgen can decide to withdraw subjects 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 
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 the investigational product include any of the following: 
 
subject request  
 
safety concern (eg, due to an adverse event)  
 
ineligibility determined 
 
protocol deviation 
 
non-compliance (eg, procedural or dosing as defined in Section 6.2.1.1) 
 
requirement for alternative therapy 
 
pregnancy 
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 
decision by Amgen (other than subject request, safety concern, or lost to 
follow-up) 
 
decision by investigator (other than subject request, safety concern, or lost to 
follow-up) 
 
death 
 
lost to follow-up 
 
Confirmed Disease Progression per IMWG (Appendix D) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by Amgen  
 
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 expected by the investigator’s assessment.  A pre-existing condition 
that has not worsened more than anticipated (ie, more than usual fluctuation of disease) 
during the study or involves an intervention such as elective cosmetic surgery or a 
medical procedure while on study, is not considered an adverse event.   
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event eCRF. 
For situations when an adverse event or serious adverse event is due to multiple 
myeloma 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).  
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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 therapy 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 therapy 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. 
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 study 30 to 37 days after the last dose of investigational 
product are reported using the Event eCRF. 
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The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
o Dates of onset and resolution (if resolved), 
o Severity [and/or toxicity per protocol], 
o Assessment of relatedness to investigational product, and 
o Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  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 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 and/or procedure 
(including any screening procedures).  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, 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 
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 
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consent through 30 to 37 days after the last dose 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. 
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.  
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 is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event eCRF. 
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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.  
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 3 months after the last dose of investigational product.  
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a 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 lactation case occurs while the female subject is 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 monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
3 months after the last dose of investigational product.  
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
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If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoints 
 
Safety: Incidence of DLTs, treatment-related, treatment-emergent adverse 
events and clinically significant changes in vital signs, physical examinations, 
ECGs and clinical laboratory tests  
Secondary Endpoints   
 
PK profile: PK parameters for AMG 224 conjugated antibody, Total anti-BCMA 
antibody, and total unconjugated DM1including, but not limited to maximum 
observed concentration (Cmax), minimum observed concentration (Cmin),  area 
under the concentration-time curve (AUC), clearance (CL),  and if feasible 
half-life (t1/2) 
 
Overall response according to International Myeloma Working Group (IMWG) 
uniform response criteria, relative reduction in M-component, time to progression 
(TTP), duration of response (DOR) 
 
Conversion to MRD negativity 
 
Incidence of anti-AMG 224 antibody formation 
Exploratory Endpoints   
 
Quantification of BCMA expression in pre-dose bone marrow biopsy and 
bone-marrow aspirates 
 
Pre-dose bone marrow biopsy and/or plasma DNA gene expression profiles. 
 
Serum level of BCMA, BCMA ligands, APRIL and BAFF  
 
Quantification of circulating tumor cells, plasma cells and/or BCMA specific tumor 
cells 
10.1.2 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 224.  The analysis of DLT will be restricted to DLT-evaluable subjects 
(see Section 3.4).  The PK Analysis Set will contain all subjects who have received at 
least 1 dose of the investigational product and have at least 1 PK sample collected.  
These subjects will be evaluated for PK analysis unless the number of data points 
required for analysis is not enough, or significant protocol deviations have affected the 
data, or if key dosing or sampling information is missing. 
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10.1.3 
Covariates and Subgroups 
The relationship of covariates to efficacy endpoints will be explored if appropriate.  
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses.  The analyses of biomarkers may be performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints.   
10.2 
Sample Size Considerations 
It is anticipated that approximately 60 subjects will be enrolled in this study.  
Approximately 40 subjects will be enrolled in the dose exploration cohorts and up to 
20 additional subjects will be enrolled in the dose expansion cohort. 
The sample size in the dose exploration is based on practical consideration and it is 
consistent with conventional oncology studies with the objective to identify the MTD.  
With 3 subjects per cohort, there is a 27 to 70% probability of observing at least one DLT 
if the true DLT rate is 10 to 33% and with 6 subjects per cohort, there is a 47 to 
91% probability. 
In the dose expansion cohort, a subject number of 20 (regardless of group) will provide a 
64% probability of observing at least one adverse event with 5% incidence rate and 
88% probability of observing at least one adverse event with 10% incidence rate.  An 
exact 80% binomial confidence interval (CI) will be provided for overall response rate 
(ORR).  With the 20 subjects and 20% ORR, the 80% CI would be 9% to 36%.  
10.3 
Planned Analyses 
The following data analyses are planned: (1) dose decision analyses in the 
dose-exploration cohorts, (2) the primary analysis when target enrollment is complete 
6 months on study or withdraws from the study, and (3) the final analysis after all 
subjects have ended the study. 
10.3.1 
Interim Analyses 
Safety data will be reviewed on an ongoing basis.  The Dose Level Review Team 
(DLRT, see Section 10.3.2) will review all available cumulative data by cohort prior to 
making dose escalation decisions.  Adverse events and DLTs observed in all subjects 
will be evaluated continually and considered in all enrollment and dosing decisions.  
During dose-expansion, the DLRT will review safety after 5 subjects have enrolled 
(combining Group A and Group B subjects) and completed 28 days on study.  A TPI 
Bayesian model (see Section 10.4.2.3) utilizing all current DLT-evaluable subjects will be 
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fit to evaluate the appropriateness of the preliminary MTD from dose exploration.  The 
subsequent subjects to be enrolled in dose expansion may be dosed with the updated 
dose level, determined by the DLRT. 
10.3.2 
Data Monitoring Committee (DMC), Data Review Team (DRT) or Dose 
Level Review Team (DLRT) 
Dose Level Review Meetings (DLRMs) will be held to review data, monitor safety, and 
make decisions on dose escalation / change.  The DLRT will be composed of the 
investigators or designees, and the following Amgen representatives: medical monitor, 
global safety officer or designee, clinical study manager, biostatistician, additional 
members may be added as needed (eg, clinical pharmacologist).  The following 
members are responsible for DLRT decisions: investigators, Amgen medical monitor, 
and global safety officer or designee.  All available study data, including data collected 
after the initial DLT window, and including demographics, IP administration, medical 
history, concomitant medications, adverse events, ECGs, vital signs, laboratory data, 
and PK/PD information will be reviewed.  In addition to DLTs, all ≥ grade 3 toxicities not 
meeting DLT criteria will be reviewed and may be considered in DLRT decisions.  
Modeling of available potential safety risk data (eg, for thrombocytopenia) to predict 
safety risk for dose escalation decisions may also be considered. 
10.3.3 
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.  
10.3.4 
Final Analysis 
A final analysis is planned after all dose-exploration cohorts and dose-expansion 
subjects have ended the study.   
10.4 
Planned Methods of Analysis 
10.4.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD and 
biomarker data by dose, dose schedule, and time as appropriate.  Descriptive statistics 
on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may also be presented.  
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10.4.2 
Primary Endpoints 
10.4.2.1 
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 224. 
10.4.2.2 
Adverse Events 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  The number and percentage of subjects reporting 
adverse events will be evaluated overall and by dose level and will also be tabulated by 
relationship to study drug. 
Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product, and significant treatment emergent adverse 
events will also be provided. 
10.4.2.3 
Dose Limiting Toxicities  
The analysis of the probability of dose limiting toxicities (DLT) will include data from 
DLT-evaluable subjects, both from dose-exploration and dose-expansion 
(see section 3.4 for definition of DLT-evaluable).  The primary analysis will only include 
DLTs that occur within the protocol defined DLT evaluation interval.  If DLTs occur 
outside the specified evaluation interval, a sensitivity analysis will be performed where 
DLTs occurring outside of the specified time interval are included.  The preliminary 
estimate of the MTD will be identified using the 3+3 design.  A final estimate of the MTD 
will be made based on a toxicity probability interval (TPI) Bayesian model utilizing all 
DLT evaluable subjects from the dose exploration and dose expansion cohorts 
(Babb, 1998).  A minimally informative prior distribution will be used for the model 
parameters (Neuenschwander, 2008).  The MTD target probability interval is (0.20, 0.35) 
and TPIs of (0.35, 0.60) and (0.60, 1.00) are defined as excessive and unacceptable, 
respectively.  The model’s predicted MTD is the dose with the highest probability of the 
target TPI, but with a less than 0.25 probability of an excessive or unacceptable TPI. 
10.4.2.4 
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 
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provided.  Tables of maximum shifts from baseline for selected laboratory values may 
also be provided. 
10.4.2.5 
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. 
10.4.2.6 
Electrocardiograms 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects’ maximum change from baseline in QT interval corrected by 
Fridericia’s formula will be categorized and the number and percentage of subjects in 
each group will be summarized.  Subjects’ maximum post baseline values will also be 
categorized and the number and percentage of subjects in each group will be 
summarized.  All on-study ECG data will be listed and select parameters of interest may 
be plotted. 
10.4.3 
Pharmacokinetic Endpoints 
The analysis of pharmacokinetic endpoints will include data from all subjects who have 
received at least 1 dose of the investigational product and have at least 
1 pharmacokinetic sample collected. 
The PK parameters for AMG 224 conjugated antibody (anti-BCMA antibody with at least 
one DM1 molecule conjugated to the antibody), Total anti-BCMA antibody (sum of 
unconjugated anti-BCMA antibody and AMG 224 conjugated antibody), and DM1 (total 
unconjugated DM1), including, but not limited to maximum observed concentration 
(Cmax), minimum observed concentration (Cmin),  area under the concentration-time curve 
(AUC), clearance (CL),  and if feasible half-life (t1/2) will be estimated using standard 
non-compartmental PK methods and summarized by dose groups using means, 
standard deviations, medians, minimums and maximums for intensive and peak/trough 
determinations.  AMG 224 conjugated antibody, total anti-BCMA antibody and DM1 
concentrations at each time point along with PK parameter values may be listed for each 
subject.  Individual AMG 224 conjugated antibody, total anti-BCMA antibody and DM1 
concentration/time profiles will be plotted by dose groups.  Summary statistics will be 
computed for each sampling time and parameter as appropriate.  Analysis of the 
relationship between AMG 224 dose and exposure parameters (AUC and Cmax) will be 
conducted and plots of the relationship between AMG 224 dose and exposure 
parameters along with dose proportionality assessment will be provided.  Analysis of the 
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relationship between AMG 224 conjugated antibody concentrations and change from 
baseline in QTc will be conducted and plots of the relationship between AMG 224 
conjugated antibody concentrations and change from baseline in QTc will be provided.  
Additional analyses to explore relationship between exposure and safety and exposure 
and efficacy may also be performed.  
10.4.4 
Secondary Endpoint(s) 
10.4.4.1 
Efficacy Endpoint Analyses 
Listings will be produced for all subjects in the dose-exploration cohorts and the 
dose-expansion cohorts indicating the time to progression, time to response, and 
duration of response.  The proportion of subjects with a partial response to treatment or 
better per the IMWG with corresponding exact 80% CI will be calculated using the 
Clopper-Pearson method (Clopper and Pearson, 1934) and tabulated for subjects 
treated at the MTD.  The proportion of subjects with minimal residual disease and the 
proportion of subjects’ progression-free at 6 months with corresponding exact 80% CI 
will be calculated using the Clopper-Pearson method.  Kaplan Meier curve will be 
presented for time to progression and duration of response with estimates for rates and 
80% CI at selected weeks.  
10.4.4.2 
Anti-AMG 224 Antibodies 
The incidence and percentage of subjects who develop anti-AMG 224 antibodies 
(binding) at any time will be tabulated by treatment group.  If greater than 10% of 
subjects have a positive anti-AMG 224 antibody test, then summaries of results over 
time will be provided. 
10.4.5 
Exploratory Endpoints 
Details of analyses on exploratory endpoints will be provided in either a data analysis 
plan or a supplemental statistical analysis plan. 
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 Clinical Study Manager to the investigator.  
The written informed consent document is to be prepared in the language(s) of the 
potential subject population. 
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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol specific screening procedures or AMG 224 
is administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject’s participation in the clinical study.   
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 or a legally acceptable representative and by the person who conducted the 
informed consent discussion (not necessarily an Investigator).  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 or legally acceptable 
representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.)   
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. 
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The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval /renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
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 Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit 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. 
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The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  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 to Amgen. 
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 study contract.  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 pre-study 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. 
No study document should be destroyed without prior written agreement between 
Amgen and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Amgen in writing of 
the new responsible person and/or the new location.  
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 Amgen’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 
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conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the eCRFs must be maintained 
and readily available. 
 
Updates to eCRFs 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 to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self-Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects who are 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 (Table 5.), the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
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 encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), 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.  Authors should meet conditions 
1, 2, and 3. 
 
When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
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Lonial S, Dimopoulos M, Palumbo A, et al.  Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma.  N Engl J Med. 2015;373(7):621-631. 
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Moreaux J, Legouffe E, Jourdan E, Quittet P, Rème T, Lugagne C, Moine P, Rossi JF, 
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Greipp PR, Jelinek DF. Expression of BCMA, TACI, and BAFF-R in multiple myeloma:  a 
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Palumbo A, Chanan-Khan A, Weisel K, et al.  Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma.  N Engl J Med.  2016;375(8):754-766. 
Panowski SH, Kuo T, Chen A, et al.  Preclinical Evaluation of a Potent Anti-Bcma CD3 
Bispecific Molecule for the Treatment of Multiple Myeloma.  Blood.  2016;128:383. 
Poon KA, Flagella K, Beyer J, et al.  Preclinical safety profile of trastuzumab emtansine 
(T-DM1):  Mechanism of action of its cytotoxic component retained with improved 
tolerability. Toxicol Appl Pharmacol  273, 298-313, 2013. 
Rajkumar VS, Harousseau J, Durie B, 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. 
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(1995).  
Siegel R. Cancer Statistic 2015. Cancer J Clin 2015;65:5–29.  
Smith D, Yong K. Multiple Myeloma. BMJ 2013;346:f3863 doi: 10.1136/bmj.f3863. 
Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, Podar K, Hideshima T, Chauhan 
D, Raje N, Schlossman R, Richardson P, Munshi NC, Anderson KC. Role of  
B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the 
bone marrow microenvironment. Cancer Res. 2006 Jul 1;66(13):6675-82. 
Thompson JS, Bixler SA, Qian F, et al. BAFF-R, a newly identified TNF receptor that 
specifically interacts with BAFF. Science 293, 2108-2111 (2001). 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based 
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Wang J, Song P, Schrieber S, et al. Exposure–Response Relationship of T-DM1: Insight 
Into Dose Optimization for Patients With HER2-Positive Metastatic Breast Cancer. 
Clinical Pharmacology & Therapeutics. 2014;95(5):558-64. 
Yu G, Boone T, Delaney J, et al. APRIL and TALL-1 and receptors BCMA and TACI: 
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Zhao C, Inoue J, Imoto I, et al. Pou2AF1, an amplification target at 11q23, promotes 
growth of multiple myeloma cells by directly regulating expression of B-cell maturation 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE version 4.0 is available at the following location:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.4 require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours 
of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded) 
 
The appropriate eCRF (eg, Event eCRF) 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 9.2.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product is withheld (either permanently or 
conditionally) due to potential DILI as specified in Sections 6.4.2 and 6.4.3 or who 
experience AST or ALT elevations > 3 x ULN 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 has been discontinued AND 
the subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or 
elevated TBL: 
- Obtain complete blood count (CBC) with differential to assess for 
eosinophilia 
- Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 
(LKM1) to assess for autoimmune hepatitis 
Approved 
 
 


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Protocol Number:  20130314 
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CONFIDENTIAL 
 
 
- Obtain serum acetaminophen (paracetamol) levels 
- Obtain a more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special 
diets 
 
Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms 
- Obtain viral serologies 
- Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
- Perform appropriate liver imaging if clinically indicated 
 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
 
Obtain 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.  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 eCRFs. 
Approved 
 
 


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Appendix B.  Sample Serious Adverse Event Form 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
Approved 
 
 


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Approved 
 
 


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Appendix D.  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 
Page 1 of 2 
Footnotes defined on last page of this table 
Approved 
 
 


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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: 
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 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 / ratio.  An abnormal / ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  
An abnormal ratio reflecting presence of an abnormal clone is / of > 4:1 or < 1:2. 
d Determination of PD while on study requires 2 consecutive assessments made at any time before 
classification of PD and/or the institution of new therapy.  Serum M-component increases of ≥ 1 g/dL from 
nadir are sufficient to define progression if nadir M-component is ≥ 5 g/dL.   
e Plasmacytomas: A definite increase in the size is defined as a ≥ 50% increase as measured serially by the 
sum of the products of the cross-diameters of the measurable lesion.  A plasmacytoma is considered 
measurable if the longest diameter is at least 1 cm and the product of the cross diameters is at least 
1 cm2.  Plasmacytomas of lesser size will be considered non-measurable.   
f The requirement for bi-directional measurements applies only to plasmacytomas. 
g The plasmacytoma specifications for PD are based on interpretation of the IMWG-URC and practical 
considerations for study execution. 
Approved 
 
 


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Appendix E.  ECOG Performance Status and NYHA Classification 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0. Fully active, able to carry out 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. 
Approved 
 
 


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Appendix F.  Medications That May Cause QTc Prolongation 
List of medications known to cause QTc interval prolongation is available at the following 
link: https://crediblemeds.org/index.php/login/dlcheckIf participant in this study does not 
have access to the internet, they can contact the institution investigational pharmacy or 
contact their study physician to obtain a list. 
The following table presents a list of drugs that may prolong the QTc.  This is not an 
inclusive list of drugs and is provided for guidance only.  The participant is encouraged 
to follow the list in this link above for the most up-to-date information.  These drugs are 
prohibited during the study.  Washout period is based on roughly 5 half-lives and 
rounded to a convenient interval.  This list includes (but is not limited to) the following: 
Compounds 
Compound Half-Life 
Possible 
Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
Alfuzosin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone 
(cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient 
variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26-64) 
 
10 
Chloral hydrate 
Readily converted to 
Trichloroethanol (active 
metabolite T1/2= 7 -10 hours) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
 
Clarithromycin 
Non-linear PK3-4 hr (250mg Q12) 
5-7 hr (500 mg Q12) 
36 
 
Chloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
>24 hours, wide interpatient 
variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hours 
48 
 
Dolasetron 
8.1 hours 
 
 
Domperidone 
7-8 hours 
48 
 
Doxepin* 
> 24 hours, wide interpatient 
variability 
 
 
Droperidol 
2.2 hours 
10 
 
Page 1 of 3 
Footnotes defined on last page of this table 
Approved 
 
 


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


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 103 of 105 
CONFIDENTIAL 
 
 
Compounds 
Compound Half-Life 
Possible 
Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
Procainamide 
3-4 hours for PA and NAPA 
(active metabolite) 
24 
 
Protriptyline* 
> 24 hours, wide interpatient 
variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in 
children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active 
metabolite) T1/2 = 21-30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours (only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours 
in Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hours 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenafil 
4 to 5 hours 
 
 
Venlafaxine 
5 +/- 2 hours for parent comp. 
11 +/- 2 hours for OVD (active 
metabolite) 
60 
 
Voriconazole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hours 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
Page 3 of 3 
*Weakly associated with Torsades de pointes and/or QT prolongation but that are unlikely to be a risk for 
Torsades de pointes when used in usual recommended dosages and in patients without other risk factors 
(eg, concomitant QT prolonged drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, 
concomitant drugs that inhibit metabolism). 
References: 
1. 
Physician’s Desk Reference 2002 
2. 
Facts and Comparison (update to June 2005) 
3. 
The Pharmacological Basis of Therapeutics 9th Edition, 1999. 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 104 of 105 
CONFIDENTIAL 
 
 
Appendix G.  Definition of Relapsed or Refractory 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. 
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).  
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  16 July 2017 
Page 105 of 105 
CONFIDENTIAL 
 
 
Appendix H.  Peripheral Neuropathy Assessment 
TNSr Items 
0 
1 
2 
3 
4 
Symptom extension 
(tingling, 
numbness, 
neuropathic pain)a 
None 
Symptoms 
limited to 
fingers or 
toes  
Symptoms 
extend to 
ankle or wrist 
Symptoms 
extend to knee 
or elbow 
Symptoms 
above knees 
or elbows or 
functionally 
Disability  
Pin sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to wrist/ankle 
Reduced up to 
elbow/knee 
Reduced up 
to above 
elbow/knee 
Vibration sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to wrist/ankle 
Reduced up to 
elbow/knee 
Reduced up 
to above 
elbow/knee 
Strengthb 
Normal 
Mild 
weakness 
Moderate 
weakness 
Severe 
Weakness 
Paralysis 
Tendon reflexes 
Normal 
Ankle reflex 
reduced 
Ankle reflex 
absent 
Ankle reflex 
absent/others 
reduced 
All reflexes 
absent 
a The worse score of the 3 subcomponents (tingling/paresthesia, numbness, and neuropathic pain proximal 
extension) was used as the subjective symptom extension score. 
b The muscle with the worse score is used as the strength score (toe, ankle, wrist and finger extensors and 
flexors, quadriceps, hamstrings, biceps, and triceps).  TNSr and pain items were adapted with permission 
[Lavoie Smith, 2010]sss 
Approved 
 
 


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Amgen Protocol Number AMG 224 20130314 

Amendment Date: 
16 July 2018 
 
5DWLRQDOH
The purpose of this protocol amendment is to implement changes needed regarding 
dosage delays, weight-based dosing, maximum dose allowed, and dose adjustments.    
These changes were included in protocol amendment 3; however, protocol 
amendment 3 was not implemented because the FDA did not agree with the plan for frail 
subjects.  To implement these changes without the plan for frail subjects, this new 
amendment was needed. 
Dosing delay changes were made to allow subjects who have a second dose delayed for 
more than 48 hours but could still have the second dose of IP within the 28-day 
DLT-window. This change will allow those subjects to still be DLT evaluable. 
Weight-based dosing changes were made to provide clarification to sites how subject 
weight should be taken in preparation for weight-based dosing. 
After protocol amendment 2 was approved, the maximum dose allowed was determined 
to be 
.  The maximum dose allowed was added to this protocol to ensure subject 
safety. 
For subject safety, dose adjustments are being implemented for subjects experiencing 
thrombocytopenia.  From available safety data, grade 4 thrombocytopenia was seen with 
AMG 224 over 
 To mitigate the risk, the revised protocol will include two starting 
doses for all patients along with a dose adjustment schedule based on platelet count 
prior to dosing. 
Approved 
 
 


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Section: Global 
Change: Minor editorial changes have been made to improve overall clarity and 
consistency of the protocol language.  
Section:  Global 
Change:  correcting typographical and formatting errors 
Section:  Global 
Change:  added amendment  3 date 16 July 2018 
Section: Cover Page  
Change: Updated Sponsor Contacts 
Section:  Synopsis, Hypothesis 
Change: Add  
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Section: Synopsis, Hypothesis 
Change: Remove 
At least one dose level of AMG 224 administered by IV infusion is expected to achieve 
acceptable safety and tolerability in subjects with relapsed or refractory multiple 
myeloma. 
Section: Synopsis, Study Design, Dose Exploration  
Change: Remove 
If the preliminary MTD is not reached within the pre-planned dose range, Amgen’s 
medical monitor in conjunction with the investigators, after careful consideration of all 
available safety, laboratory, and PK information, may investigate doses > 
 
Additionally, dose levels lower than 30 mg may also be explored if required or supported 
by emerging data. Intermediate doses and alternative dose frequencies may also be 
explored if required or supported by emerging data.
Approved 
 
 


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Section: Synopsis, Study Design, Dose Expansion 
Change: Replace 
In the Part 1 of the study, a fixed dosing (ie, dose not adjusted for individual subject’s 
body weight) will be evaluated and in the Part 2 of study body weight-based dosing will 
be evaluated.  Subjects will be treated with preliminary MTD identified from the Dose 
Exploration part of the study adjusted for their body weight.   
With 
In the Part 1 of the study, a fixed dosing (ie, dose not adjusted for individual subject’s 
body weight) will be evaluated, and in the Part 2 of study body weight-based dosing will 
be evaluated.  Subjects will be treated with preliminary MTD identified from the Dose 
Exploration part of the study 
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Section: Protocol Synopsis, Amgen Investigational Product Dosage and Administration 
Change: Replace 
AMG 224 will be supplied as 5 mL deliverable volume in a single use 8cc glass vial 
stored at liquid temperatures of 
 at 10 mg/mL protein concentration formulated 
with 
 mM sodium acetate, 
(w/v) sucrose,
 (w/v) polysorbate 20, pH 
 
AMG 224 will be administered as an IV infusion given over 60 ± 10 minutes once Q3W 
in the first 2 cycles.  The doses range from 30 to 300 mg.  For each subject, the infusion 
time may be shortened to 30 ± 5 minutes in the later cycles if subjects experience no 
infusion reaction or lengthened up to 120 ± 10 minutes if subjects experience infusion 
reaction. 
With 
AMG 224 will be supplied as 5 mL deliverable volume in a single use 8cc glass vial 
stored at liquid temperatures of 
 at 10 mg/mL protein concentration formulated 
with 
 mM sodium acetate, 
 (w/v) sucrose, 
 (w/v) polysorbate 20, pH 
 
Approved 
 
 


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AMG 224 will be administered as an IV infusion given over 60 ± 10 minutes once Q3W 
in the first 2 cycles.  7KHGRVHRI$0*ZLOOYDU\E\VWXG\SDUW 
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Section 2.4.2 Dose Selection Rationale, Dose Exploration Phase (Part 1) 
Change: Delete 
If the preliminary MTD is not reached within the pre-planned dose range, Amgen’s 
medical monitor in conjunction with the investigators, after careful consideration of all 
available safety, laboratory, and PK information, may also investigate doses > 
 
Q3W. 
Section 2.4.2 Dose Selection Rationale, Dose Expansion Phase (Part 2) 
Change: Add 
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Approved 
 
 


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Section 2.5 Clinical Hypotheses 
Change: Add 
 
AMG 224 administered by IV infusion at (or one dose level below) the preliminary 
MTD identified during the dose escalation part of the study is expected to achieve 
acceptable safety and tolerability in subjects with relapsed or refractory multiple 
myeloma and frail subjects with relapsed or refractory multiple myeloma.  
Section 2.5 Clinical Hypotheses 
Change: Delete 
 
At least one dose level of AMG 224 administered by IV infusion is expected to 
achieve acceptable safety and tolerability in subjects with relapsed or refractory 
multiple myeloma. 
Section 3.1 Study Design, Part 1 – Dose Exploration 
Change: Delete 
If the preliminary MTD is not reached within the pre-planned dose range, Amgen’s 
medical monitor in conjunction with the investigators, after careful consideration of all 
available safety, laboratory, and PK information, may investigate doses > 
 
Additionally, dose levels lower than 30 mg may also be explored if required or supported 
by emerging data. Intermediate doses and alternative dose frequencies may also be 
used if required or supported by emerging data. 
Section 3.1 Study Design, Part 2 – Dose Expansion 
Change Add 
« Exploration part of the study 
 adjusted for their body weight. 6XEMHFWVZLWK
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Approved 
 
 


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Section 4.2 Exclusion Criteria 
Change: Replace 
Current use of anticoagulation unless agreed upon with investigator and Amgen medical 
monitor (eg, use of agents such as low-dose aspirin and low-dose warfarin may be 
allowed) 
With 
Current use of anticoagulation DJHQWV unless agreed upon with investigator and Amgen 
medical monitor (eg, use of agents such as low-dose aspirin and low-dose warfarin may 
be allowed) 1RWH8VHRIWKHUDSHXWLFDQWLFRDJXODWLRQDJHQWVPD\EHSHUPLWWHGLI
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Section 6.2.1.1 Dosage, Administration and Schedule 
Change: Replace 
AMG 224 will be administered as an intravenous (IV) infusion Q3W. The pre-specified 
nominal AMG 224 (mg) doses are 30, 
 
(non-weight-base dosing). 
AMG 224 will be administered as an IV infusion given over 60 ± 10 minutes Q3W in the 
first 2 cycles. The doses range from 30 to 300 mg. For each subject, the infusion time 
may be shortened to 30 minutes ± 5 in the later cycles if the subject did not experience 
an infusion reaction or lengthened up to 120 ± 10 minutes if the subject experienced an 
infusion reaction. The dose, start date/time, stop date/time and lot number is to be 
recorded for each subject in the eCRF. No other investigational product will be used or 
provided in this study. 
The effects of overdose of this product are not known. 
With: 
AMG 224 will be administered as an intravenous (IV) infusion Q3W. ,Q3DUWRIWKH
VWXG\ tThe pre-specified nominal AMG 224 (mg) doses are 30, 
 
 (non-weight-based dosing). 
Approved 
 
 


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first 2 cycles.  
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first 2 cycles.  7KHGRVHRI$0*ZLOOYDU\E\VWXG\SDUW
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The doses range from 30 to 300 mg. For each subject, the infusion time may be 
shortened to 30 minutes ± 5 in the later cycles if the subject did not experience an 
infusion reaction or lengthened up to 120 ± 10 minutes if the subject experienced an 
infusion reaction. The dose, start date/time, stop date/time and lot number is to be 
recorded for each subject in the eCRF. No other investigational product will be used or 
provided in this study. 
Approved 
 
 


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The effects of overdose of this product are not known. 
Section 6.2.1.5 Dose Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation, Dose Adjustments 
Change: Replace
The subject should continue on the same dose of AMG 224 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 exploration part of the study. 
 The study drug can be resumed once the adverse events recover to baseline or Grade 
1 and the reintroduction of AMG 224 is deemed safe by the Investigator, Amgen’s 
Medical Monitor, and Global Safety Officer.  
 Subjects must be informed of the risk of continuing on therapy. Each subject is only 
allowed a single dose reduction. 
Subjects should not be rechallenged with AMG 224 if the following AMG 224-related 
adverse events occur: 
o Any life-threatening adverse events 
o DILI (Drug Induced Liver Injury) meeting Hy’s law 
o Persistent grade 3 adverse events that do not recover to baseline or Grade 1 within 
4 weeks. Any treatment-related adverse event meeting DLT-criteria that recurs 
With 
The subject should continue on the same dose of AMG 224 throughout the study unless 
the following events occur: 
x 
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 (ie 'RVH
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o The study drug can be resumed once the adverse events recover to baseline 
or Grade 1 and the reintroduction of AMG 224 is deemed safe by the 
Investigator, Amgen’s Medical Monitor, and Global Safety Officer.  
Approved 
 
 


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o Any life-threatening adverse events 
o DILI (Drug Induced Liver Injury) meeting Hy’s law  
o Persistent grade 3 adverse events that do not recover to baseline or Grade 1 
within 4 weeks.  Any treatment-related adverse event meeting DLT-criteria 
that recurs 
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During the DLT-window, if the dosing is delayed for more than 48 hours the subject will 
be removed from the study and will be replaced.   
With 
During the DLT-window, if the dosing is delayed for more than GD\V the subject will be 
removed from the study and will be replaced.   
Approved 
 
 


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Hematological toxicity:   
o Grade 4 neutropenia lasting > 7 days  
o Grade 3 or 4 neutropenia with fever > 38.5°C 
o Grade 3 thrombocytopenia with ≥ Grade 2 hemorrhage   
o Grade 4 thrombocytopenia lasting > 7 days or requiring AMG 224 dose 
reduction is a DLT 
o Grade 3 anemia with symptoms or required intervention (eg, transfusion) 
o Grade 4 anemia   
Lymphopenia of any grade is not considered a DLT
Section 6.3.1 Management of Thrombocytopenia 
Change: Replace 
Increased monitoring should be implemented in subjects whose platelet counts are 
< 100 x 109/L.  Hematology panels should be repeated on days 5, 6, or 7, or as clinically 
indicated, following each dose, if platelet counts are < 75 x 109/L, until platelet counts 
are ≥ 75 x 109/L (Grade 1). 
Following initiation of treatment, if platelet counts decrease to between 25 to 50 x 109/L 
(Grade 3), AMG 224 will not be administered until platelet counts are ≥ 75 x 109/L 
(Grade 1) or back to baseline before starting therapy with AMG 224 then the subject will 
be administered AMG 224 at the same dose level. 
If platelet counts decrease to < 25 x 109/L (Grade 4), AMG 224 will not be administered 
until platelet counts are ≥ 75 x 109/L (Grade 1) or back to baseline before starting 
therapy with AMG 224, then the subject may be administered AMG 224 at the immediate 
lower dose level that has been previously investigated in this study.Details of dose 
modification based on pre-dose platelet count are described in Table 4. 
The investigator should notify Amgen immediately before administration of the lower 
dose of AMG 224. 
AMG 224 will not be administered to any subject whose platelet levels are <50 x 109/L 
before subsequent dosing or subjects with any platelet level experiencing grade 
≥ 2 bleeding.  Treatment for thrombocytopenia should be initiated per standard of care 
as clinically indicated.  Any subject who experiences a Grade 3 or 4 thrombocytopenia 
that cannot be managed per standard of care, will be discontinued from the study. 
Approved 
 
 


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Increased monitoring should be implemented in subjects whose platelet counts are 
< 100 x 109/L DQGVXEMHFWVRQDQWLFRDJXODQWRUDQWLSODWHOHWWUHDWPHQW Hematology 
panels should be repeated on days 5, 6, or 7, or as clinically indicated, following each 
dose, if platelet counts are < 75 x 109/L, until platelet counts are ≥ 75 x 109/L (Grade 1). 
6XEMHFWVVKRXOGQRWUHFHLYHDQWLFRDJXODQWWKHUDS\RUDQWLSODWHOHWWKHUDS\ZKLOH
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AMG 224 will not be administered to any subject whose platelet levels are <50 x 109/L 
before subsequent dosing or subjects with any platelet level experiencing grade 
≥ 2 bleeding.  
Treatment for thrombocytopenia should be initiated per standard of care as clinically 
indicated.  Any subject who experiences a Grade 3 or 4 thrombocytopenia that cannot 
be managed per standard of care, will be SHUPDQHQWO\ discontinued from AMG 224 
treatment the study. 
Approved 
 
 


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Section 7.1 Schedule of Assessments Dose Exploration and Dose Expansion 
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Section 9.3 Pregnancy and Lactation Reporting 
Change: Add 
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If a lactation case occurs while the female subject is 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 monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
3 months after the last dose of investigational product.  
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Listings will be produced for all subjects in the dose-exploration cohorts and the dose-
expansion cohorts indicating the time to progression, time to response, and duration of 
response. The proportion of subjects with a partial response to treatment or better per 
the International Myeloma Working Group criteria (IMWG) with corresponding exact 
80% CI will be calculated using the Clopper-Pearson method (Clopper and 
Pearson, 1934) and tabulated for subjects treated at the MTD. The proportion of 
Approved 
 
 


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subjects with minimal residual disease and the proportion of subjects progression-free at 
6 months with corresponding exact 80% CI will be calculated using the Clopper-Pearson 
method. Kaplan Meier curve will be presented for time to progression, time to response 
(partial response or better) and duration of response with estimates for rates and 80% CI 
at selected weeks. 
Approved 
 
 


Product:  AMG 224
Protocol Number:  20130314
Date:  02 March 2018
Page 1 of 28
CONFIDENTIAL
Amendment 3
Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects With Relapsed 
or Refractory Multiple Myeloma
Amgen Protocol Number AMG 224 20130314
Amendment Date:
02 March 2018
Rationale:
Approximately one-third of multiple myeloma patients at diagnosis are frail and the 
number of older adults with myeloma is increasing.  Frail patients carry more 
comorbidities, and are often excluded from clinical trials. Because of high unmet medical 
needs and safety profile of AMG 224, up to twenty frail patients with relapsed or 
refractory multiple myeloma will be examined as Group C defined by International 
Myeloma Working Group (IMWG) frailty score in the dose expansion phase of the study. 
To enroll frail patients with comorbidities, inclusion and exclusion criteria will be 
modified. 
In addition, to further characterize AMG 224 in terms of safety and efficacy with a 
weight-based dosing regimen, up to 30 patients (10 additional patients) will be examined 
in Groups A and B in the dose expansion phase. These additional patients/groups will 
change our overall sample size from 20 to 50 and frequency of Dose Level Review 
Meetings (DLRMs).
From available safety data, grade 4 thrombocytopenia was seen with AMG 224 over 
 To mitigate the risk, the revised protocol will include two starting doses for all 
patients along with the dose adjustment schedule based on platelet count prior to 
dosing.
Approved 
 
 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  12 July 2017 
Page 1 of 29 
Amendment 2 
Protocol Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects With Relapsed 
or Refractory Multiple Myeloma 
 
Amgen Protocol Number AMG 224 20130314 
 
Amendment Date: 
12 July 2017 
Rationale: 
Since an MTD (Maximum Tolerated Dose) for the exploration phase of the 20130314 
protocol dated 07 October 2015 has not been reached with Cohort 6 
 Q3W, nor 
has a DLT (Dose Level Toxicity) occurred, an amendment to include additional cohorts 
of 
 Q3W is supported.  Cohort 6 preliminary safety data supports these 
higher doses. 
These additional cohorts will change our overall sample size from 50 to approximately 
60.  The exploratory phase of the study will include an approximate additional 
10 subjects and the dose expansion phase will remain the same at 20 subjects.  
However the dose expansion phase will be divided into Group A of subjects who had 
prior treatment with a CD 38-targeting antibody (at least 10 subjects) and Group B 
subjects who is naïve to CD 38-targeting antibody treatment (approximately 
10 subjects). 
CONFIDENTIAL

 
Approved 
 
 


Product:  AMG 224 
Protocol Number:  20130314 
Date:  07 October 2015 
Page 1 of 5 
CONFIDENTIAL 
 
 
Amendment 1 
Title:  A Phase 1 First in Human Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects with 
Relapsed or Refractory Multiple Myeloma 
Amgen Protocol Number 20130314 
 
Change Summary Date:  
 
 
 
07 October 2015 
Rationale: 
Protocol was updated based off FDA recommended changes to the AMG 224 IND 
submission dated 21 August 2015: 
1. Recommend a study population of patients with multiple myeloma with relapse or 
refractory disease after at least 3 therapeutic treatment regimens for multiple 
myeloma.  In addition, patients must have received prior treatment with 
proteasome inhibitors (eg, bortezomib) and immunomodulatory drugs 
(eg, lenalidomide). 
2. Trial stopping rules should be in the protocol. These criteria would serve as a 
worst case scenario, such that, if the criteria are met, the trial is halted. 
3. Correct typographical errors throughout the document. 

SAP_001.pdf: 
Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 1 of 41 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1 First in Human Study Evaluating the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 224 in Subjects with 
Relapsed or Refractory Multiple Myeloma 
Short Protocol Title: 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 224 in subjects with 
relapsed or refractory multiple myeloma 
Protocol Number: 
20130314 
NCT Number: 
NCT02561962 
Authors: 
 and 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1-805-447-1000 
SAP Date: 
Document Version 
Date 
Original (v 2.0) 
28-Aug-2018 
 
PI
 
PI


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 2 of 41 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ..................................................................................................... 2 
1. 
Introduction .............................................................................................................. 6 
2. 
Objectives, Endpoints and Hypotheses .................................................................... 6 
2.1 
Objectives and Endpoints ............................................................................. 6 
2.2 
Hypotheses and/or Estimations .................................................................... 7 
3. 
Study Overview ........................................................................................................ 7 
3.1 
Study Design ................................................................................................ 7 
3.2 
Sample Size ............................................................................................... 10 
4. 
Covariates and Subgroups ..................................................................................... 10 
4.1 
Planned Covariates .................................................................................... 10 
4.2 
Subgroups .................................................................................................. 10 
5. 
Definitions .............................................................................................................. 11 
6. 
Analysis Sets .......................................................................................................... 17 
6.1 
Safety Analysis Set ..................................................................................... 17 
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 17 
6.2.1 
Pharmacokinetic Concentration Analyses Set ............................ 17 
6.3 
Dose Limiting Toxicity Evaluable Analysis Set ........................................... 17 
7. 
Planned Analyses .................................................................................................. 17 
7.1 
Interim Analysis and Early Stopping Guidelines ......................................... 17 
7.2 
Data Monitoring Committee (DMC), Data Review Team (DRT) 
or Dose Level Review Team (DLRT) .......................................................... 18 
7.3 
Primary Analysis ......................................................................................... 18 
7.4 
Final Analysis ............................................................................................. 18 
8. 
Data Screening and Acceptance ............................................................................ 18 
8.1 
General Principles ...................................................................................... 18 
8.2 
Data Handling and Electronic Transfer of Data .......................................... 18 
8.3 
Handling of Missing and Incomplete Data .................................................. 18 
8.4 
Detection of Bias ........................................................................................ 19 
8.5 
Outliers ....................................................................................................... 19 
8.6 
Distributional Characteristics ...................................................................... 19 
8.7 
Validation of Statistical Analyses ................................................................ 19 
9. 
Statistical Methods of Analysis ............................................................................... 19 
9.1 
General Considerations .............................................................................. 19 
9.2 
Subject Accountability ................................................................................ 20 
9.3 
Important Protocol Deviations .................................................................... 20 
9.4 
Demographic and Baseline Characteristics ................................................ 21 
9.5 
Efficacy Analyses ....................................................................................... 21 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 3 of 41 
CONFIDENTIAL  
 
 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) ................................... 21 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) .............................. 21 
9.5.2.1 
Best Overall Response Rate .................................... 21 
9.5.2.2 
Minimal Residual Disease Conversion 
Rate ......................................................................... 22 
9.5.2.3 
Progression Free Subject Rate ................................ 22 
9.5.2.4 
Time to progression ................................................. 22 
9.5.2.5 
Time to Response (TTR) ......................................... 22 
9.5.2.6 
Duration of Response (DOR) ................................... 22 
9.5.2.7 
Anti-AMG224 Antibodies .......................................... 22 
9.6 
Safety Analyses .......................................................................................... 23 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 23 
9.6.1.1 
Adverse Events and Disease-related 
Events ...................................................................... 23 
9.6.1.2 
Dose Limiting Toxicities ........................................... 23 
9.6.1.3 
Laboratory Test Results ........................................... 25 
9.6.1.4 
Vital Signs ................................................................ 26 
9.6.1.5 
Electrocardiogram .................................................... 26 
9.6.2 
Exposure to Investigational Product ........................................... 27 
9.6.3 
Exposure to Concomitant Medication ......................................... 27 
9.7 
Exploratory Endpoints ................................................................................ 28 
9.8 
Other Analyses ........................................................................................... 28 
9.8.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 28 
9.8.1.1 
Pharmacokinetic Endpoints ..................................... 28 
10. 
Changes From Protocol-specified Analyses .......................................................... 29 
11. 
Literature Citations / References ............................................................................ 30 
12. 
Prioritization of Analyses ........................................................................................ 31 
13. 
Data Not Covered by This Plan .............................................................................. 31 
14. 
Appendices ............................................................................................................ 32 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ......................................................... 33 
Appendix B.  Reference Values/Toxicity Grades ................................................... 37 
Appendix C.  Concomitant Medications ................................................................. 38 
Appendix D.  Clinical Outcome Assessment Forms/Instruments ........................... 39 
Appendix E.  Health Economic Forms/Instruments ................................................ 40 
Appendix F.  Details of PK or PK/PD Methods for Modeling .................................. 41 
List of Table 
Table 1.  3+3 Dose Level Decision Rules ......................................................................... 9 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 4 of 41 
CONFIDENTIAL  
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADC 
antibody drug conjugates 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
APRIL 
A proliferation inducing ligand 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
BAFF 
B-cell activating factor 
BAFF-R 
B-cell activating factor receptor 
BCMA 
B-cell maturation antigen 
BP 
blood pressure 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CR 
complete response 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
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 
electronic data capture 
eSAE 
electronic serious adverse event 
FIH 
first in human 
GCP 
Good Clinical Practice 
heart rate / HR 
number of cardiac cycles per unit of time 
ICH 
International Conference on Harmonisation 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 5 of 41 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
Ig 
immunoglobulin 
IMWG 
International myeloma working group 
IMWG-URC 
International myeloma working group uniform response criteria 
MR 
minor response 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
N, n 
number 
ORR 
overall response rate 
PD 
pharmacodynamics or progressive disease 
PK 
pharmacokinetics 
PKDM 
pharmacokinetics and data management 
PT 
prothrombin time 
Q3W 
once every 3 weeks 
QD 
once daily 
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 
QD 
once daily 
RP2D 
recommended phase 2 dose  
sCR 
stringent complete response  
SD 
standard deviation / Stable disease 
SFLC 
serum free light chain 
SPEP 
serum protein electrophoresis 
T1/2 
half-life 
tmax 
time of maximum observed serum concentration 
TPI 
TNSr 
toxicity probability interval 
total neuropathy score-reduced  
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 6 of 41 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the draft protocol amendment 4 for 
study 20130314, AMG 224 dated 16 July 2018. The scope of this plan includes the 
primary analysis and the final analyses that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 224 monotherapy in subjects 
with relapsed or refractory multiple 
myeloma 
 
Safety: Incidence of DLTs, 
treatment-related, treatment-emergent 
adverse events and clinically 
significant changes in vital signs, 
physical examinations, ECGs and 
clinical laboratory tests 
 
Determine the maximum tolerated 
dose (MTD) and/or recommended 
phase 2 does (RP2D) of AMG 224, if 
possible 
 
Secondary 
 
Characterize the pharmacokinetics 
(PK) of AMG 224 when administered 
intravenously (IV) once every 3 weeks 
(Q3W) 
 
PK profile: PK parameters for 
AMG 224 conjugated antibody 
(anti-BCMA antibody with at least one 
DM1 molecule conjugated to the 
antibody), total anti-BCMA antibody 
(sum of unconjugated anti-BCMA 
antibody and AMG 224 conjugated 
antibody), and DM1 (total 
unconjugated DM1) including, but not 
limited to maximum observed 
concentration (Cmax), minimum 
observed concentration (Cmin), area 
under the concentration-time curve 
(AUC), clearance (CL), and if feasible 
half-life (t1/2) 
 
Evaluate preliminary efficacy of 
AMG 224 when given as monotherapy 
in relapsed and refractory multiple 
myeloma according to International 
Myeloma Working Group (IMWG) 
uniform response criteria (Durie, 2006 
and Rajkumar 2011). 
 
Overall response according to 
International Myeloma Working Group 
(IMWG) uniform response criteria, 
relative reduction in M-component, 
time to progression (TTP), duration of 
response (DOR) 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 7 of 41 
CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Secondary(Continued) 
 
Evaluate the preliminary rate of 
conversion to minimal residual 
disease (MRD) negativity 
 
Conversion to MRD negativity 
 
Evaluate the incidence of 
anti-AMG 224 antibody formation. 
 
Incidence of anti-AMG 224 antibody 
formation 
  
Exploratory 
 
Correlate clinical response with B-cell 
maturation antigen (BCMA) 
expression in pre-dose bone marrow 
biopsies /and or bone-marrow 
aspirates. 
 
Quantification of BCMA expression in 
pre-dose bone marrow biopsy and 
bone-marrow aspirates 
 
Evaluate gene expression profiling by 
sequencing in pre-dose 
biopsies/plasma to identify gene 
signatures for response 
 
Pre-dose bone marrow biopsy and/or 
plasma DNA gene expression profiles. 
 
Determine prognostic and predictive 
value of serum BCMA and BCMA 
ligands a proliferation inducing ligand 
(APRIL)/B-cell activation factor 
(BAFF) from multiple myeloma serum 
samples 
 
Serum level of BCMA, BCMA ligands, 
APRIL and BAFF 
 
Assess multiple myeloma blood 
samples for the relevant circulating 
tumor cells. 
 
Quantification of circulating tumor 
cells, plasma cells and/or BCMA 
specific tumor cells 
 
2.2 
Hypotheses and/or Estimations 
 
At least one dose level of AMG 224 administered by IV infusion is expected to 
achieve acceptable safety and tolerability in subjects with relapsed or refractory 
multiple myeloma. 
 
A favorable PK profile will be achieved with AMG 224 administered by IV infusion 
Q3W. 
 
Objective responses by IMWG uniform response criteria will be observed at a 
dose level that achieves acceptable safety and tolerability 
3. 
Study Overview 
3.1 
Study Design 
This is a Phase 1, first-in-human, multicenter; non-randomized, open-label, 
dose-exploration and dose expansion study of AMG 224 IV Q3W for subjects with 
relapsed or refractory multiple myeloma. The study will be conducted in two parts: 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 8 of 41 
CONFIDENTIAL  
 
 
Part 1- Dose Exploration to define the MTD and / or RP2D followed by Part 2 - Dose 
Expansion to obtain further safety and efficacy data. 
Eligible subjects enrolled in the study will receive AMG 224 IV once Q3W beginning at 
study Day 1. During the initial DLT window (Day 1 through Day 28) subjects will be 
assessed for DLT. DLTs are defined in protocol Section 6.2.1.6. Dosing with AMG 224 
may continue Q3W unless there is evidence of progressive disease (PD) defined by 
IMWG, the subject becomes intolerant to the study medication, signs and symptoms of 
clinical progression are evident as determined by the principal investigator, or the 
subject withdraws consent. 
Part 1 – Dose Exploration 
In Part 1 for the first dose level and at each new higher dose level, the first enrolled 
subject will be treated, and then after a period of 24 hours, subsequent subjects will be 
treated, provided that there are no safety concerns relating to the treatment of the first 
subject. 
The dose-exploration cohorts will define the preliminary MTD, safety, tolerability, PK, 
and PD of AMG 224. A 3+3 design will be used to make a preliminary estimate of MTD.  
The preliminary MTD is defined as the maximum dose at which fewer than 33% of 
subjects experience a DLT. A final estimate of the MTD will be made using data from 
Dose Exploration and Dose Expansion. Planned dose levels for the dose-exploration 
cohorts are as follows: 30, 
 of AMG 224 
(IV; Q3W).  
Dose exploration decisions will be made by the Dose Level Review Team (DLRT). All 
cumulative safety and laboratory data will be reviewed prior to making dose exploration 
decisions. Safety data from all enrolled subjects in preceding cohorts and dose levels 
will also be considered. Additionally, the DLRT may stop enrolment into a cohort at any 
time to evaluate safety. 
3+3 Design: 
Dose escalation decisions will be made in accordance with a 3+3 design modified to 
allow flexibility in the initial cohort size (decision rules noted in Table 1). Dose escalation 
will occur at the planned dose levels until the MTD is determined or until the highest 
dose level is tested. The MTD is defined as the highest dose level with an observed 
incidence of DLT in < 33% of subjects enrolled in a cohort dose level. At least 6 subjects 
will be treated at the MTD or highest tested dose. 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 9 of 41 
CONFIDENTIAL  
 
 
Table 1.  3+3 Dose Level Decision Rules 
#Subjectsa 
#Subjects with DLT 
Decision 
3-4 
1 
Enrol 2-3 additional subjects at same dose level 
3-4 
0 
Escalateb 
3-4 
≥ 2 
De-escalatec 
6 
1 
Escalateb 
6 
≥ 2 
De-escalatec 
a Subjects who are not DLT-evaluable (see protocol Section 3.4) are excluded from the count of subjects 
b If final dose level has been reached, accrual will be suspended. 
c If 6 subjects already entered at next lower dose level, the estimated MTD has been established. 
Part 2 – Dose Expansion: 
In the Part 2 of the study up to 20 subjects with relapsed or refractory multiple myeloma 
will be treated. Subjects will be divided into the following 2 groups based on the 
status of prior treatment with CD38 targeting antibody (eg, Daratumumab): 
 Group A will consist of subjects who had prior treatment with a CD 
38-targeting antibody (at least 10 subjects). 
 Group B will consist of subjects who are naïve to CD 38-targeting antibody 
treatment (approximately 10 subjects). 
A body weight based dosing will be evaluated in the Dose Expansion part of the 
study. Subjects will be treated with preliminary MTD identified from the Dose 
Exploration part of the study ( 
 adjusted for their body weight. Criteria for 
adjustment in dosing based on stages of thrombocytopenia will be implemented 
as explained in the protocol.  
In the Part 1of the study a fixed dosing (ie, dose not adjusted for individual 
subject’s body weight) will be evaluated and in the Part 2 of study body weight 
based dosing will be evaluated. When sufficient AMG 224 clinical data becomes 
available, a full assessment of body size effect on PK/PD will be conducted to 
determine the optimal dosing approach prior to conducting the registration trial 
for AMG 224 in multiple myeloma patients. 
PI
During dose-expansion, after 5 subjects have enrolled (combining Group A and 
B subjects) and completed 28 days on study. A toxicity probability interval (TPI) 
Bayesian model utilizing all current DLT-evaluable subjects will be fit to evaluate 
the appropriateness of the preliminary MTD from dose exploration. The 
subsequent subjects to be enrolled in dose expansion may be dosed with the 
updated dose level. A final estimate of the MTD will be made based on a toxicity 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 10 of 41 
CONFIDENTIAL  
 
 
probability interval (TPI) Bayesian model utilizing all DLT evaluable subjects from 
the dose exploration and dose expansion cohorts. 
The DLRT will review safety after 5 subjects have enrolled and completed 28 days 
on study. The review will include all available safety data. If concerns arise from 
either planned or unplanned safety reviews, the DLRT may request additional 
review or recommend modifying or suspending the study. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section in protocol. 
The study endpoints are defined in protocol Section 10.1.1. 
3.2 
Sample Size 
Participants in this clinical investigation shall be referred to as “subjects”. It is anticipated 
that approximately 60 subjects will be enrolled in this study. 
In the dose exploration cohorts, approximately 40 subjects will be enrolled and up to 
6 subjects will be enrolled at the MTD or highest tested dose to gain additional safety 
and PK information. In the expansion cohorts, up to 20 subjects will be enrolled and 
treated with MTD or highest tested dose of AMG 224. 
The sample size in the dose exploration is based on practical consideration and it is 
consistent with conventional oncology studies with the objective to identify the MTD.  
With 3 subjects per cohort, there is a 27 to 70% probability of observing at least one DLT 
if the true DLT rate is 10 to 33% and with 6 subjects per cohort, there is a 47 to 91% 
probability. 
In the dose expansion cohort, a subject number of 20 (regardless of group) will provide a 
64% probability of observing at least one adverse event with 5% incidence rate and 88% 
probability of observing at least one adverse event with 10% incidence rate. An exact 
80% binomial confidence interval (CI) will be provided for overall response rate (ORR). 
With the 20 subjects and 20% ORR, the 80% CI would be 9% to 36%. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship of covariates to efficacy endpoints will be explored if appropriate. 
4.2 
Subgroups 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses. The analyses of biomarkers may be performed after collection of all samples 


Product:  AMG 224  
Protocol Number:  20130314 
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Page 11 of 41 
CONFIDENTIAL  
 
 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints. 
5. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the 
clinical database. 
AUC0-3 week = AUC0-504 hrs 
It is defined as the area under the concentration-time curve from time 0 to 504 hours. 
Baseline  
Unless otherwise specified the baseline value for parameters/assessments scheduled to 
be performed on the same day as the first administration of AMG 224 (Q3W), is the last 
value measured before the first administration of AMG 224 on that day.  For 
parameters/assessments not scheduled to be performed (or scheduled but not 
performed) on the same day as the first administration of AMG 224, the baseline value is 
the value from the screening period measured closest to the day of first administration of 
AMG 224.  In the event that multiple assessments are done on the same day as the first 
administration of AMG 224 and there is no time associated with the assessments, the 
value associated with the last clinically planned event before the first administration of 
AMG 224 will be used as the baseline value.    
For baseline ECG, three triplicate ECGs to be collected ≥ 30 minutes apart, with each 
ECG in triplicate approximately 30 seconds apart (3 set collected predose on day 1 with 
total of 9 ECGs]) planned to be taken predose. Mean value will be calculated and used 
in the analysis. The mean of the values within a triplicate should be calculated before 
taking the mean of the triplicate averages.  Where an ECG is missing within a triplicate, 
all available data will be averaged for that time point. 
Best Overall Response 
Best overall response for a subject is the best observed post baseline disease response 
per the International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma (IMWG-URC).  
Best Overall Response/Progression CRF will be employed to determine the response. 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 12 of 41 
CONFIDENTIAL  
 
 
Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
Body Mass Index (BMI) 
Body Mass Index should be calculated using the following formula 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2 
Change From Baseline 
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline. 
Cmax 
Maximum observed serum AMG 224 concentration during a treatment cycle. 
Cmin 
Minimum observed serum AMG 224 concentration during a treatment cycle. 
Death Date 
Death Date for each subject is defined as the date collected on the End of Study CRF 
where the reason for ending the study is equal to Death. 
Dose Limiting Toxicity (DLT): 
A DLT is defined as a Grade 3 or higher non-hematological or a Grade 4 hematologic 
adverse event that occurs during the DLT window (day 1 through day 28 after the 
administration of the first dose of AMG 224) in Part 1 Dose Exploration unless clearly 
attributable to causes other than AMG 224 treatment. DLTs do not include fatigue, 
nausea, diarrhea, vomiting, neutropenia, anemia, thrombocytopenia and lymphopenia, 
increased serum creatinine or electrolytes abnormalities that are not clinical significant 
and require no treatment unless the following criteria are met: 
Hematological toxicity: 
 
Grade 4 neutropenia lasting > 7 days 
 
Grade 3 or 4 neutropenia with fever > 38.5°C 
 
Grade 3 thrombocytopenia with ≥ Grade 2 hemorrhage 
 
Grade 4 thrombocytopenia lasting > 7 days or requiring AMG 224 dose reduction 
is a DLT 
 
Grade 3 anemia with symptoms or required intervention (eg, transfusion) 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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CONFIDENTIAL  
 
 
 
Grade 4 anemia 
 
Lymphopenia of any grade is not considered a DLT 
Non-hematological toxicity: 
 
≥ Grade 3 nausea, vomiting or diarrhea persisting more than 3 days despite 
optimal medical support 
 
Grade 3 fatigue persisting > 7 days 
 
≥ Grade 3 acute kidney injury (creatinine >3 X baseline or > 4.0 mg/dL) lasting 
> 3 days 
 
Elevation of either AST or ALT according to the following criteria: 
o > 8x ULN; 
o > 5x ULN but < 8x ULN for ≥ 2 weeks; 
o > 5x ULN but < 8x ULN and unable to adhere to enhanced monitoring 
schedule; or 
o > 3x ULN with clinical signs or symptoms that is consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice, rash or eosinophilia (> 5%). 
 
TBIL > 3x ULN 
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. 
Duration of Response (DOR)  
Duration of response is defined as the number of days between the date of the first 
observation indicating an objective response as PR (or better)  through to the 
subsequent date of disease progression as classified by per the International Myeloma 
Working Group Uniform Response Criteria for Multiple Myeloma or death or where 
applicable date of censoring [date of first progressive disease assessment or death or 
date of censoring – date of the first observation indicating PR (or better) as an objective 
response +1]. Subjects who respond (PR or better) and have not progressed while on 
study or not died will be censored at the date of assessment of the last evaluable 
response as documented on International Myeloma Working Group Uniform Response 
Criteria for Multiple Myeloma CRF. Subjects who do not achieve an objective response 
will be excluded from the analysis of duration of response.  


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 14 of 41 
CONFIDENTIAL  
 
 
End of IP Administration Date 
End of IP Admin for each subject is defined as the date the decision was made to end IP 
as recorded on the End of Investigational Product Administration CRF page. 
End of Study (Individual Subject) 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study CRF page.  
Enrollment Date 
Enrollment Date is defined as the date collected on ‘Subject Enrollment’ CRF. 
Fridericia-corrected QT Interval (QTcF)  
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  QTcF=QT/(RR/1000)0.33 
Use above definition for derivation only if QTcF is not collected in the CRF. 
Investigational Product 
The term ‘investigational product’ is used in reference to AMG 224. 
Last Investigational Product Dose Date  
The last IP dose date for each subject is defined as the latest date IP is administered. 
Measurable Plasmacytoma 
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. 
Maximum Tolerated Dose (MTD) 
The dose exploration part of study is aimed at determining preliminary maximum 
tolerated dose (MTD). The preliminary MTD is defined as the maximum dose at which 
fewer than one third (< 33%) of subjects enrolled in a cohort dose level experience a 
DLT. A final estimate of the MTD will be made based on a toxicity probability interval 
(TPI) Bayesian model utilizing all DLT-evaluable subjects from the dose exploration and 
dose expansion cohorts. Based on the TPI model, the MTD is defined as the dose with 
the highest probability of a DLT rate between (0.20 and 0.35) while controlling the 
probability of excessive and unacceptable toxicity. 


Product:  AMG 224  
Protocol Number:  20130314 
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Page 15 of 41 
CONFIDENTIAL  
 
 
Minimal Residual Disease (MRD) Negativity 
Tumor load of 10-5 target cutoff level is considered for the definition of MRD negativity 
ie, less than 1 clonal cell in 105 normal cells is defined as MRD negative. 
(Paiva B, 2015)   
Objective Response  
Objective response is defined as a tumor response assessment of either stringent 
complete response, complete response, very good partial response or partial response 
per the International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma (IMWG-URC) and will be determined only for subjects with measurable 
disease at baseline as per IMWG-URC for Multiple Myeloma.   
Objective response will be determined based on the responses collected using Best 
Overall Response/Progression CRF. 
Objective Response Rate (ORR) 
Incidence of either PR or better (sCR, CR, VGPR) while on study as defined by the 
IMWG-URC. All subjects that do not meet the criteria for objective response by the 
analysis cutoff date will be considered non-responders.   
Percent Change From Baseline 
Percent change from Baseline is the arithmetic difference between post-Baseline and 
Baseline divided by Baseline values times 100. 
Study Day 
Post study day: 
study day= (date - date of Study Day 1) + 1 
Pre study day:  
study day= (date – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment.  The day prior to Study Day 1 is considered Day -1.  
Serious TEAE 
Serious adverse events (SAEs) are events categorized as AEs that are starting on or 
after first dose of investigational product as determined by the flag indicating if the 
adverse event started prior to the first dose on the Events CRF and up to and including 
37 days after the end of investigational product.  


Product:  AMG 224  
Protocol Number:  20130314 
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Page 16 of 41 
CONFIDENTIAL  
 
 
Time to Response (TTR) 
Time to response is calculated as the number of days from the first administration 
of AMG 224 to the first response as per IMWG-URC. It is calculated for subjects 
with PR or better. 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is any adverse event starting on or after the first 
administration of investigational product, as determined by the flag indicating if the 
adverse event started prior to the first dose on the Events CRF, and up to and including 
37 days after the end of investigational product. The severity of each adverse event will 
be graded using the CTCAE version 4.0. Adverse events will be coded using MedDRA. 
Treatment-Related AE  
A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by the investigational product. 
Time to Progression (TTP) 
Time to progression is calculated as the number of days from the first administration of 
AMG 224 to the first objective assessment of disease progression as per IMWG-URC or 
deaths or if applicable date of censoring (date of progressive disease / death or 
censoring – date of first administration of AMG 224 +1).  
If a subject’s disease has not progressed and the subject is alive, time to progression will 
be censored at the last date they are known to be progression-free (ie, date of 
assessment of the last evaluable response as documented on International Myeloma 
Working Group Uniform Response Criteria for Multiple Myeloma CRF). 
If a subject has no evaluation related to assessment of response criteria of Multiple 
Myeloma (IMWG-URC) in the study, time of response will be censored at the date of the 
first administration of AMG 224. 
Subjects who withdraw consent to participate in the study prior to disease progression 
will be censored at their last evaluable assessment of response documented on 
IMWG-URC for Multiple Myeloma CRF. 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
Page 17 of 41 
CONFIDENTIAL  
 
 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 224. 
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
6.2.1 
Pharmacokinetic Concentration Analyses Set 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected. These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
6.3 
Dose Limiting Toxicity Evaluable Analysis Set  
The analysis of DLT will be restricted to DLT-evaluable subjects. A subject is not 
DLT-evaluable if he / she discontinues treatment for any reason other than a DLT prior 
to completing the first 28 days of AMG 224 treatment or does not receive 2 doses of 
AMG 224 during the 28 day DLT window.  
7. 
Planned Analyses 
The Planned analysis is described in following sections. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis. The Dose Level Review Team 
(DLRT, see protocol Section 10.3.2) will review all available cumulative data by 
cohort prior to making dose escalation decisions. Adverse events and DLTs 
observed in all subjects will be evaluated continually and considered in all 
enrollment and dosing decisions. 
During dose-expansion, the DLRT will review safety after 5 subjects have enrolled 
(combining Group A and Group B subjects) and completed 28 days on study. A 
TPI Bayesian model (see protocol Section 10.4.2.3) utilizing all current 
DLT-evaluable subjects will be fit to evaluate the appropriateness of the 
preliminary MTD from dose exploration. The subsequent subjects to be enrolled in 
dose expansion may be dosed with the updated dose level, determined by the 
DLRT. 
Early stopping guidelines will be implemented as explained in the protocol 
Sections 6.2.1.2-1.4. 


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Page 18 of 41 
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7.2 
Data Monitoring Committee (DMC), Data Review Team (DRT) or Dose 
Level Review Team (DLRT) 
Dose Level Review Meetings (DLRMs) will be held to review data, monitor safety, and 
make decisions on dose escalation / change. The DLRT will be composed of the 
investigators or designees, and the following Amgen representatives: medical monitor, 
global safety officer or designee, clinical study manager, biostatistician, additional 
members may be added as needed. The following members are responsible for DLRT 
decisions: investigators, Amgen medical monitor, and global safety officer or designee. 
All available study data, including data collected after the initial DLT window, and 
including demographics, IP administration, medical history, concomitant medications, 
adverse events, ECGs, vital signs, laboratory data, and PK/PD information will be 
reviewed. In addition to DLTs, all ≥ grade 3 toxicities not meeting DLT criteria will be 
reviewed and may be considered in DLRT decisions. Modeling of available potential 
safety risk data (eg, for thrombocytopenia) to predict safety risk for dose escalation 
decisions may also be considered. 
7.3 
Primary Analysis 
The primary analysis will occur when target enrolment is complete and each subject 
either completes 6 months on study or withdraws from the study. 
7.4 
Final Analysis 
A final analysis is planned after all dose-exploration cohorts and dose-expansion 
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 for missing or incomplete data will be performed if required: 
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A. 


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Page 19 of 41 
CONFIDENTIAL  
 
 
Non-pharmacokinetic measurements (eg, biomarker data) that are below the lower limit 
of quantification will be considered equal to half of the lower limit of quantification for all 
analyses unless specified otherwise.   
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort.  
The clinical study team will identify and document the criteria for important protocol 
deviations.  
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
Pharmacokinetic (PK) serum 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, East 6.4 or later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographic, safety, PK, PD and 
biomarker data.  Unless otherwise stated, the data analysis will be conducted using 
subjects in the Safety analysis set. 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 


Product:  AMG 224  
Protocol Number:  20130314 
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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. Data listings will include all available data from 
all enrolled subjects unless specified otherwise. 
Data analysis will occur at the following time points: 
 
Dose decision analyses will occur in the dose exploration cohorts and also after 
enrolling 5 subjects from Cohort A and Cohort B (combined) in dose 
expansion cohort. 
 
The primary analysis will occur when target enrollment is complete and each 
subject either completes 6 months on study or withdraws from the study. 
 
A final analysis is planned after all dose-escalation cohorts and dose-expansion 
subjects have ended the study. 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled, received investigational product, 
completed investigational product, discontinued from investigational product (including 
reasons for discontinuing, completed study, discontinued the study (including reasons 
for discontinuing) will be summarized by cohort.   
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. 
A subject listing and summary noting inclusion in each analysis subset will be provided 
for all subjects enrolled.  A subject listing noting duration of AMG 224 administration, 
reason for discontinuation of treatment, and reason for discontinuing the study will be 
provided.  A list of subjects screened but not enrolled (screen failures) will be provided. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first patient visit and updated during the IPD reviews throughout the study prior to 
database lock.  If a snapshot is being taken during the study rather than a database lock 
at the end of the study, categories should be updated during the IPD reviews throughout 
the study prior to database lock.  These definitions of IPD categories, sub-category 
codes and descriptions will be used during the course of the study.  The final IPD list is 
used to produce the Summary of IPDs table and the List of Subjects with IPDs. In 
addition, a separate listing of all inclusion and exclusion deviations will be provided. 


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9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced: Demographic (ie, age, age groups [< 65, >= 65 and >= 75], sex, race, 
ethnicity), prior line of therapies (median, range) and baseline characteristics (height, 
weight, Eastern Cooperative Oncology Group (ECOG) Performance Status, ECHO or 
MUGA, refractory status, neurological evaluation status and % of subjects exposed to 
duratumumab) will be summarized using descriptive statistics. If multiple races have 
been reported for a subject, the subject will be categorized as multiple. 
A listing of the demographic and baseline characteristics will be provided.  In addition 
listings of medical history, hepatic history, prior anti-cancer therapy and prior 
radiotherapy usage will be provided. 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
No efficacy parameter is considered in primary endpoints. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Listings will be produced for all subjects in the dose-exploration cohorts and the 
dose-expansion cohorts indicating the time to progression, time to response, and 
duration of response. The proportion of subjects with a partial response to treatment or 
better per the International Myeloma Working Group criteria (IMWG) with corresponding 
exact 80% CI will be calculated using the Clopper-Pearson method (Clopper and 
Pearson, 1934) and tabulated for subjects treated at the MTD. The proportion of 
subjects with minimal residual disease and the proportion of subjects progression-free at 
6 months with corresponding exact 80% CI will be calculated using the Clopper-Pearson 
method. Kaplan Meier curve will be presented for time to progression and duration of 
response with estimates for rates and 80% CI at selected weeks. 
9.5.2.1 
Best Overall Response Rate 
The number and percent of subjects with objective response as determined by the 
IMWG-URC will be calculated using the Clopper-Pearson method and it will be tabulated 
for subjects treated at the MTD.  If the preliminary MTD and the final MTD are different 
then a preliminary BOR, final BOR and combined BOR rate will be presented.  
BOR will be calculated for subjects with prior CD38 treatment in expansion phase. 
BOR will also be calculated per refractory status. 


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The number and percentage of subjects with a best overall response of stringent 
complete response, complete response, very good partial response, partial response, 
minor response, stable disease and progressive disease will be presented by dose. 
9.5.2.2 
Minimal Residual Disease Conversion Rate 
The proportion of subjects with negative minimal residual disease with corresponding 
exact 80% CI will be calculated using the Clopper-Pearson method. 
Rate of conversion of MRD negativity will be calculated as, 
= (No of subjects with MRD negativity / Total person months of subjects in safety 
analysis set) * 100. 
It would be calculated only if no. of subjects with MRD negativity >=1. 
9.5.2.3 
Progression Free Subject Rate 
The proportion of subjects who are progression free (IMWG-URC) at 6 months with 
corresponding exact 80% CI will be calculated using the Clopper-Pearson method. 
9.5.2.4 
Time to progression 
Time to progression (IMWG-URC) will be analyzed using the Kaplan-Meier method. 
Kaplan-Meier survival curves and median time to progression along with 80% CI will be 
presented.  
9.5.2.5 
Time to Response (TTR) 
Time to response will be descriptively analyzed, summary statistics of the number, 
percentage will be reported. 
9.5.2.6 
Duration of Response (DOR) 
Duration of response will be conducted based on the subset of subjects having objective 
response. Kaplan-Meier estimates of median DOR, and their 80% confidence intervals 
may also be estimated. 
9.5.2.7 
Anti-AMG224 Antibodies 
The incidence and percentage of subjects who develop anti-AMG 224 antibodies 
(binding) at any time will be tabulated by treatment group.  If greater than 10% of 
subjects have a positive anti-AMG 224 antibody test then summaries of results over time 
will be provided. 


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9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
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 224. 
9.6.1.1 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version version 13.0 or later 
will be used to code all adverse events to a system organ class and a preferred term. 
Treatment-emergent adverse events are events with an onset after the administration of 
the first dose of investigational product.  
The subject incidence of adverse events will be summarized for all treatment-emergent, 
serious treatment emergent, treatment related, serious treatment related,  those leading 
to withdrawal of investigational product, fatal, and of special interest (if applicable).  The 
identification of adverse events of special interest is a continuous process.  Events may 
be identified and documented as the safety profile of the drug is characterized. The 
severity of each adverse event will be graded using CTCAE version 4.0 criteria.  
Subject incidence of all treatment-emergent, serious, treatment-related, serious 
treatment related,  those leading to withdrawal of investigational product, events of 
special interest (if applicable) and fatal adverse events will be tabulated by system organ 
class and preferred term in descending order of frequency. Where appropriate the tables 
will also be presented by worst grade. The above adverse event tables will not be 
created if two or fewer subjects experience the adverse event.  
Summaries of treatment-emergent and serious AEs occurring in all subjects by preferred 
term in any cohort will be provided in descending order of frequency. 
Details of each adverse event will be listed.  Listings and/or narratives of any on-study 
deaths, serious and significant treatment-emergent adverse events, including early 
withdrawals due to adverse events, also will be provided should they occur. 
9.6.1.2 
Dose Limiting Toxicities 
The analysis of the probability of DLT will be based on the DLT Evaluable Analysis Set. 
A listing and summary of the subject incidence of DLT will be provided.  
A final estimate of the MTD will be estimated from the TPI Bayesian model utilizing all 
DLT-evaluable subjects.  A sensitivity analysis may also be performed where DLTs 


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occurring outside of the specified time interval are included.  A listing of DLTs occurring 
outside of the specified time interval will be produced to aid in determining if the 
sensitivity analysis should be conducted.   
The planned doses for dose exploration cohort are 30, 
 
 of AMG 224. It will use a standard 3+3 design to guide dose escalation 
decisions and to make a preliminary estimate of the MTD. Dose level decision rules are 
specified in Table 1.  
In the dose expansion cohort, up to 20 subjects would be treated at the preliminary 
MTD. After 5 subjects (combining Group A and B) have completed 28 days on study, 
there will be a safety review by the DLRT. A TPI Bayesian model utilizing all current DLT 
evaluable subjects will be fit to evaluate appropriateness of preliminary MTD from dose 
exploration phase. As more subjects are treated, there may be a higher than expected 
incidence of DLTs or a higher than expected tolerance of treatment. If these scenarios 
(either with higher toxicity or tolerance) occur during expansion cohort the additional 
data will be used to refine the estimate of MTD established during the dose escalation 
phase. (Iasonos A and O’Quigley J, 2013).  
A minimally informative prior distribution will be used for the model parameters 
(Neuenschwander, 2008). The MTD target probability interval is (0.20, 0.35) and TPIs of 
(0.35, 0.60) and (0.60, 1.00) are defined as excessive and unacceptable, 
respectively.The model’s predicted MTD dose is the dose with the highest probability of 
the target TPI, but with a less than 0.25 probability of an excessive or unacceptable TPI.  
The TPI 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 that the dose has an excessive or 
unacceptable DLT rate (Babb et al, 1998).The probability of a DLT at dose level di is 
assumed to follow a Bernoulli distribution with probability pi where the logit of pi 
increases linearly with the log of the standardized dose in the following 2-parameter 
logistic model: 
log [pi / (1-pi)] = logit(pi) = log[a] + exp(log[b]) log (di / dmax) 
where a and b are random variables and dmax is the maximum planned dose.   
The probability of each TPI and of a DLT will be summarized by dose along with the 
estimated dose-toxicity curve. A final estimate of the MTD will be estimated from the TPI 
Bayesian model utilizing all DLT-evaluable subjects. Please refer to Appendix A (Toxicity 
Probability Interval (TPI) Bayesian Design section) for more details on the TPI model.   


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9.6.1.3 
Laboratory Test Results 
9.6.1.3.1 
Chemistry, Hematology and Coagulation 
Individual chemistry, hematology and coagulation laboratory data will be listed and other 
selected laboratory parameters of interests may be plotted. The selected laboratory 
parameters of interest include: platelets, white blood cell, hemoglobin, hematocrit, 
absolute neutrophil count, lymphocyte, AST, ALT, total bilirubin, and alkaline 
phosphatase, serum creatinine, PT, PTT, and INR.   Values outside the normal 
laboratory reference ranges will be flagged as high or low on the listings.  CTCAE 
grades will also be highlighted where appropriate. Unscheduled assessments will be 
incorporated in the laboratory analyses where possible.  
The number and percentage of subjects experiencing treatment emergent laboratory 
toxicities with worst post dose CTCAE grades of ≥ 1, ≥ 2, ≥ 3 and 4 will be presented.  
The direction of the laboratory worsening will be denoted. The summary will be 
presented for all laboratory parameters for which at least one subject experienced a 
treatment emergent toxicity with a worst grade ≥ 3.   
Additionally, the number and percentage of subjects experiencing 1, 2, 3 and 4 
worsening CTCAE grade shifts from baseline will be presented.  The direction of the 
laboratory worsening will again be denoted.   
Shift tables indicating the change between the baseline and the maximum post dose 
CTCAE grades for an increased value, and the maximum post dose grade for a 
decreased value will be provided for selected laboratory parameters of interest. 
A listing of CTCAE grade 3 or higher laboratory toxicities will be provided.  This listing 
will include all laboratory data for the subject and laboratory parameter of interest in 
order to provide proper context.  A flag will indicate the grade 3 or higher toxicity. 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters of interest (such as 
platelets, white blood cell, hemoglobin, hematocrit, absolute neutrophil count, 
lymphocyte ,AST, ALT, total bilirubin, alkaline phosphatase, serum creatinine, PT, PTT, 
and INR). 
A summary of the change from baseline to the post dose maximum, time to post-dose 
maximum, change from baseline to the post dose minimum, and the time to the post 
dose minimum may also be provided for selected parameters of interest (such as 
platelets, white blood cell, hemoglobin, hematocrit, absolute neutrophil count, 


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lymphocyte, AST, ALT, total bilirubin, alkaline phosphatase, serum creatinine, PT, PTT, 
and INR).    
Potential Hy’s law cases will be listed and may also be summarized per cohort and 
overall. A listing of AST, ALT, Total Bilirubin values at each time point will be produced 
for the subjects suspected of fulfilling the criteria for Hy’s law. 
9.6.1.3.2 
Urinalysis 
Individual urinalysis data will be listed. 
9.6.1.4 
Vital Signs 
Vital signs data (systolic / diastolic blood pressure, heart rate, respiratory rate, and 
temperature) will be listed and reviewed for each subject. Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline 
over time may be provided. 
9.6.1.5 
Electrocardiogram 
All on-study electrocardiogram (ECG) data will be listed.  All on-study electrocardiogram 
(ECG) data will be listed and  QTcF will be plotted. 
Where multiple 12-lead ECG measurements are taken at the same assessment (they 
are planned to be recorded in triplicate 30 seconds apart) the mean value will be 
calculated and used in the analysis.  For baseline ECG, three triplicate ECGs to be 
collected ≥ 30 minutes apart, with each ECG in triplicate approximately 30 seconds apart 
(3 set collected predose on day 1 with total of 9 ECGs]). Mean value will be calculated 
and used in the analysis. The mean of the values within a triplicate should be calculated 
before taking the mean of the triplicate averages.   
For pre and post dose ECG measurements, unscheduled ECG measurements taken up 
to 5 minutes after the last assessment of a triplicate will be included in the average for a 
time point.  Where an ECG is missing within a triplicate, all available data will be 
averaged for that time point.  
Summaries over time and/or changes from baseline over time will be provided for all 
12-lead ECG parameters.   
Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcF. Unscheduled assessments will be included in the determination of the 
maximum change. 


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 
<= 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 224 and change from 
baseline in QTcF may be explored graphically.  
Analysis of the relationship between AMG 224 serum concentrations and change from 
baseline in QTcF will be conducted and plots of the relationship between AMG 224 
serum concentrations and change from baseline in QTcF will be provided. 
In addition, the relationship between drug concentration (AMG 224 conjugated antibody, 
Total anti-BCMA antibody, and DM-1) and QTcF will be explored graphically. 
9.6.2 
Exposure to Investigational Product 
Details for each AMG 966 administration will be listed for every subject. In addition a 
listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided. 
Descriptive statistics will be produced to describe the exposure to investigational product 
by dosing schedule. Number of cycles, number of doses of investigational product and 
the total dose by unit will be summarized. Summaries of the number and percentage of 
subjects with dose modifications and reason for modification will be provided. 
9.6.3 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary.  A subject listing of all prior 
and concomitant medications will be presented. 


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9.7 
Exploratory Endpoints 
The statistical analysis in this section will be considered exploratory and will be 
performed only when deemed appropriate.  Details of analysis will be provided in 
supplemental analysis plan for exploratory biomarker analysis. Relationships between 
the PK and the markers for safety and efficacy may also be explored. 
9.8 
Other Analyses 
All other analyses will be covered in a separate analysis plan. 
9.8.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
9.8.1.1 
Pharmacokinetic Endpoints 
PK parameters will include, but are not limited to maximum observed concentration 
(Cmax), minimum observed concentration (Cmin) and area under the concentration-time 
curve over the dosing interval [AUC] and if feasible half-life (t1/2).  
The PK parameters of AMG 224 conjugated antibody, Total anti-BCMA antibody, and 
DM1  will be estimated using standard noncompartmental methods and summarized by 
dose level using means, standard deviations, medians, minimums and maximums. 
Serum concentrations below the lower limit of quantifications will be set to zero for the 
estimation of the pharmacokinetic parameters for each subject and for the calculation of 
the summary statistic for each time point.  Actual dosing and sampling time will be used 
for all calculations.  The reasons for excluding any sample from the analyses will be 
provided.   
Individual concentration-time data will be summarized by dose level. AMG 224 
conjugated antibody, Total anti-BCMA antibody, and DM1 concentrations at each time 
point along with PK parameter values may be listed for each subject. Individual 
concentration-time data will be tabulated and presented graphically. Summary statistics 
will be computed for each sampling time and parameter as appropriate.  
Analysis of the relationship between AMG 224 dose and exposure parameters (AUC and 
Cmax) will be conducted and plots of the relationship between AMG 224 dose and 
exposure parameters along with dose proportionality assessment will be provided. 
Analysis of the relationship between AMG 224 conjugated antibody concentrations and 
change from baseline in QTcF will be conducted and plots of the relationship between 
AMG 224 conjugated antibody concentrations and change from baseline in QTcF will be 


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provided. The above analysis will also be conducted for the Total anti-BCMA antibody, 
and DM1. 
Additional analyses to explore relationship between exposure and safety and exposure 
and efficacy may also be performed. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses.  


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11. 
Literature Citations / References 
Babb, J, Rogatko A, Zacks S.  Cancer phase I clinical trials: efficient dose escalation 
with overdose control.  Stat Med 1998;17:1103-1120. 
Bailey S, Neuenschwander B, Laird G, Branson M. A Bayesian case study in oncology 
phase I combination dose-finding using logistic regression with covariates. J Biopharm 
Stat. 2009;19:469-484. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometrika.  1934;26:404-413. 
Durie BG, Harousseau JL, Miguel JS, 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, B G.M. International Myeloma Foundation. Multiple Myeloma Cancer of the Bone 
Marrow. Concise Review of the disease and treatment Options. 2011/2012. Iasonos A 
and O’Quigley J. Design Considerations for Dose-expansion Cohorts in Phase I Trials. J 
Clin Oncol. 2013 
Paiva B, van Dongen J M, Orfao A. New criteria for response assessment: role of 
minimal residual disease in multiple myeloma. Blood, 2015;(125)3059-3068. 
Rajkumar VS, Harousseau J, Durie B, 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. 


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12. 
Prioritization of Analyses 
No prior analyses planned for this study 
13. 
Data Not Covered by This Plan 
Exploratory data not included in this plan may be analyzed at a later date or may be 
analyzed by a different Amgen Department. 


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14. 
Appendices 


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
Imputation Rules for Partial or Missing Stop Dates: 
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial. Imputation Rules for Partial or 
Missing Start Dates 
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start 
Date 
 
< 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: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
Code Fragments: 
Provisional Code Fragments for calculating a confidence interval using the Clopper 
Pearson Method. The following example SAS code will be utilized for the response rate 


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analysis providing the proportion of subjects responding to treatment with corresponding 
80% confidence intervals. 
data propci (keep = ns p low_ci upp_ci); 
n=xx; * total n within the treatment group; 
do ns= xx; *number of responders; 
p=ns/n; * response rate; 
q=1-p; 
lowF=FINV(0.1, 2*ns, 2*(n-ns+1)); /* use for 2-sided 80% CI */ 
UppF=FINV(1-0.1, 2*(ns+1), 2*(n-ns)); /* use for 2-sided 80% CI */ 
low_ci = 1 / (1+(n-ns+1) / (ns*lowf)); * lower CI for response rate; 
upp_ci = 1 / (1+(n-ns) / ((ns+1)*uppf)); *upper CI for response rate; 
if p=1 then upp_ci=1; 
if p=0 then low_ci =0; 
output; 
end;run; 
Toxicity Probability Interval (TPI) Bayesian Design: 
Expansion phase of the study will use a TPI Bayesian model utilizing data of all current 
DLT-evaluable subjects. It will evaluate the appropriateness of the preliminary MTD from 
dose exploration.  
The MTD target TPI for DLT is (0.20, 0.35), and TPIs of (0.35, 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 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 𝛼+ 𝛽log ( 𝑑𝑖
𝑑𝑚𝑎𝑥
)  
where 𝛼 and 𝛽 are random variables and 𝑑𝑚𝑎𝑥 is the maximum planned dose.  
A minimally informative prior distribution (Neuenschwander et al, 2008) was selected for 
𝜃= (log 𝛼, log 𝛽) where the probability that the true DLT rate is ≤ 0.60 at the lowest dose 
(30 mg Q3W) is 0.90 and the probability the true DLT rate is ≤ 0.20 at the maximum 
dose (
 Q3W) is 0.21. These values were selected such that 𝑝𝑖 is around 0.275 for 
105 mg dose level, which is approximately in the median of the planned dose range. 


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Median values for 𝑝𝑖 were interpolated per the logistic model. For each 𝑑𝑖, 2 quantiles for 
𝑝𝑖 were selected from a Beta distribution with the target median and a precision less 
than 2. This set of quantiles fully specified a target prior for theta. A bivariate normal 
distribution for theta was assumed where log 𝛼 has a normal distribution with mean 𝜇𝛼 
and standard deviation 𝑠𝛼, and log 𝛽 has a normal distribution with mean 𝜇𝛽 and 
standard deviation 𝑠𝛽, and 𝛾 is the correlation between log 𝛼 and log 𝛽 . Numerical 
integration with the SAS QUAD function was used to calculate Pr[𝑝𝑖≤𝑞(𝑑𝑖)], where 
𝑞(𝑑𝑖) is a quantile for dose 𝑑𝑖. An optimal bivariate normal distribution was estimated 
that achieved the minimum sum of squared difference between achieved and specified 
quantiles across all doses using a non-linear optimization by a quasi-Newton method 
with the SAS IML NLPQN function. The bivariate normal distribution prior solution has 
𝜇𝛼= 0.0536, 𝑠𝛼= 1.685, 𝜇𝛽= −0.1469, 𝑠𝛽= 1.001 and 𝛾= −0.216.  
The operating characteristics of the TPI Bayesian design will be evaluated at each dose 
using accumulated data of DLT evaluable subjects. Here, two parameters logistic 
regression would be fitted to accumulated data of all DLT evaluable subjects from dose 
exploration and expansion phase. Theta= (log a, log b) ~ BVN with parameters 
information mentioned above (use of prior). Theta would be estimated and would be 
used to estimate pi for each of di using 2 parameter logistic model. Pi for each of di 
would be compared with MTD target TPI for DLT. An “acceptable” final dose was defined 
as one with the highest or second highest target TPI probability and a less than 
0.25 excessive or unacceptable TPI probability. 
DLRM Outputs List: 
Listings: 
1. Subject demographics  
2. Date, time, dose of investigational product administration 
3. Electrocardiogram (ECG) results, change from baseline   
4. ECHO or MUGA results 
5. Vital signs  
6. Reported adverse events (AEs) 
7. Safety laboratory data (chemistry, hematology, urinalysis, coagulation) 
8. Current malignancy 
9. Medical history  
10. Concomitant medications 
11. Prior anti-cancer therapy and prior radiotherapy data 
12. Quantification of Immunoglobulins 
13. SPEP 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Figures 
1. Line plot of vital signs by time course 
2. Line plot of all safety labs by time course 
3. Line plot of ECGs results by time course  
4. Plot of the posterior probability of DLT (Expansion phase) 
5. Distribution plot of the predicted MTD (Expansion phase) 
6. Bar chart of the number of subjects studied per dose in dose exploration phase 
7. Protein_M1 line plot 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Appendix B.  Reference Values/Toxicity Grades 
Not applicable 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Appendix C.  Concomitant Medications 
Not applicable 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Appendix D.  Clinical Outcome Assessment Forms/Instruments 
Not applicable 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Appendix E.  Health Economic Forms/Instruments 
Not applicable 


Product:  AMG 224  
Protocol Number:  20130314 
Date:  28-Aug-2018 
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Appendix F.  Details of PK or PK/PD Methods for Modeling 
This is covered in a separate analysis plan.