Clinical trial NCT03571828
Conditions: Diffuse Large B-cell Lymphoma(DLBCL) Mantle Cell Lymphoma (MCL) Follicular Lymphoma (FL)
Sponsor: Amgen
Start date: 2018-10-29; Completion date: 2022-01-12
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose \[RP2D\])

Detailed description:

Arms: arm 1: Dose exploration cohorts to estimate the MTD, safety, tolerability, and PK of different doses of AMG 562 in subjects with relapsed/refractory DLBCL, MCL or FL using a Bayesian logistic regression model (BLRM; Neuenschwander et al, 2008). arm 2: dose expansion part to gain further clinical experience, safety and efficacy data for AMG 562 in subjects with relapsed / refractory DLBCL. The dose to be evaluated will be at or below the MTD estimated in the dose exploration cohorts.
Interventions: intervention 1: AMG 562
Intervention descriptions: intervention 1: AMG 562 is a BiTE® antibody construct that targets CD19 and is intended for the treatment of patients with B-cell malignancies.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 1 of 158 
CONFIDENTIAL 
Title:  A Phase 1, First-in-human, Open-label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / 
Refractory Diffuse Large B Cell Lymphoma, Mantle Cell Lymphoma or Follicular 
Lymphoma 
Amgen Protocol Number (AMG 562) 20170533 
EudraCT Number 2017-005063-41 
Clinical Study Sponsor: 
Amgen Inc.
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805-447-1000 
Key Sponsor Contacts: 
, PhD 
Early Development Lead 
Phone: 
 
Email: 
 
, MPH, PhD 
Global Clinical Trial Manager 
Phone: 
 
Email: 
 
Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
10 January 2018 
20 February 2018 
30 November 2018 
10 March 2019 
07 August 2019 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; <<for all other countries, insert the local toll-free Medical Information
number>> Amgen’s general number in the US (1-805-447-1000).
Approved
NCT Number: NCT03571828
This NCT number has been applied to the document 
for the purposes of posting on clinicaltrials.gov


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 2 of 158 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase 1, First-in-Human, Open-Label Study 
Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in 
Subjects With Relapsed / Refractory Diffuse Large B cell Lymphoma, Mantle Cell 
Lymphoma or Follicular Lymphoma ”, dated 07 August 2019, and agree to abide by all 
provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: 
•
me (including, if applicable, my spouse [or legal partner] and dependent children)
•
my subinvestigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
Signature 
Name of Investigator 
Date (DD Month YYYY) 
Approved


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 3 of 158 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / Refractory Diffuse Large 
B-cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma 
Study Phase:  1 
Indication: Adult subjects with relapsed / refractory Diffuse Large B-cell Lymphoma (DLBCL), 
Mantle Cell Lymphoma (MCL) or Follicular Lymphoma (FL) 
Objectives: 
Primary Objectives: 
• 
Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL or FL 
• 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
(eg, recommended phase 2 dose [RP2D]) 
Secondary Objectives: 
• 
Characterize the pharmacokinetics (PK) of AMG 562 
• 
Evaluate anti-lymphoma activity of AMG 562 
Exploratory Objectives:  
• 
Evaluate the formation of anti-AMG 562 antibodies 
Hypothesis: 
The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 562 will 
have an acceptable safety profile and evidence of anti-lymphoma activity in patients with relapsed 
and/or refractory B-NHL, specifically DLBCL, MCL or FL as measured by the overall response 
rate (ORR) and rate of CR. 
Endpoints: 
Primary Endpoint:   
• 
Safety: Incidence of dose limiting toxicities (DLTs), treatment-emergent adverse events, 
treatment-related adverse events, disease-related events and clinically-significant changes in 
vital signs, physical examinations, electrocardiograms (ECG)s and clinical laboratory tests 
Secondary Endpoints:   
• 
AMG 562 PK parameters including, but not limited to, maximum concentration (Cmax), 
minimum concentration (Cmin), time of maximum concentration (Tmax), area under the 
concentration-time curve (AUC), and if feasible, half-life (t1/2)  
• 
Efficacy parameters:  
− 
ORR according to Lugano classification 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 4 of 158 
CONFIDENTIAL 
 
 
− 
Overall response by category. [Response terminology reflects the response criteria used. 
The Lugano Classification response definitions for positron emission 
tomography-computed tomography (PET-CT) evaluations of fluorodeoxyglucose 
(FDG)-avid lymphomas uses the terminology complete metabolic response (CMR), 
partial metabolic response (PMR), no metabolic response  (NMR), or progressive 
metabolic disease (PMD). Corresponding designations from earlier response criteria 
include complete response (CR), partial response (PR), stable disease (SD), or 
progressive disease (PD)]. 
− 
Duration of response (DOR) 
− 
Progression free survival (PFS) 
− 
Overall survival (OS)  
Exploratory Endpoints: 
• 
Incidence of anti-AMG 562 antibody formation 
Study Design: 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study which will 
consist of a sequential dose exploration part to evaluate safety and tolerability of AMG 562 in 
adult subjects with relapsed / refractory DLBCL, MCL, or FL. The dose exploration part will be 
followed by dose expansion to gain further safety and efficacy with AMG 562 in adult subjects 
with relapsed / refractory DLBCL. AMG 562 will be administered weekly as an IV infusion with or 
without a run-in phase (step-up dosing). The run-in phase consists of administration of a low dose 
on day 1 of treatment and a higher dose (target dose) on day 2. Additional dose steps may be 
administered subsequently at daily intervals. After administration of the target dose, treatment will 
continue with weekly administrations of the target dose. 
Dose Exploration 
The dose exploration cohorts will estimate the MTD, safety, tolerability, PK, and 
pharmacodynamics of different doses of AMG 562 in subjects with relapsed / refractory DLBCL, 
MCL, or FL. Dose exploration will be conducted in 2 stages using a Bayesian logistic regression 
model (BLRM) design to guide dose escalation. In the initial cohorts, single subjects will be 
enrolled at dose levels anticipated to be lower than the dose levels at which adverse events 
related to AMG 562 may be observed. Enrollment will proceed with multiple subject cohorts of 
3 to 4 subjects per cohort when higher dose levels are open for enrollment by the Dose Level 
Review Team (DLRT) or if at least one subject experiences any of the three safety events below 
(whichever occurs earlier): 
1. Non hematologic adverse event grade ≥ 2   
2. Hematologic adverse event grade ≥ 3 including anemia, neutropenia, leukopenia, 
thrombocytopenia, and lymphopenia   
3. DLT 
AMG 562 will be administered as IV infusions at weekly intervals. If no DLTs are observed, the 
dose escalation will continue to the next planned dose cohort as shown Table 1 below. Once a 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 5 of 158 
CONFIDENTIAL 
 
 
subject experiences a DLT, the dose for the subsequent cohorts will be recommended by the 
DLRT after evaluating all available safety, laboratory, and PK data as well as the 
recommendation from the BLRM. Subsequent dose escalation will be limited to 2-fold increases 
or lower after a subject experiences a DLT or ≥ 2 patients experience a grade ≥ 2 adverse event. 
Table 1.  Planned Dose Levels (IV)  
Cohort 
Dose (µg) 
Cohort Size 
1 
0.1 
1 
2 
0.3 
1 
The DLRT may also recommend altering the dosing schedule (dosing interval) for subsequent 
cohorts. The changes to the dosing schedule may also include the implementation of step-up 
dosing for future cohorts based on tolerability as observed in the clinical and pharmacological 
data.  
The DLT evaluation period will be at least 28 days for all cohorts. The DLT evaluation period may 
also be extended to assess events starting within the DLT window. Any adverse event occurring 
outside the DLT window that meets the DLT definition and is determined by the investigator to be 
possibly related to AMG 562, and 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 event and all available safety data. A DLRM will be 
conducted after the subjects in each dose cohort have had the opportunity to complete the DLT 
evaluation period. The DLRT may also convene at any time to review safety data if deemed 
necessary.   
Subjects who complete the DLT period may proceed to a higher dose level for the next dosing 
(intra-subject dose escalation) once this higher dose level has been deemed safe by the DLRT 
and after consultation with the Amgen Medical Monitor if: 
• 
no DLT has been reported for this subject during or after completion of the DLT period 
• 
the subject has not experienced any  grade ≥ 2 adverse events (deemed treatment related by 
the investigator) during treatment 
DLTs experienced by subjects after completing the DLT period will be considered in the BLRM 
design to account for any late onset toxicity. 
Dose exploration will continue until any of the following events: 
• 
The highest planned dose level is determined to be safe and tolerable (minimum of 
6 treated subjects) 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 6 of 158 
CONFIDENTIAL 
 
 
• 
An MTD is identified where BLRM repeats the recommendation of a dose level (minimum 
of 6 treated subjects) 
• 
If fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability. 
Dose Expansion 
At completion of the dose exploration cohorts, additional subjects (up to 55) will be enrolled in a 
dose expansion cohort to gain further clinical experience, safety and efficacy data for AMG 562 in 
subjects with relapsed / refractory DLBCL. The dose to be evaluated will be at or below the MTD 
estimated in the dose exploration cohorts. Additional expansion cohorts may be covered by a 
protocol amendment to test alternative dose levels or biologic subsets or other disease entities 
included in the dose exploration. A final estimate of the MTD and RP2D will be evaluated and 
confirmed utilizing all DLT-evaluable subjects from the dose exploration and the dose expansion 
cohorts. The clinical activity of AMG 562 in the expansion cohort will be examined using a 
Bayesian predictive probability design. If posterior probability is more than 85% that the ORR is 
40% or less then, this is considered insufficient anti-lymphoma activity. If the ORR is too low, 
enrollment may be terminated early due to insufficient anti-lymphoma activity. The guidelines for 
futility due to insufficient efficacy assuming a prior beta distribution (0.8, 1.2) are presented in 
Table 2.  
Table 2.  Futility Guidelines 
Number of Treated Subjects 
Efficacy Futility Guideline 
15 
4 or fewer responders 
20 
5 or fewer responders 
25 
7 or fewer responders 
30 
9 or fewer responders 
35 
11 or fewer responders 
40 
12 or fewer responders 
45 
14 or fewer responders 
50 
16 or fewer responders 
55 
Trial will stop 
The DLRT will be convened in the dose expansion part of the study to review efficacy data after 
the first 15 subjects are enrolled and have had the opportunity to receive at least five weeks of 
treatment (with recruitment ongoing).  
Additionally, the DLRT will review safety data and conduct evaluations of the ongoing DLT rate to 
assess if the threshold for early trial termination has been reached. The stopping rules use a 
Bayesian approach to terminate the study if the posterior probability that the DLT rate is greater 
than 33% is > 90%.  The stopping boundaries assuming a prior beta distribution (0.66, 1.33) are 
presented in Table 17. The evaluations could occur more frequently if necessary to address 
emerging safety concerns 
Sample Size: 
It is anticipated that approximately 85 subjects will be enrolled in this study. Approximately 
30 subjects will be enrolled in the dose escalation cohorts and up to 55 additional subjects will be 
enrolled in the dose expansion cohort. The sample size in the dose escalation is based on 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 7 of 158 
CONFIDENTIAL 
 
 
practical considerations and is consistent with conventional oncology studies with the objective to 
estimate the MTD. With 3 subjects per cohort, there is a 27-70% probability of observing at least 
one DLT if the true DLT rate is 10-33% and with 4 subjects per cohort, there is a 34-80% 
probability. In the dose expansion cohort, 55 subjects will provide a 43% probability of observing 
at least one adverse event with a true 1% incidence rate and 94% probability of observing at least 
one adverse event with a true 5% incidence rate. With 55 subjects and a 40% overall response 
rate, the expected 90% CI would be 29% to 52%. 
Summary of Subject Eligibility Criteria:   
Male or female subjects ≥ 18 year of age at the time of informed consent who have  
• 
Relapsed / refractory DLBCL after appropriate prior treatment, with relapse after at least 
2 lines of therapy, with one or more regimens including an anthracycline AND an 
approved anti-CD20 agent 
or 
• 
Relapsed / refractory FL after appropriate prior treatment, with relapse after at least 
3 lines of therapy, with at least one or more  regimens including an approved  
anti-CD20 agent 
or 
• 
Relapsed / refractory MCL after appropriate prior treatment, with relapse after at least 
3 lines of therapy, with at least one or more regimens including an approved  
anti-CD20 agent  
at time of screening. The diagnosis must be biopsy proven and subjects must have measurable 
disease at screening as defined in the inclusion criteria. Subjects who received prior CD19 
directed  CAR-T cell therapy are excluded. 
Investigational Product 
Amgen Investigational Product Dosage and Administration: 
AMG 562 will be manufactured and packaged by Amgen Inc. and distributed using Amgen clinical 
study drug distribution procedures. 
AMG 562 is supplied as a sterile, preservative-free lyophilized powder for IV administration after 
reconstitution with sterile water for injection (WFI).   
AMG 562 solution for infusion will be prepared in bags for IV infusion and delivered through 
infusion lines. The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, and 
administration of AMG 562. 
The initial duration of infusion will be 
 This duration may be extended up to 
6 hours for future dose cohorts or subsequent cycles for all subjects in the initial dose cohort 
based on review of safety and PK data by the DLRT.  
• 
Minimum hospitalization times for subjects will be as follows: 
• 
Without step-up dosing: 
• 
72 hours after infusion at C1D1 and C1D8 
• 
48 hours after infusion at C1D15 and C1D22 if there are no adverse events ≥ grade 1 
up to day 15, otherwise 72 hours.  
• 
For all subsequent infusions subjects should be monitored in hospital or outpatient 
clinic for at least 4 hours after start of each infusion with hospitalization at the 
discretion of the investigator 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 8 of 158 
CONFIDENTIAL 
 
 
• 
With step-up dosing:  
• 
72 hours after infusion at day 1, after every step dose infusion and for the first two 
infusions at target dose (similar to C1D1 and C1D8 without step-dosing)  
• 
48 hours after the 3rd and 4th infusion at target dose if there are no adverse events  
≥ grade 1, otherwise 72 hours.  
• 
For all subsequent infusions, subjects should be monitored in hospital or outpatient 
clinic for at least 4 hours after start of each infusion with hospitalization at the 
discretion of the investigator 
The DLRT may recommend on changes in hospitalization requirements after review of available 
safety data.  
Treatment can be administered as long as the subject is deriving benefit per the judgment of the 
investigator, unless one of the criteria for permanent discontinuation of treatment is met. 
Treatment can be discontinued 4 weeks after a CR/CMR is confirmed by the investigator after 
consultation with the Amgen Medical Monitor.  
Procedures: After providing informed consent, eligible subjects will undergo the following 
assessments during this study: physical examination, neurological examination, Eastern 
Cooperative Oncology Group (ECOG) status, height, weight, vital signs, pulse oximetry, ECG 
triplicate measurement, laboratory assessments (including serum pregnancy test, if applicable, 
coagulation, hematology, blood chemistry profiles, urinalysis, hepatitis serology, and 
anti-AMG 562 antibody test), biomarker and PK assessments, immunoglobulin levels (IgG, IgA, 
IgM), PET-CT (per standard of care), and bone marrow biopsy (per standard of care). Reporting 
of adverse events, disease related events, and cases of pregnancy and lactation will be 
performed as described in the study procedures. 
Statistical Considerations:  The primary analysis for the dose exploration part will occur when 
targeted enrollment is complete and each subject either completes 3 months on study or is taken 
off from the study by the Investigator. The primary analysis for the dose expansion part will occur 
when targeted enrollment is complete and each subject had the opportunity to receive at least 
3 months of treatment at the target dose. 
In the dose exploration part, the DLRT will review the safety data after each cohort and make a 
recommendation on the next dose level to be explored for the estimate of RP2D/MTD based on a 
BLRM design. In the dose expansion part, efficacy futility and safety will be assessed using a 
Bayesian predictive probability design. 
Descriptive statistics will be provided for selected demographics, safety, PK, pharmacodynamic, 
efficacy and biomarker data by dose, dose schedule, and time as appropriate. Descriptive 
statistics on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages. ORR will be 
presented with 90% exact CI. PFS will be summarized using the Kaplan-Meier method.  
Graphical summaries of the data may also be presented. 
For a full description of statistical methods, please refer to Section 10. 
--------------------------------------------------------------------------------------------------------------------------------- 
Sponsor:   
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Tel: 805-447-1000 
Fax: 805-499-9495 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 9 of 158 
CONFIDENTIAL 
 
 
Cohort 1: 0.1 µg* n = 1** 
Cohort 2: 0.3 µg* n = 1** 
SCHEMA: Part 1 - Dose Exploration (n ~ 30) 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 10 of 158 
CONFIDENTIAL 
 
 
Treatment period with AMG 562 
Q1W treatment with AMG 562 IV until disease progression, intolerance, or withdrawal of consent 
r/r DLBCL patients (n = 55) 
SCHEMA: Part 2 - Dose Expansion 
 
* From first dose of AMG 562 
Screening (up to 21 days) 
Enrollment (C1D1) 
Safety follow-up 30 (+7) days after last cycle 
Long-term follow-up: 2 years* 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 11 of 158 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
18FDG-PET 
18-fluorodeoxyglucose-positron emission tomography 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BLRM 
Bayesian logistic regression model 
BM 
bone marrow 
B-NHL 
B-cell Non-Hodgkin Lymphoma 
CAR 
chimeric antigen-receptor 
CBC 
complete blood count 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CMR 
complete metabolic response 
CNS 
central nervous system 
COO 
cell-of-origin 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CSF 
cerebro spinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DILI 
drug induced liver injury  
DLBCL 
diffuse large B-cell lymphoma 
DLRM 
Dose level review team meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicities 
DOR 
duration of response 
EC50 
half maximal effective concentration 
EC90 
effective concentration leading to 90% response  
EDC 
electronic data capture 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 12 of 158 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Follow-up 
defined as when the last subject completes the last  
protocol-specified assessment in the study 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject (ie, the date the subject 
withdraws full consent from the study, completes the safety follow-up 
visit or long-term follow up [whichever is later] or death). 
End of Study (primary 
completion) 
the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
analysis 
End of Study (end of trial) the time when the last subject is assessed or receives an 
intervention for evaluation in the study. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FISH 
fluorescent in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte macrophage colony-stimulating factor  
HepBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
HSC 
hematopoietic stem cell 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator’s brochure 
IC 
investigator’s choice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IgA 
immunoglobin A 
IgG 
immunoglobin G 
IgM 
immunoglobin M 
INR 
international normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
IRR 
institutional review board/independent ethics committee 
infusion related reaction 
IV 
intravenous 
KM 
Kaplan-Meier 
MABEL 
minimum anticipated biological effect level 
MRD 
minimal residual disease  
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 13 of 158 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NHL 
non-Hodgkin’s lymphoma 
ORR 
objective response rate 
OS 
overall survival 
PB 
peripheral blood 
PD 
progressive disease 
PET/CT 
positron emission tomography/computed tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PMD 
progressive metabolic disease 
PMR 
partial metabolic response 
PR 
partial response 
PT 
thromboplastin time 
PTT 
partial thromboplastin time 
Q-PCR 
QTc interval  
Quantitative Polymerase Chain Reaction 
QT interval corrected for heart rate using accepted methodology 
RP2D 
recommended phase 2 dose 
R/R 
relapsed or refractory 
SD 
stable disease 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research. The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include subject 
identification, randomization identification, and stratification value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
products are administered to the subject 
TBL 
total bilirubin 
Tmax 
time of maximum concentration 
TPI 
toxicity probability interval 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHODRUG 
World Health Organization Drug 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 14 of 158 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
SCHEMA: Part 1 - Dose Exploration (n ~ 30) .................................................................. 9 
SCHEMA: Part 2 - Dose Expansion ............................................................................... 10 
Study Glossary .............................................................................................................. 11 
1. 
OBJECTIVES ....................................................................................................... 20 
1.1 
Primary ..................................................................................................... 20 
1.2 
Secondary ................................................................................................. 20 
1.3 
Exploratory ................................................................................................ 20 
2. 
BACKGROUND AND RATIONALE ...................................................................... 20 
2.1 
Disease ..................................................................................................... 20 
2.2 
Amgen Investigational Product Background .............................................. 22 
2.2.1 
Pharmacology ........................................................................... 23 
2.2.2 
Pharmacokinetics ...................................................................... 24 
2.2.3 
Toxicology ................................................................................. 24 
2.2.4 
Dosing Experience With Other BiTE® Antibody 
Constructs ................................................................................. 25 
2.3 
Benefit-risk Assessment ............................................................................ 26 
2.3.1 
Key Benefits .............................................................................. 27 
2.3.2 
Key Risks, Identified and Potential, and Mitigations ................... 27 
2.4 
Rationale ................................................................................................... 30 
2.4.1 
Dose Selection Rationale .......................................................... 31 
2.5 
Clinical Hypotheses ................................................................................... 33 
3. 
EXPERIMENTAL PLAN ........................................................................................ 33 
3.1 
Study Design ............................................................................................. 33 
3.2 
Number of Sites ........................................................................................ 44 
3.3 
Number of Subjects ................................................................................... 44 
3.4 
Replacement of Subjects .......................................................................... 44 
3.5 
Estimated Study Duration .......................................................................... 45 
3.5.1 
Study Duration for Subjects ....................................................... 45 
3.5.2 
End of Study .............................................................................. 45 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 46 
4.1 
Inclusion Criteria ....................................................................................... 46 
4.2 
Exclusion Criteria ...................................................................................... 48 
5. 
SUBJECT ENROLLMENT .................................................................................... 50 
5.1 
Treatment Assignment .............................................................................. 51 
6. 
TREATMENT PROCEDURES .............................................................................. 52 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 15 of 158 
CONFIDENTIAL 
 
 
6.1 
Classification of Products, and/or Medical Devices ................................... 52 
6.2 
Investigational Product .............................................................................. 52 
6.2.1 
Amgen Investigational Product AMG 562 .................................. 52 
6.2.1.1 
Dosage, Administration, and Schedule .................... 52 
6.2.1.2 
Overdose ................................................................ 54 
6.2.1.3 
Dose Limiting Toxicities (DLTs) ............................... 54 
6.2.1.4 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 56 
6.3 
Other Protocol-required Therapies ............................................................ 71 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 72 
6.4.1 
Criteria for Permanent Withholding of AMG 562 due to 
Potential Hepatotoxicity ............................................................. 72 
6.4.2 
Criteria for Conditional Withholding of AMG 562 due to 
Potential Hepatotoxicity ............................................................. 73 
6.4.3 
Criteria for Rechallenge of AMG 562 After Potential 
Hepatotoxicity............................................................................ 73 
6.5 
Concomitant Therapy ................................................................................ 74 
6.5.1 
Supportive Care ........................................................................ 74 
6.5.2 
Growth Factors .......................................................................... 74 
6.5.3 
Infections ................................................................................... 74 
6.6 
Medical Devices ........................................................................................ 75 
6.7 
Product Complaints ................................................................................... 75 
6.8 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period .................................................................................. 76 
7. 
STUDY PROCEDURES ....................................................................................... 76 
7.1 
Schedule of Assessments ......................................................................... 76 
7.2 
General Study Procedures ........................................................................ 97 
7.2.1 
Screening .................................................................................. 98 
7.2.2 
Treatment ................................................................................ 100 
7.2.3 
Safety Follow-up Visit(s)/End of Study Visit ............................. 101 
7.2.4 
Long-term Follow-up ................................................................ 102 
7.2.5 
End of Study ............................................................................ 102 
7.3 
Description of Study Procedures ............................................................. 102 
7.3.1 
Informed Consent .................................................................... 102 
7.3.2 
Demographic Data................................................................... 103 
7.3.3 
Medical History ........................................................................ 103 
7.3.4 
Prior Therapy ........................................................................... 103 
7.3.5 
Concomitant Medication .......................................................... 104 
7.3.6 
Clinical Evaluation ................................................................... 104 
7.3.6.1 
Physical Examination ............................................ 104 
7.3.6.2 
ECOG Performance Status ................................... 104 
7.3.6.3 
Height Measurements ........................................... 104 
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7.3.6.4 
Weight Measures .................................................. 104 
7.3.7 
Vital Signs ............................................................................... 104 
7.3.8 
Pulse Oximetry ........................................................................ 105 
7.3.9 
Neurological Examination ........................................................ 105 
7.3.9.1 
Extended Neurological Examination ...................... 105 
7.3.9.2 
Limited Neurological Examination ......................... 105 
7.3.10 
Electrocardiogram (ECG) Performed in Triplicate .................... 106 
7.3.11 
Clinical Laboratory Tests ......................................................... 106 
7.3.11.1 
Pregnancy Test ..................................................... 108 
7.3.12 
Response Assessments .......................................................... 108 
7.3.12.1 
Clinical Tumor Assessment ................................... 108 
7.3.12.2 
Radiographic Assessment ..................................... 108 
7.3.12.3 
Bone Marrow Biopsy for Disease 
Assessment .......................................................... 109 
7.3.12.4 
Minimal Residual Disease ..................................... 109 
7.3.13 
Events ..................................................................................... 109 
7.3.14 
Vital Status .............................................................................. 109 
7.3.15 
Pharmacokinetic Blood Sampling ............................................ 109 
7.4 
Antibody Testing Procedures .................................................................. 110 
. 110 
. 111 
. 112 
. 112 
7.7 
Sample Storage and Destruction ............................................................. 112 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 113 
8.1 
Subjects’ Decision to Withdraw ............................................................... 113 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 114 
8.3 
Reasons for Removal From Treatment or Study ..................................... 114 
8.3.1 
Reasons for Removal From Treatment .................................... 114 
8.3.2 
Reasons for Removal From Study ........................................... 115 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 115 
9.1 
Definition of Safety Events ...................................................................... 115 
9.1.1 
Disease-related Events ........................................................... 115 
9.1.2 
Adverse Events ....................................................................... 116 
9.1.3 
Serious Adverse Events .......................................................... 117 
9.2 
Safety Event Reporting Procedures ........................................................ 117 
9.2.1 
Reporting Procedures for Disease-related Events ................... 117 
9.2.2 
Adverse Events ....................................................................... 118 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .......................... 118 
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9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ................................................................... 119 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................. 120 
9.3 
Pregnancy and Lactation Reporting ........................................................ 120 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 121 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 121 
10.1.1 
Study Endpoints ...................................................................... 121 
10.1.2 
Analysis Sets ........................................................................... 122 
10.1.3 
Covariates and Subgroups ...................................................... 123 
10.1.4 
Handling of Missing and Incomplete Data ................................ 123 
10.2 
Sample Size Considerations ................................................................... 123 
10.3 
Adaptive Design ...................................................................................... 124 
10.4 
Planned Analyses ................................................................................... 124 
10.4.1 
Interim Analyses ...................................................................... 124 
10.4.2 
Dose Level Review Team (DLRT) ........................................... 126 
10.4.3 
Primary Analysis ...................................................................... 127 
10.4.4 
Final Analysis .......................................................................... 127 
10.5 
Planned Methods of Analysis .................................................................. 127 
10.5.1 
General Considerations ........................................................... 127 
10.5.2 
Primary Endpoint(s) ................................................................. 127 
10.5.3 
Secondary Endpoints .............................................................. 129 
10.5.3.1 
Pharmacokinetics Data Analysis ........................... 129 
10.5.3.2 
Efficacy Endpoint Analyses ................................... 129 
10.5.4 
Exploratory Endpoints ............................................................. 130 
11. 
REGULATORY OBLIGATIONS .......................................................................... 130 
11.1 
Informed Consent .................................................................................... 130 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 131 
11.3 
Subject Confidentiality ............................................................................. 131 
11.4 
Investigator Signatory Obligations ........................................................... 132 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 132 
12.1 
Protocol Amendments and Study Termination ........................................ 132 
12.2 
Study Documentation and Archive .......................................................... 133 
12.3 
Study Monitoring and Data Collection ..................................................... 133 
12.4 
Investigator Responsibilities for Data Collection ...................................... 134 
12.5 
Language ................................................................................................ 135 
12.6 
Publication Policy .................................................................................... 135 
12.7 
Compensation ......................................................................................... 135 
13. 
REFERENCES ................................................................................................... 136 
14. 
APPENDICES .................................................................................................... 138 
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List of Tables 
Table 1.  Planned Dose Levels (IV) ................................................................................. 5 
Table 2.  Futility Guidelines ............................................................................................. 6 
Table 3.  Important Potential Risks of AMG 562 ............................................................ 27 
Table 4.  Summary of Important Potential Risks of AMG 562 ........................................ 29 
Table 5.  First-in-human Doses and Predicted Exposure Margins (Potency 
Adjusted) From the Pivotal Repeat-dose Intravenous Toxicity 
Study of AMG 562 in the Cynomolgus Monkey ....................................... 32 
Table 6.  Infusion Interruptions/Delays/Withholding/Permanent 
Discontinuations and Management of Adverse Events 
Including Dose Reductions ..................................................................... 58 
Table 7.  Grading and Management of Cytokine Release Syndrome ............................. 66 
Table 8.  Schedule of Assessments for Screening and Treatment Cycle 1 .................... 77 
Table 9.  Schedule of Assessments for Screening and Treatment Cycle 1 
With 24 hour Step-up Dosing Intervals ................................................... 82 
Table 10.  Schedule of Assessments for Treatment Cycle 2 .......................................... 87 
Table 11.  Schedule of Assessments for Treatment Cycle 3 and Following to 
End of Study ........................................................................................... 91 
Table 12.  Dosing Schedule with 48, 72, and 96 hour Step-up dosing Intervals ............. 96 
Table 13.  List of Analytes ........................................................................................... 107 
Table 14.  Disease-related Events by System Organ Class ......................................... 115 
Table 15.  Guideline for Insufficient Efficacy ................................................................ 125 
Table 16.  Operating Characteristics for futility With Batch Size of 5 Subjects ............. 125 
Table 17.  Stopping Boundaries .................................................................................. 126 
Table 18.  Operating Characteristics for stopping early With Batch Size of 
5 Subjects ............................................................................................. 126 
Table 19.  Medications That May Cause QTc Prolongation ......................................... 147 
Table 20.  True Probability of DLT by Scenario for Simulated Studies 
Estimating MTD .................................................................................... 155 
Table 21.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD When the Target TPI is (0.20, 0.33) ...................... 156 
Table 22.  Operating Characteristics by Scenario for Simulated Studies 
Estimating the MTD Using a 3+3 Design .............................................. 156 
Table 23.  Cairo-bishop Definition of Laboratory Tumor Lysis Syndrome ..................... 157 
Table 24.  Cairo-bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 158 
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List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 139 
Appendix B.  Sample Serious Adverse Event Form or eSerious Event 
Contingency Form ................................................................................ 141 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 144 
Appendix D.  Response Assessment per the Lugano Classification ............................ 146 
Appendix E.  Medications That May Cause QTc Prolongation ..................................... 147 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ............................................................ 150 
Appendix G.  Examples of CYP450 Substrates With Narrow Therapeutic 
Range ................................................................................................... 151 
Appendix H.  Extended Neurological Examination ....................................................... 152 
Appendix I.  Protocol Sampling Scheme (Nominal Times) ........................................... 153 
Appendix J.  Two-parameter BLRM Design ................................................................. 154 
Appendix K.  Cairo-bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 157 
 
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1. 
OBJECTIVES 
1.1 
Primary 
• 
Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL 
or FL 
• 
Estimate the maximum tolerated dose (MTD) and/or a biologically active dose 
(eg, recommended phase 2 dose [RP2D]) 
1.2 
Secondary 
• 
Characterize the pharmacokinetics (PK) of AMG 562  
• 
Evaluate anti-lymphoma activity of AMG 562 
1.3 
Exploratory 
• 
Evaluate the formation of anti-AMG 562 antibodies 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
The annual incidence of Non-Hodgkin’s Lymphoma (NHL) in Europe and the United 
States is estimated to be 15 to 20 cases/100.000 (Fisher and Fisher, 2004).  NHL is a 
heterogeneous set of malignancies with many histologic subtypes. For practical clinical 
purposes, NHL can be divided into indolent and aggressive lymphomas. Most NHLs are 
B-cell derived (90%) and express common B-cell antigens such as CD19, CD20, and 
CD22 (Katz and Herishanu, 2014; Evens and Blum, editors, 2015).  
DLBCL is an aggressive Lymphoma and the most common subtype of NHL, accounting 
for 30% to 40% of cases.  The incidence is approximately 8 cases per 100 000 and rises 
with age; the median age at diagnosis is 70 years (Haematological Malignancy 
Research Network).  Distinct patterns of gene expression are observed within DLBCL, 
with different prognostic and potentially predictive implications. The main histological 
subtype of indolent NHL is FL, which accounts for approximately 20% of all NHL. MCL 
comprises 9% of all NHL. Management of NHL varies considerably, ranging from no 
initial therapy at all to multimodality therapy using radiotherapy, cytotoxic chemotherapy, 
and or chemoimmunotherapy (Evens and Blum, editors, 2015). 
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Left untreated, DLBCL is uniformly fatal.  Anthracycline-based frontline chemotherapy, 
introduced in the 1970s, resulted in the long term cure of 30% of patients 
(DeVita et al, 1975). Twenty-five years later, introduction of the human-mouse chimeric 
monoclonal anti-CD20 immunoglobulin G (IgG) rituximab increased the cure rate 
significantly and is now a standard agent in frontline therapy, resulting in cure for 60% of 
patients (Sehn and Gascoyne 2015). 
Patients with DLBCL who do not respond to frontline therapy, or who experience 
relapse after a remission, are generally considered incurable unless able to receive 
either high dose chemotherapy (HDT) with autologous or allogeneic haematopoietic 
stem cell transplant (HSCT) (Robinson et al, 2016).  HSCT is preceded by a course of 
salvage chemotherapy.  “Chemoresponsivess”, indicating a partial response (PR) or 
complete response (CR) to salvage chemotherapy, has been used as one criterion to 
define HSCT eligibility, since early trials demonstrated the extremely poor outcomes of 
patients without an objective response to salvage chemotherapy (Philip et al, 1987).  
Despite the improvements observed since the introduction of rituximab into front-line 
treatments, relapse continues to be observed in 10 to 20% and 30 to 50% of patients in 
favorable and poor prognostic groups respectively (Martelli et al, 2013). The efficacy of 
salvage regimens have been compared in 2 large, multicenter randomized trials, CORAL 
(R-DHAP vs R-ICE) and NCIC Ly.12 (R-DHAP vs R-GDP) (Crump et al, 2014; 
Gisselbrecht et al, 2010). A third trial, ORCHARRD, tested an alternative anti-CD20 
agent, ofatumomab, versus rituximab in combination with DHAP  
(Van Imhoff et al, 2014). The different response and survival rates observed in these 
large trials may be attributed to heterogeneity in patient selection criteria as well as in 
the nature and timing of post-treatment assessments. Nonetheless, these results 1) fail 
to demonstrate superiority of any specific regimen and 2) underscore the need for new 
agents in the salvage treatment of this disease. Recently axicabtagene ciloleucel, 
YESCARTA, and tisagenlecleucel, KYMRIAH, were approved in the US based on single 
arm study for refractory or relapsed large B-cell lymphoma after two or more lines of 
therapy. Although response rates compare favorably with other therapies in this setting, 
serious side effects are frequent and clinical experience stems mostly from patients with 
good performance status  
(YESCARTA prescribing information, 2017; KYMRIAH prescribing information, 2018).  
Thus, there is a significant medical need for novel, effective and well tolerated therapies 
in relapsed or refractory DLBCL. 
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Newly diagnosed FL and MCL is generally treated with chemoimmunotherapy. Earlier 
stages of FL can be managed by watch and wait or radiotherapy in cases of localized 
disease. The majority of MCL patients present with advanced disease and require 
treatment at diagnosis. For MCL, eligible patients generally receive consolidation 
through autologous transplantation, which confers prolonged progression free survival. 
For FL and older MCL patients Rituximab maintenance should be offered after standard 
chemoimmunotherapy (Evens and Blum, editors, 2015).  
There are several treatment options for symptomatic relapsed or refractory FL patients, 
including chemoimmunotherapy, immunotherapy, chemotherapy, radioimmunotherapy, 
antibody drug conjugates and novel targeted therapies. In general, response rates and 
response durations decrease substantially with each line of treatment and cumulative 
toxicities of multiple treatment lines can reduce quality of life. Relapsed or refractory FL 
is considered incurable with few exceptions (Evens and Blum, editors, 2015). 
For treatment of relapsed or refractory MCL ibrutinib is a preferred agent but other 
targeted agents, chemoimmunotherapy and autologous as well as allogeneic stem cell 
transplantation are used in this setting. As with FL, therapies become less effective with 
successive lines of treatment and advanced MCL cannot be cured with standard 
therapies (Evens and Blum, editors, 2015). 
In conclusion there is a significant medical need in the relapsed or refractory setting in 
MCL as well as in FL for novel treatment options with higher response rates and 
increased duration of response to reduce burden caused by multiple lines of therapy and 
to provide effective treatment options for patients with aggressive disease.   
2.2 
Amgen Investigational Product Background 
BiTE® antibody constructs (bispecific T cell engagers) have been designed to direct T 
cells towards target cells. AMG 562 consists of 2 single chain variable fragment (scFv) 
binding domains, specific for CD19, an antigen expressed by B cells, and the epsilon 
subunit of the CD3 complex present on T cells. The cross-linking of the CD19 and CD3 
antigens mediated by the BiTE® triggers target cell specific cytotoxicity closely 
resembling standard cytotoxic T lymphocyte activation. 
AMG 562 is a BiTE® antibody construct belonging to the so called Half Life Extended 
(HLE) BiTE® antibody constructs, which is being developed with the intent to treat 
patients with DLBCL, MCL, and FL. Compared to canonical BiTE®  Antibody constructs 
like blinatumomab, a scFc fragment has been introduced into the molecule in order to 
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prolong its half-life. T cells are bound by its anti-CD3 moiety, whereas lymphoma cells 
are bound by the anti-CD19 moiety. This feature of AMG 562 allows it to transiently 
cross-link malignant cells with T cells via their CD3 complex, thereby inducing T-cell 
mediated killing of the bound  malignant cell. In preclinical models, AMG 562-mediated 
T-cell activation involves the transient release of inflammatory cytokines and proliferation 
of T cells. The subsequent lysis of malignant cells by AMG 562-activated T cells closely 
resembles a natural cytotoxic T-cell reaction.  
Refer to the specific section of the Investigator’s Brochure (IB) for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s) of 
AMG 562. 
2.2.1 
Pharmacology 
The activity of AMG 562 requires the simultaneous binding to both target cells and 
T cells.  The pharmacological effect of AMG 562 is mediated by specific redirection of 
previously primed cytotoxic CD8+ or CD4+ T lymphocytes to kill CD19+ cells.  AMG 562 
is a potent molecule showing mean half-maximal lysis of human tumor cell lines by 
human effector cells in vitro over a range of 0.031 to 1.870 pM.  In addition, AMG 562 
induced a dose-dependent lysis of primary human B cells by autologous T cells with 
EC50 values for the individual dose-response curves varying between 0.060 and 
1.422 pM. 
As part of the T cell activation process, BiTE® antibody constructs, such as AMG 562, 
cause the formation of a cytolytic synapse between T cells and target cells.  This has 
been exemplified using an EpCAM-specific BiTE® antibody construct (Offner et al, 2006).  
The subsequent release of the pore-forming protein perforin and the apoptosis-inducing 
proteolytic enzyme granzyme B by T cells results in the induction of apoptosis in the 
target cells.  AMG 562-mediated T-cell activation not only induces the directed release of 
cytotoxic proteins to target cells, but also results in a transient production of cytokines 
such as tumor necrosis factor (TNF), interferon gamma (IFN-γ), interleukin-2 (IL-2), and 
IL-6 by T cells in vitro.  These in vitro studies also demonstrated that cytokine release by 
AMG 562-activated T cells is attenuated by corticosteroids, which is accompanied by a 
slight reduction in cytotoxic potency. 
The anti-tumor activity of AMG 562 was evaluated in a mantle cell lymphoma xenograft 
model in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice.  In 
the orthotopic model NOD/SCID mice were intravenously injected with Granta-519 
mantle cell lymphoma cells.  Administration of AMG 562 at doses of 0.01, 0.1 or 1 mg/kg 
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every 5 days for a total of 3 IV bolus administrations resulted in a significant prolonged 
survival even at a dose of 0.01 mg/kg AMG 562. 
2.2.2 
Pharmacokinetics 
Single-dose pharmacokinetics (PK) of AMG 562 was characterized after IV 
administration in cynomolgus monkeys. After a single IV bolus injection of 5 µg/kg, 
serum concentrations of AMG 562 declined in a biphasic manner with mean clearance 
(CL) values of 2.3 mL/hr/kg and a steady-state volume of distribution of 548 mL/kg. The 
mean half-life (t1/2) of AMG 562 was 210 hours.   
The repeat-dose PK of AMG 562 was also characterized in cynomolgus monkeys. 
AMG 562 was administered over 16 days of IV administration by 30-minute infusions. All 
animals received 5 µg/kg on day 1, and 25 µg/kg or 50 µg/kg on days 2, 5, 8, 11, and 14. 
The exposure of AMG 562 increased proportionally with increasing dose between the 
three dose groups. Concentrations of AMG 562 were measured in cerebral spinal fluid 
(CSF) at day 16 and were only detected in animals of the 50 µg/kg dose group. The 
mean concentration of AMG 562 in CSF was 354 pg/mL. 
Based on allometric scaling of cynomolgus monkey PK, the predicted human terminal  
t1/2 of AMG 562 is approximately 16 days. 
2.2.3 
Toxicology 
The nonclinical safety assessment of AMG 562 was conducted in the cynomolgus 
monkey by IV administration and consisted of a 33-day repeat-dose GLP toxicology 
study. The cynomolgus monkey was selected as the toxicology species based on target 
binding affinity and bioactivity data (Investigator’s Brochure).  Intravenous administration 
in the cynomolgus monkey was chosen based on the intended clinical route of 
administration. Details of the AMG 562 nonclinical toxicology study are provided in the 
Investigator’s Brochure. 
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In the GLP repeat-dose study AMG 562 was dosed either at 5 µg/kg on days 1, 5, 12, 
19, and 26 (flat-dosing regimen) or at 5 µg/kg on day 1, followed by 50 µg/kg on days 5, 
12, 19, and 26 (step-dosing regimen)..  AMG 562 exposure was dose-proportional with 
evidence of accumulation by the end of the study.   
Administration of AMG 562 was very well tolerated with no AMG 562-related mortalities, 
clinical observations or changes in body weight, food consumption, body temperature, 
respiratory rate, or neurologic, electrocardiographic, ophthalmologic, coagulation, or 
urinalysis parameters. 
The results of the 33-day monkey toxicology study were consistent with the expected 
pharmacology of a CD19-targeting BiTE® antibody construct.  Changes in response to 
the first IV dose of 5 µg/kg included decreased lymphocytes, with a complete depletion 
of circulating B cells that persisted until the end of the study.  Serum cytokines, including 
monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interferon gamma 
(IFN-γ)  increased on day 1 with a minimal increase in MCP-1, particularly at 50 µg/kg on 
day 5. In addition, c-reactive protein (CRP) transiently increased 24 hours after dosing.  
In addition, serum globulin levels were decreased in animals of both AMG 562 dose 
groups at the end of the study on day 33. 
At ≥ 5 µg/kg, microscopic changes in lymphoid tissue consisted of marked decreased 
cellularity of lymphoid follicles and germinal centers in both dose groups.  Minimal to 
mild neutrophilic infiltration of the large intestine observed at ≥ 5 µg/kg was considered 
likely related to reduced local immunity secondary to AMG 562 pharmacology. 
In conclusion, AMG 562-associated changes were generally consistent with the 
expected pharmacology of a CD19-targeting BiTE® antibody construct. None of the 
AMG 562-related changes in the GLP study were considered adverse.  The highest 
non-severely toxic dose (HNSTD) was 5 µg/kg in the flat-dosing regimen and 5/50 µg/kg 
in the step-dosing regimen, respectively. 
2.2.4 
Dosing Experience With Other BiTE® Antibody Constructs 
Bispecific antibody molecules, including bispecific T cell engager (BiTE®) antibody 
constructs, exert both unique and uniform mechanism of action independent of the 
respective targets, such that experiences with other BiTE® antibody constructs may be 
relevant for AMG 562. 
Most clinical experience exists with blinatumomab (BLINCYTO®, AMG 103), a BiTE® 
antibody construct with specificity for CD3 and CD19, approved in multiple regions for 
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the treatment of Philadelphia chromosome-negative relapsed or refractory B cell 
precursor acute lymphoblastic leukemia. In clinical trials conducted for blinatumomab, 
the most commonly reported adverse reactions (≥ 20%) were infections, pyrexia, 
headache, infusion-related reactions, aanemia, febrile neutropenia/neutropenia, and 
thrombocytopenia (Blincyto® United States Prescribing Information). Additional adverse 
reactions, listed in regional prescribing information, included cytokine release syndrome 
(CRS), neurologic toxicities, tumor lysis syndrome (TLS), neutropenia/febrile 
neutropenia, effects on ability to drive and use machines, elevated liver enzymes, 
leukoencephalopathy, and pancreatitis. Preparation/administration errors have also 
occurred with blinatumomab treatment and is listed as a warning in the regional 
prescribing information. 
2.3 
Benefit-risk Assessment 
At this time, there is no clinical experience with AMG 562 in humans. Based on 
biological possibility, nonclinical toxicity studies of AMG 562, and clinical safety 
experience with blinatumomab and other BiTE® antibody constructs in hematology, the 
important potential safety risks of AMG 562 include CRS, decreased immunoglobulins, 
neutropenia and neurologic events. Clinical signs and symptoms of CRS vital signs and 
other safety laboratories, will be monitored during the study and at the appropriate time 
points to ensure subjects’ safety. Refer to Section 6.2.1.4.2 for specific 
recommendations regarding the mitigation and management of potential risk of CRS. 
Section 6.2.1.4.2 also provides treatment procedures for concomitant therapy for 
infections, including recommendations for antimicrobial prophylaxis for neutropenia and 
opportunistic infections.   
Neutropenia and febrile neutropenia (including life-threatening cases), observed in 
patients receiving blinatumomab, were among the most common adverse reactions 
(≥ 20%) in blinatumomab clinical trials (Blincyto® Prescribing Information). Experiences 
with other CD19-targeted therapies for hematologic malignancies indicate the potential 
for neurotoxicity. AMG 562 is a BiTE® antibody construct with prolonged half-life 
targeting CD19, similar to blinatumomab, a BiTE® antibody construct also targeting 
CD19. A wide range of commonly-observed neurological symptoms have been 
associated with the use of blinatumomab, and among patients receiving blinatumomab, 
grade ≥ 3 neurologic events following initiation of blinatumomab administration included 
encephalopathy, convulsions, speech disorders, disturbances in consciousness, 
confusion and disorientation, and coordination and balance disorders 
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(Blincyto® Prescribing Information). Neurologic toxicities have also been reported among 
patients receiving axicabtagene ciloleucel and tisagenlecleucel, both CD19-directed 
genetically modified autologous T cell immunotherapies indicated for the treatment of 
adult patients with relapsed or refractory large B cell lymphoma, including diffuse large B 
cell lymphoma (DLBCL) (Yescarta Prescribing Information, 2017; KYMRIAH prescribing 
information, 2018). 
For a listing of important potential risks, see Table 3. Please refer to the AMG 562 
Investigator’s Brochure for further description of potential risks.  
Table 3.  Important Potential Risks of AMG 562 
Potential Risk 
Description 
Cytokine Release 
Syndrome (CRS) 
Non-antigen-specific toxicity occurring as a result of high-level 
immune activation (Lee et al., 2014) 
Signs and symptoms many include the following: 
• 
Constitutional – fever, rigors, fatigue, malaise 
• 
Neurologic – headache, mental status changes, dysphasia, 
tremors, dysmetria, gait abnormalities, seizure 
• 
Respiratory – dyspnea, tachypnea, hypoxemia 
• 
Cardiovascular – tachycardia, hypotension 
• 
Gastrointestinal – nausea, vomiting, transaminitis, 
hyperbilirubinemia 
• 
Hematology – bleeding, hypofibrinogenemia, elevated D-dimer 
• 
Skin – rash 
Decreased 
Immunoglobulins 
Decreases in circulating immunoglobulins secondary to depletion of 
B cells. 
Neutropenia 
Transient decreases in the number of circulating leukocytes, 
including neutrophils. 
Neurologic Events 
Neurological symptoms reported with the use of blinatumomab, a 
BiTE® antibody construct targeting CD19, included tremor, 
dizziness, encephalopathy, paresthesia, aphasia, and confusional 
state. 
2.3.1 
Key Benefits 
For the proposed study, some participants in the dose escalation phase may derive 
benefit from AMG 562 during dose escalation. Based on the pharmacological activities 
and similarity to blinatumomab, it is expected that with the selected RP2D utilized for the 
expansion cohort more participants may benefit from AMG 562.   
2.3.2 
Key Risks, Identified and Potential, and Mitigations 
Identified risks are untoward occurrences (eg, adverse events, laboratory, or 
radiographic abnormalities) that have been observed in subjects who have received 
AMG 562, and for which a causal relationship to AMG 562 has been established based 
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upon all available evidence. Potential risks are safety concerns based on mechanism of 
action, nonclinical data, or clinical data from similar compounds that have either not yet 
been observed in human subjects receiving AMG 562 or for which a causal association 
with AMG 562 has not yet been established. 
There are currently no important identified risks for AMG 562. Based on the toxicology 
evaluation in cynomolgus monkeys and the known effects of other bispecific antibody 
molecules, including BiTE® molecules, the following are the important potential risks and 
proposed clinical monitoring strategies for AMG 562 (Table 4). 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 29 of 158 
CONFIDENTIAL 
 
 
Table 4.  Summary of Important Potential Risks of AMG 562 
Safety Risks 
Nonclinical Data for AMG 
562 
Clinical Data for Other 
BiTE® Molecules 
Safety Monitoring 
Cytokine release 
syndrome 
AMG 562-related changes 
in clinical chemistry 
parameters in GLP 
toxicology study in 
cynomolgus monkeys 
consistent with an acute 
phase response, including 
increased cytokines 
(MCP-1, IL-6 and IFN-γ) 
on Day 1 (4 hours 
post-dose) 
CRS observed in clinical 
trials evaluating other 
BiTE® molecules, 
including blinatumomab 
[1] 
Monitoring of vital signs, 
hematology, 
comprehensive 
metabolic profiles and 
associated AEs 
Requirements for use of 
steroids, tocilizumab and 
monitoring of CRS 
Hospitalization and 
specific infusion 
interruption and stopping 
rules 
Decreased 
immunoglobulins 
Decreased globulins 
observed in GLP 
toxicology study in 
cynomolgus monkeys 
consistent with expected 
pharmacology (B cell 
depletion) of AMG 562 
Decreased 
immunoglobulins 
observed in clinical trial 
evaluating blinatumomab 
among patients with 
relapsed/refractory ALL 
[2] 
Monitoring of laboratory 
assessments, including 
serum immunoglobulins 
Guidance regarding 
infection prophylaxis and 
treatment per standard of 
care 
Neutropenia 
AMG 562-related changes 
in hematology parameters 
in GLP toxicology study in 
cynomolgus monkeys 
included decreased WBC 
counts, including 
neutrophils, with recovery 
by the end of the study 
Neutropenia observed in 
clinical trials evaluating 
other BiTE® molecules, 
including blinatumomab 
[1] 
Monitoring of vital signs, 
hematology parameters 
and associated AEs 
Subject eligibility criteria 
for hematology 
parameters 
Guidance regarding 
dose-holding and 
stopping rules pertaining 
to hematology 
parameters, including 
neutropenia, and 
infection prophylaxis and 
treatment of infections 
per standard of care 
Neurologic events 
AMG 562 detected in CSF 
without associated 
neurotoxicity in 
repeat-dose PK/PD study 
No AMG 562-neurological 
effects observed in GLP 
toxicology study in 
cynomolgus monkeys 
Neurologic toxicities 
reported in association 
with other CD19-targeting 
drugs [1, 3] 
Neurologic evaluations 
and monitoring of AEs 
Subject eligibility criteria 
for clinically relevant 
central nervous system 
pathology 
Guidance regarding dose 
reductions, infusion 
interruptions and 
stopping rules due to 
AEs 
AE = adverse event; ALL = acute lymphoblastic leukemia; BiTE = bispecific T cell engager;  
CRS = cytokine release syndrome;  
CSF = cerebrospinal fluid; GLP = Good Laboratory Practice; IFN = interferon; IL = interleukin;  
MCP = monocyte chemoattractant protein; WBC = white blood cell 
[1] Blincyto® (blinatumomab) [US Prescribing Information]. Thousand Oaks, CA: Amgen Inc; 2017. 
[2] Kantarjian H et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia.  
N Engl J Med. 2017;376:836-847. 
[3] Yescarta (axicabtagene ciloleucel) [US Prescribing Information]. Santa Monica, CA: Kite Pharma Inc; 
2017. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 30 of 158 
CONFIDENTIAL 
 
 
2.4 
Rationale 
BiTE® antibody constructs are designed to engage T cells to exert cytotoxic activity 
against cells targeted by surface expression of a selected antigen. BiTE® antibody 
constructs consists of 2 single chain variable fragment (scFv) binding domains, specific 
for a selected target antigen, eg an antigen expressed by malignant cells, and the 
epsilon subunit of the CD3 complex present on T cells.  The cross-linking of the target 
antigen and CD3 antigen mediated by the BiTE® triggers target cell specific cytotoxicity 
closely resembling standard cytotoxic T lymphocyte activation.   
AMG 562 is a BiTE® antibody construct that targets CD19 and is intended for the 
treatment of patients with B-cell malignancies. CD19 (Leu-12, CVID3, B4) is a 
transmembrane protein expressed on B-lineage cells and the majority of B-cell 
malignancies. It belongs to the immunoglobulin super family and forms a signaling 
complex with CD21, CD225 and CD81 (Bradbury, 1992; Katz and Herishanu, 2014). 
CD19 has been shown to contribute to B-cell receptor mediated signaling and defects in 
CD19 are associated with hypogammaglobulinemia with varying degrees of 
immunodeficiency (Conley, 2009).  
CD19 has been used as a target in several different approaches to treat B-cell 
malignancies. The success of these novel therapies supports CD19 as a suitable target.  
Relevant for AMG 562 is the clinical experience with the Bispecific T cell engager 
(BiTE®) antibody construct blinatumomab targeting CD19. Blinatumomab demonstrated 
clinical activity in acute lymhoblastic leukemia (ALL), administered as a continuous 
infusion,  was granted approval in December 2014, for the treatment of relapsed and 
refractory B-cell precursor ALL .   
Recently CD19 chimeric antigen receptor T (CAR-T)-cell therapies have been approved 
for the treatment of relapsed / refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) 
(tisagenlecleucel) and relapsed / refractory diffuse large B-cell lymphoma (r/r DLBCL) 
(axicabtagene ciloleucel). Blinatumomab also showed signs of clinical activity in a 
phase 2 study in r/r DLBCL (Viardot et al., 2016)  AMG 562, which also targets CD19 
and engages T cells via CD3 binding, is a novel BiTE molecule intended to treat patients 
with B-cell malignancies such as relapsed / refractory non-Hodgkin lymphoma.  
AMG 562 is a half-life extended (HLE) BiTE® antibody construct combining the binding 
specificities for CD19 and CD3 genetically fused to the N-terminus of a single chain IgG 
Fc (fragment crystallizable; scFc) region. The fusion to the Fc domain is a 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 31 of 158 
CONFIDENTIAL 
 
 
well-established strategy to prolong the half-life of protein therapeutics. This key 
modification, designed to maintain very efficient CD19-dependent target cell killing, 
should permit administration as intermittent short IV infusions.The PK of AMG 562 in 
humans was estimated using allometric scaling of PK parameters obtained from 
nonclinical studies in cynomolgus monkeys at doses ranging between 5–50 µg/kg.  In 
repeat-dose studies cynomolgus monkeys, evidence suggesting changes in CD19 
abundance or saturation of CD19 binding was observed.  As such, parallel linear and 
nonlinear clearance pathways were incorporated to characterize the AMG 562 PK from 
the pooled monkey data. 
2.4.1 
Dose Selection Rationale 
The planned doses of AMG 562 in this study are 0.1, 0.3, 
 
 
 
   
AMG 562 human PK profiles and exposures were predicted using a 2-compartment 
model with parallel linear and non-linear elimination that accounts for observed 
non-linearity in AMG 562 PK following repeat-dose administration in cynomolgus 
monkeys.  Human PK parameters were scaled using allometry from estimated PK 
parameters in cynomolgus monkey studies described in Section 2.2.2.  Based on 
predicted AMG 562 PK, a starting dose of 0.1 µg following a clinical IV infusion (1 hour) 
is predicted to acheive maximum serum concentrations approximating the MABEL (in 
vitro concentration required for half-maximal effect [EC50] of AMG 562-mediated 
autologous B cell depletion, 35.7 pg/mL).  The use of the EC50 as the MABEL and basis 
for the FIH starting dose is supported by the previous and safe implementation of this 
strategy to identify the maximum recommended starting doses of previous bi-specific 
CD3-targeting molecules in clinical development while minimizing the number of dose 
escalations necessary to establish a maximum tolerated dose (Saber et al., 2017).   
Additionally, relative to human exposure predictions at the starting dose, mean AUC168hr 
and Cmax exposures achieved at the highest non-severely toxic dose (HNSTD) of the 
flat-dose regimen of 5 µg/kg in the 33-day toxicology study in cynomolgus monkeys were 
approximately 1800-fold and 320-fold greater than human AUC168hr and Cmax exposures 
predicted at the 0.1 µg starting dose, respectively, after correction for a 17-fold potency 
difference in human and cynomolgus monkey effector cells.  Of note, relative to the 
step-dose regimen of 5 µg/kg followed by a step up to 50 µg/kg (5/50 µg/kg) also 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 32 of 158 
CONFIDENTIAL 
 
 
evaluated in the 33-day toxicology study, AUC168hr and Cmax exposures were 
approximately 20000-fold and 3400-fold greater than human exposure predictions, after 
a 17-fold potency correction. 
Subsequent planned escalations in AMG 562 dose up to 
 µg are shown in Table 5.  
At the highest planned clinical dose of 
 µg, the ratio of mean AUC168hr and Cmax 
exposures achieved at the 5 µg/kg HNSTD in the 33-day toxicology study in cynomolgus 
monkeys and predicted human AUC168hr and Cmax exposures were approximately  
 respectively, after a 17-fold potency difference in human and cynomolgus 
monkey effector cells (ratio of mean AUC168hr and Cmax exposures achieved at the 
5/50 µg/kg HNSTD in the 33-day toxicology study were approximately 
  
, respectively, after potency correction). 
Table 5.  First-in-human Doses and Predicted Exposure Margins (Potency 
Adjusted) From the Pivotal Repeat-dose Intravenous Toxicity Study of AMG 562 in 
the Cynomolgus Monkey 
 
Predicted Human 
Exposuresa 
Potency-corrected 
Predicted Exposure 
Margins 
(HNSTD = 5 µg/kg)b 
Potency-corrected 
Predicted Exposure 
Margins 
(HNSTD = 5/50 µg/kg)b 
AMG 562 
IV Dose 
Q1W (µg) 
AUC168h 
(h·ng/mL) 
Cmax 
(ng/mL) 
AUC168hc 
(h·ng/mL) 
Cmaxc 
(ng/mL) 
AUC168hc 
(h·ng/mL) 
Cmaxc 
(ng/mL) 
0.1 
0.41 
0.03 
1800 
320 
20000 
3400 
0.3 
1.2 
0.1 
600 
110 
6500 
1100 
AUC168h = area under the concentration-time curve from 0 to 168 hours; Cmax = maximum observed 
concentration in a dosing interval; GLP = good laboratory practices; HNSTD = highest non-severely toxic 
dose; IV = intravenous; Q1W = once a week.  
a Predicted human exposures at steady state (based on free serum AMG 562 concentrations) following 
once-weekly AMG 562 dosing for 4 weeks (Investigator’s Brochure). 
b Predicted exposure margins were calculated as follows:  (AUC168h,cyno,day 26 / AUC168h,human,SS) ÷ 17; 
(Cmax,cyno,day 26 / Cmax,human,SS)  ÷ 17; where 17 is a correction for a 17-fold difference in AMG 562 potency 
between human and cynomolgus monkey effector cells in an autologous B cell depletion assay 
(Investigator’s Brochure). 
c The average AUClast and Cmax observed in the GLP toxicology study on day 26 at the HNSTD (5 µg/kg) 
were 12.6 hr·µg/mL and 0.182 µg/mL. At the step-dosing HNSTD of 5/50 µg/kg the average AUClast and 
Cmax were 137 hr·µg/mL and 1.88 µg/mL (Investigator’s Brochure). 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 33 of 158 
CONFIDENTIAL 
 
 
Minimally efficacious exposures of AMG 562 were estimated based on the predicted 
human AMG 562 PK, the evaluation of nonclinical assessments of AMG 562 activity and 
clinical concentrations of blinatumomab, a CD19-targeting bispecific T cell engager, that 
were associated with response in NHL patients.  Based on the in vitro assessment of 
individual dose-response curves of autologous B cell depletion from 16 different donors, 
a mean EC90 of 125 pg/mL was calculated.  An AMG 562 dose of 
 µg is predicted to 
provide trough coverage of the EC90 following once weekly administration and is 
expected to achieve pharmacological response. Clinical experience from blinatumomab 
in NHL patients was also used to inform efficacy predictions of AMG 562.  In a phase 2 
study in NHL patients, exposure to blinatumomab at a dose of 112 µg/day for at least 
one week appeared to be required for efficacy (overall response rate [43%]; complete 
response [19%]; Viardot et al., 2016).  Correcting for the differences in CD19 affinities 
between AMG 562 and blinatumomab, an AMG 562 dose of 
 µg is expected to 
provide trough coverage of the equivalent blinatumomab exposure associated with 
complete response.   
Collectively, minimally efficacious exposures of AMG 562 are predicted at doses ranging 
between 
 µg, following once weekly administration.  
2.5 
Clinical Hypotheses 
The following hypotheses will be tested with this clinical protocol. 
• 
At least one dose level of AMG 562 administered by IV infusion is expected to 
achieve acceptable safety and tolerability in subjects with relapsed and/or 
refractory DLBCL, MCL, or FL. 
• 
A favorable PK profile will be achieved with AMG 562 administered by IV 
infusion. 
• 
Objective responses will be observed at a dose level that achieves acceptable 
safety and tolerability.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, Phase 1, first-in-human (FIH), non-randomized, open-label study in 
adult subjects with relapsed / refractory DLBCL, MCL, or FL. AMG 562 will be 
administered weekly as short term IV infusions 
 
The study will consist of up to a 21-day screening period, a treatment period, a safety 
follow-up (SFU) visit conducted 30 (+ 7) days after the last dose of AMG 562, and a 
long-term follow-up (LTFU) period that will begin after the SFU visit is completed. 
Subjects will be followed for response evaluation at week 5, week 15, week 25, and at 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 34 of 158 
CONFIDENTIAL 
 
 
end of treatment if end of treatment is at week 35 or beyond (± 3 days).  Subjects who 
stopped response evaluations will be followed every 3 months (± 2 weeks) for survival 
follow-up. The total duration of the LTFU will be up to 2 years from the first dose of 
AMG 562.  
Treatment Holiday:  
Starting with cycle 4, a longer treatment holiday between cycles may be implemented on 
a per subject basis for individual treatment cycles after approval by the Amgen Medical 
Monitor (see Section 6.2.1.1 for details).  
For subjects identified as having confirmed CR/CMR, investigators may choose to 
implement treatment-free intervals of 2-4 weeks (“Consolidation Phase”).  For subjects 
remaining in CR/CMR at 12 months, treatment-free intervals may be increased to 8 
weeks between cycles (“Maintenance Phase”).  Treatment for these subjects can be be 
continued until progression or at the discretion of the investigator. Treatment can be 
discontinued for patients remaining in CR/CMR at the discretion of the investigator. 
This phase 1 study consists of two parts: 
• 
Part 1 includes dose exploration to evaluate the safety and tolerability of 
AMG 562 as monotherapy in subjects with relapsed/refractory DLBCL, MCL, or 
FL. 
• 
Part 2 is an evaluation of AMG 562 in a dose expansion group to gain further 
efficacy and safety experience with AMG 562 as monotherapy in subjects with 
DLBCL. Part 2 will start with a dose that is identified by the DLRT following 
estimation of the MTD/RP2D in Part 1. 
Part 1: Dose Exploration 
Up to approximately 30 subjects will be enrolled to the dose exploration cohorts to 
estimate the MTD, safety, tolerability, PK, and PD of different doses of AMG 562 in 
subjects with relapsed/refractory DLBCL, MCL or FL using a Bayesian logistic 
regression model (BLRM; Neuenschwander et al, 2008).  AMG 562 will be administered 
as IV infusions at weekly intervals. Based on emerging trial data, step-dosing may be 
recommended by the DLRT if required to mitigate initial AEs (step-up dosing). Step-up 
dosing includes a lower dose for the 1st infusion on Day 1 of the treatment followed by 
escalation to the “target dose” on all subsequent dosing days.  The highest dose for the 
1st infusion on Day 1 is defined as initial dose.  The highest dose following step-up 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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CONFIDENTIAL 
 
 
dosing is defined as the target dose. Additional dose steps may be administered 
subsequently at daily intervals. After administration of the target dose, treatment will 
continue with weekly administrations of AMG 562 at the target dose. Planned dose 
levels (dose per infusion) for the dose exploration cohorts are as follows: 0.1 µg, 0.3 µg, 
. 
If the preliminary MTD is not reached within the pre-planned dose range, doses 
> 1000 µg may be investigated by submission of a protocol amendment to the 
competent authorities for review. If no DLTs are observed, the dose escalation will 
continue to the next planned dose level as per Part 1 Study Design and Schema in the 
study protocol. When enrollment is completed for each cohort (single and multiple 
subject), the DLRT will convene at the end of the DLT evaluation period and review all 
available safety, PK and pharmacodynamic data. The DLRT will provide the 
recommendation to proceed with dosing of patients in the next cohort.  
Dose escalation/de-escalation recommendations will be guided by the BLRM model of 
dose toxicity and evaluation of all available safety data, laboratory, and PK information.  
If two or more subjects experience a DLT at a dose level, enrollment to the cohort will be 
terminated and dose de-escalation may occur. If late onset adverse events occur during 
a cohort, the DLRT may adaptively re-consider the doses evaluated within a cohort for 
subsequent dosing and/or possibly trigger a de-escalation or withholding of additional 
doses in subsequent cohorts. Based on the BLRM model and after reviewing all 
available safety and tolerability data, the DLRT will make dose escalation/de-escalation 
recommendations. Subjects may continue to receive AMG 562 until evidence of disease 
progression, unacceptable toxicity or withdrawal of consent. 
In addition to the dose, the DLRT may recommend changing the dosing schedule (eg, 
dosing interval) for subsequent cohorts. The DLRT may also recommend to prolong the 
DLT window or to include step-up dosing for future cohorts based on observed 
tolerability and other clinical signs, pharmacological and PD results. 
Dose exploration will be conducted in 2 stages using the BLRM design to guide dose 
escalation. In the initial cohorts, single subjects will be enrolled at dose levels anticipated 
to be lower than the dose levels at which adverse events related to AMG 562 may be 
observed. Once higher dose levels are open for enrollment or any of the safety criteria 
listed below are observed, multiple subject cohorts of 3 to 4 subjects per cohort will open 
for enrollment. Enrollment of subjects at each dose level in the multiple subject cohorts 
will be staggered by at least 3 days. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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The switch from single to multiple subject cohorts will be triggered if at least one subject 
experiences any of the three safety events below (whichever occurs earlier):  
1. Non hematologic adverse event grade ≥ 2   
2. Hematologic adverse event grade ≥ 3 including anemia, neutropenia, leukopenia, 
thrombocytopenia, and lymphopenia 
3. DLT 
Once a subject experiences a DLT, the dose for the subsequent cohorts will be decided 
by the DLRT after evaluating all available safety, laboratory, and PK data as well as the 
recommendation from the BLRM. The dose escalation for subsequent cohorts will be 
limited to 2-fold increases or lower after a subject experiences a DLT or ≥ 2 patients 
experience a grade ≥ 2 adverse event. 
The DLT evaluation period will be 28 days for all cohorts. The DLT evaluation period 
may also be extended to assess events starting within the DLT window in case the DLT 
definition is time dependent. Any adverse event occurring outside the DLT window that 
meets the DLT definition and is determined by the investigator to be possibly related to 
AMG 562, and 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 event and all available safety data. A DLRM will 
be conducted after the subjects in each dose cohort have had the opportunity to 
complete the DLT evaluation period. The DLRT may also convene at any time to review 
safety data if deemed necessary.  
Subjects who complete the DLT period may proceed to a higher dose level for the next 
dosing (intra-subject dose escalation) once this higher dose level has been deemed safe 
by the DLRT and after consultation with the Amgen Medical Monitor if: 
• 
no DLT has been reported for this subject during or after completion of the DLT 
period 
• 
the subject has not experienced any ≥ grade 2 adverse events (deemed treatment 
related by the investigator) during treatment 
DLTs experienced by subjects after completing the DLT period will be considered in the 
BLRM design to account for any late onset toxicity.  
Premedication for Cycle 1: an 8 mg dose of IV or PO dexamethasone approximately  
1 hour prior to the start of the AMG 562 infusion is mandatory: 
o Prior to each infusion in Cycle 1 8 mg dexamethasone IV or PO as premedication 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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Premedication for Cycle 2 and beyond: 
o Pre medication with 8 mg IV or PO dexamethasone for each subsequent cycle 
will be required for any subject who experienced grade ≥ 2 neurotoxicity or grade 
≥ 2 CRS in the preceding cycle 
If CRS and neurotoxicity of grade 2 or higher did not occur in the prior cycle(s), 
premedication with dexamethasone can be reduced to 4 mg. If subjects tolerate AMG 
562 well with reduced dose dexamethasone, premedication with dexamethasone can be 
discontinued for the next cycle in consultation with Amgen Medial Monitor 
No additional premedication is permitted on the trial. If the evaluation of available safety 
and laboratory data suggests that adjustment to the dexamethasone schedule are 
required or additional premedication is necessary, the DLRT can recommend to adjust 
the current schedule and/or add additional premedication, eg, antihistamines and  
H2 blockers to the premedication regimen. In this case all future cohorts will receive this 
additional premedication. All subjects will be pre-treated unless a contraindication for this 
premedication exists.  
Once the dose exploration has provided a RP2D, tocilizumab may be evaluated as an 
alternative prophylaxis to prevent/reduce severity of CRS. A cohort of three patients may 
be treated with AMG 562 at the RP2D dose level and a single dose of 400 mg IV 
tocilizumab will be administered approximately 15 minutes prior to the day 1 dose of 
AMG 562 replacing pretreatment with dexamethasone. If no DLTs are observed three 
additional patients will be included in this cohort. The use of tocilizumab may be further 
explored based on observed tolerability and other clinical and pharmacological data. 
Step-up Dosing (Estimation of initial dose and target dose) 
Step-up dosing will be explored to prevent first dose effects that have been observed 
with other BiTE antibodies namely CRS, neurologic events and TLS. It will be introduced 
when two or more DLTs consistent with CRS, neurologic events and TLS are observed 
in one cohort. The DLRT may recommend introducing step-up dosing  earlier when 2 or 
more grade ≥1 CRS events (as referenced by Lee et al, 2014) or 2 or more grade  
≥1 neurologic events are observed in one cohort. For single patient cohorts the DLRT 
may introduce step-up dosing earlier when 2 or more grade ≥ 1 CRS or neurologic 
events are observed in 2 consecutive cohorts. The decision for CRS related events 
should be supported by confirmation of the clinical diagnosis with evaluation of all 
available clinical and laboratory parameters including observation of elevated cytokine 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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CONFIDENTIAL 
 
 
levels and / or elevated levels of other markers of inflammatory reactions consistent with 
CRS and excluding other causes for the observed symptoms.  
With step-up dosing, the dose of the first infusion on treatment day 1 (initial dose) will be 
lower than the dose of the infusion on day 2 (target dose). The target dose will be 
administered subsequently at weekly intervals starting on Day 8. Additional dose steps 
may be implemented based on tolerability as observed in the clinical and 
pharmacological data. If additional dose steps are applied, the initial dose on day 1 will 
be followed by 1, 2, or 3 stepwise increasing intermediate doses at one-day intervals. 
Following the last intermediate dose, with again a one-day interval, the highest dose 
(target dose) is administered. Administration of the target dose then continues at weekly 
intervals starting on Day 8 (see Figure 1 with an example of dosing without step-up 
dosing; Figure 2 and Figure 3 with possible variants of step-up dosing).  
To establish doses for the step-up dosing, dose selection will be performed as follows: 
Step-up dosing may be introduced after observation of adverse events in the cohort 
before introduction of step-up dosing (hereafter referred to as previous cohort). Two 
scenarios are differentiated depending on the frequency and severity of adverse events: 
scenario A with one or no DLTs in the previous cohort and scenario B with two or more 
DLTs in the previous cohort. Two sub-scenarios are differentiated depending on the 
dose escalation that determined the dose for the previous cohort: scenarios A1 and B1 
with two-fold dose escalation and scenarios A2 and B2 with three-fold dose escalation. 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Scenario A1:  
• 
one or no DLTs in the previous cohort 
• 
two-fold dose escalation for previous cohort 
• 
dose for step-up dosing on days 1 and 2 will be half the dose of the previous cohort 
 
 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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CONFIDENTIAL 
 
 
Scenario A2:  
• 
one or no DLTs in the previous cohort 
• 
three-fold dose escalation for previous cohort 
• 
dose for step-up dosing on days 1 and 2 will be a third of the dose of the previous cohort 
 
 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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CONFIDENTIAL 
 
 
Scenario B1:  
• 
two or more DLTs in the previous cohort 
• 
two-fold dose escalation for previous cohort 
• 
dose for step-up dosing on days 1 and 2 will be 3/8th of the dose of the previous cohort 
 
 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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CONFIDENTIAL 
 
 
Scenario B2:  
• 
two or more DLTs in the previous cohort 
• 
three-fold dose escalation for previous cohort 
• 
dose for step-up dosing on days 1 and 2 will be a third of the dose of the previous cohort 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
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CONFIDENTIAL 
 
 
In subsequent cohorts the dose to be administered at the step on day 2 will be escalated 
by two-fold dose increases until a DLT is observed. If a DLT is observed, the target dose 
for the step on day 2 for the following cohorts will be estimated using the BLRM, until an 
MTD (MTD for target dose) is reached.  
In case a second dose step is implemented on day 3, the  intermediate dose on day 2 
will be at or below the MTD for day 2. The MTD for the target dose of the dose step on 
day 3 will be established in the same manner as described above for the MTD for day 2. 
In the first cohort to establish the dose on day 3, subjects will receive the established 
initial dose on day 1. The intermediate dose on day 2 and the dose for day 3 will be 
determined according to the scenarios A1 to B2 described above but based on the dose 
and dose increment of day 2 of the previous cohort. In subsequent cohorts the dose to 
be administered at the step on day 3 will be escalated by two-fold dose increases until a 
DLT is observed. If a DLT is observed, the target dose for the step on day 3 for the 
following cohorts will be estimated using the BLRM, until an MTD (MTD for target dose) 
is reached.  
Potential further step doses will be established in a similar manner.  
The DLRT may recommend prolonging the dosing intervals for the step-up dosing for 
future cohorts to 2, 3, or 4 days. Other changes of the step-up dosing intervals will be 
introduced by an amendment to the protocol. 
Dose exploration will continue until any of the following events: 
• 
The highest planned dose level is determined to be safe and tolerable (minimum 
of 6 treated subjects) 
• 
An MTD is identified where BLRM repeats the recommendation of a dose level 
(minimum of 6 treated subjects) 
• 
If fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability. 
Part 2: Dose Expansion 
Upon completion of the dose exploration part of the study, up to approximately 
55 additional subjects will be enrolled in the dose expansion part to gain further clinical 
experience, safety and efficacy data for AMG 562 in subjects with relapsed / refractory 
DLBCL. The dose to be evaluated will be at or below the MTD estimated in the dose 
exploration cohorts. Additional expansion cohorts may be added to evaluate alternative 
dose levels, or biologic subsets, or other disease entities included in the dose 
exploration. A final estimate of the MTD and RP2D will be evaluated and confirmed 
Approved 
 
 


Product:  AMG 562 
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utilizing all DLT-evaluable subjects from the dose exploration and the dose expansion 
cohorts. The DLRT will be convened in the dose expansion part of the study to review 
efficacy data after the first 15 subjects are enrolled and have had the opportunity to 
receive at least five weeks of treatment (with recruitment ongoing). Additionally, the 
DLRT will review safety data in the expansion part, after the first 10 subjects were 
enrolled and had the opportunity to receive at least five weeks of treatment (with 
recruitment ongoing). The guidelines for futility due to insufficient efficacy are in Table 2. 
Ad hoc meetings may be convened at any time by the DLRT to review the safety data if 
deemed necessary. The overall study design is described by the Part 1 and Part 2 Study 
Design and 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 15-20 sites in Belgium, Canada, Germany, 
Japan, South Korea and the United States. Additional sites and countries may be added.  
Sites that do not enroll subjects into an open cohort within 6 months of site initiation 
during dose exploration, or within 3 months of site initiation during the expansion part of 
the study, respectively, may be closed or replaced.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Overall, up to approximately 85 subjects may be enrolled in the study.  Up to 30 subjects 
will be enrolled in the dose exploration Part 1.  Up to 55 subjects will be enrolled into the 
dose expansion Part 2. 
Once targeted enrollment for the expansion cohort is complete, investigators will be 
informed in writing. Once this information is sent, potential subjects should not start 
consenting/screening process   For ethical and operational reasons subjects who 
already are in the screening phase at the time of enrollment completion for a specific 
group will still be allowed to be treated. Therefore, an over running of subject recruitment 
might be possible. Based on emerging data, additional subjects may be enrolled. 
The rationale for the number of subjects is detailed in Section 10.2. 
3.4 
Replacement of Subjects 
Ineligible subjects (ie, subjects who were exposed to investigational product but post hoc 
were found to be ineligible) may be replaced. 
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Subjects enrolled in Part 1 may be replaced if they are not evaluable for DLT. Subjects 
will NOT be considered DLT evaluable if: 
• 
the subject did not receive study treatment 
• 
the subject missed 2 consecutive doses out of the 4 planned doses for reason(s) 
other than DLT during the DLT evaluation period 
• 
the subject ended the study treatment before completion of DLT evaluation 
period for a reason other than experiencing a DLT.  
Exception to this rule is: 
Discontinuation of treatment due to early progression after receiving at least 3 doses of 
investigational product and safety follow-up data for entire DLT evaluation period are 
available. 
All available safety data for subjects who are not DLT evaluable will still be evaluated 
and considered in DLRT recommendations. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 2 years. 
This includes a screening period lasting up to 21 days, a treatment period lasting for a 
median of approximately 8 months, a Safety follow-up visit 30 (+7) days after the last 
dose of AMG 562, and a follow-up period lasting up to 2 years from the first dose of 
AMG 562. 
The actual duration for individual subjects will vary depending upon tolerability of 
AMG 562, evidence of clinical progression, and willingness to participate in the study. 
End of study (EOS) for an individual subject is defined as the date of the final study visit   
3.5.2 
End of Study 
Primary Completion: The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoints, for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary analysis for the dose exploration part will occur when target enrollment is 
complete and each subject either completes 3 months on study or withdraws from the 
study. The primary analysis for the dose expansion part will occur when targeted 
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enrollment is complete and each subject has the opportunity to receive at least 3 months 
of treatment at target dose. If the study concludes prior to the primary completion date 
originally planned in the protocol (ie, early termination of the study), then the primary 
completion will be the date when the last subject is assessed or receives an intervention 
for evaluation in the study (ie, last subject last visit). 
End of Study:  The end of study (EOS) date is defined as the date when the last subject 
is assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, LTFU), 
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 activities/procedure appropriate written informed 
consent must be obtained (see Section 11.1). 
4.1 
Inclusion Criteria 
A subject that has provided written informed consent may be eligible for inclusion in this 
study only if the following criteria are met. 
101. 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures..  
102. 
Age ≥ 18 at the time of informed consent 
103. 
Biopsy proven B-NHL including:  
• 
DLBCL, which also includes DLBCL  that represents transformation of 
indolent NHL (including follicular, marginal zone, and lymphoplasmacytic 
lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma) 
and DLBCL with alterations of MYC and BCL2 and/or BCL6 also described 
as double-hit and triple-hit lymphomas.  
• 
FL 
• 
MCL 
Presentations of these histologies with substantial occurrence of malignant cells 
into the bloodstream (lymphocyte count  ≥ 7 x 10^9/L) including all leukemic 
presentations  are excluded.  
The following histologies are not eligible: 
Lymphoblastic lymphoma 
Burkitt lymphoma 
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Any histologies not specifically mentioned must be discussed with the Medical 
Monitor 
• Subjects with transformation of indolent lymphoma must have received 
therapy after a diagnosis of transformation that is appropriate for 
aggressive histology as described in 105.   
• Subjects who received prior CD19-targeting treatment are allowed (CAR-
T cell therapy is excluded) . A biopsy following CD19-targeting 
treatment is required unless no lesions are accessible or the risk of the 
biopsy is deemed too high by the investigator 
104. 
For Part 2 (Expansion in patients with DLBCL): only biopsy proven DLBCL 
(biopsy proven at least at primary diagnosis), including DLBCL that represents 
transformation of indolent NHL (including follicular, marginal zone, and 
lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or 
Hodgkin Lymphoma) are eligible. Other histologies are not eligible.  
• Presentations of these histologies with substantial occurrence of 
malignant cells into the bloodstream (lymphocyte count  ≥ 7 x 10^9/L) 
including all leukemic presentations  are excluded.  
• Subjects with transformation of indolent lymphoma must have received 
therapy after a diagnosis of transformation that is appropriate for 
aggressive histology as described in 105.. 
• Subjects who received prior CD19-targeting treatment are allowed  
(CAR-T cell therapy is excluded) A biopsy following CD19-targeting 
treatment is required unless no lesions are accessible or the risk of the 
biopsy is deemed too high by the investigator 
105. 
For DLBCL: Refractory (no prior CR/CMR) to first or later line of treatment or 
relapsed (prior CR/CMR) after two or more prior treatments, with at least one 
treatment consisting of standard multiagent chemotherapy containing an 
anthracycline AND an approved anti-CD20 agent. Examples of appropriate 
therapy include but are not limited to R-CHOP (14 or 21), R-CHOEP, and 
DA-R-EOCH.  
For FL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed 
(prior CR/CMR) after three or more prior treatments, with at least one treatment 
consisting of a standard chemotherapy containing an approved anti-CD20 agent. 
Examples of appropriate therapy include but are not limited to R-CHOP, R-CVP, 
and BR. 
For MCL: Refractory (no prior CR/CMR) to first or later line of treatment or 
relapsed (prior CR/CMR) after three or more prior treatments, with at least one 
treatment consisting of a standard chemotherapy containing an approved 
anti-CD20 agent. Examples of appropriate therapy include but are not limited to 
R-CHOP, BR and hyper-CVAD alternating with R-MTX/Ara-C. 
For subjects with refractory B-NHL and who have received radiotherapy, PET 
positivity should be demonstrated no less than 6 weeks after the last dose of 
radiotherapy 
106. 
Minimum life expectancy of 12 weeks 
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107. 
Radiographically measurable disease with a clearly demarcated nodal lesion at 
least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm 
in its largest dimension. In the dose exploration phase in case disease is not 
radiographically measurable PET positivity (ie, Deauville ≥4) instead is 
acceptable.  
108. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
109. 
Laboratory parameters (completed within 14 days prior to enrollment): 
Hematology: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L 
• 
Platelets ≥ 75 x 10^9/L 
Chemistry: 
• 
Creatinine clearance ≥ 60 mL/min (calculated using Cockcroft Gault 
equation) 
• 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 
< 3X upper limit of normal (ULN) 
• 
Total bilirubin (TBL) < 2x ULN (unless Gilbert’s disease or if liver involvement 
with lymphoma) 
4.2 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
201. 
Treatment within 30 days prior to enrollment with another investigational device 
or drug (interventional clinical study / studies). Other investigational procedures 
while participating in this study are excluded (observational studies are 
permitted) 
202. 
Prior anti-cancer therapy as specified below: 
• 
At least 6 weeks must have elapsed since any prior systemic 
inhibitory/stimulatory immune checkpoint molecule therapy (eg, ipilimumab, 
nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, 
etc) before the first dose of AMG 562  
• 
Other targeted anti-cancer therapy (chemotherapy,  molecular targeted 
therapy, steroids) within 14 days or 5 half lives (which ever is longer) prior to 
first dose of AMG 562. Patients requiring continued treatment due to 
aggressive disease may only be included if there is agreement by both the 
investigator and the Amgen Medical Monitor. 
• 
Radiation therapy completed within 28 days prior to first dose of AMG 562  
• 
Autologous HSCT within six weeks prior to start of AMG 562 treatment  
• 
At least 4 weeks must have elapsed since any prior treatment with antibody 
therapy (exception immune checkpoint inhibitors) before the first dose of 
AMG 562  
203. 
Prior CD19-directed CAR-T cell therapies  
204. 
Prior allogeneic HSCT 
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205. 
For Part 2 (Expansion in patients with DLBCL): fluorodeoxyglucose non-avid 
patients 
206. 
Baseline electrocardiogram (ECG) QTc > 470 msec 
207. 
Autoimmune disorders requiring chronic systemic steroid therapy or any other 
form of immunosuppressive therapy. Patient may be included if the treatment is 
discontinued more than 3 months prior to the first dose of AMG 562 at a low 
likelihood of relapse AND if there is agreement by both the investigator and the 
Amgen Medical Monitor. 
208. 
Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved 
to CTCAE version 4.0 grade 1, or to levels dictated in the eligibility criteria with 
the exception of alopecia or toxicities from prior anti-tumor therapy that are 
considered irreversible (defined as having been present and stable for > 28 days) 
which may be allowed if they are not otherwise described in the exclusion criteria 
AND there is agreement to allow by both the investigator and the Amgen Medical 
Monitor  
209. 
Presence of clinically relevant central nervous system (CNS) pathology such as 
epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s 
disease, cerebellar disease, organic brain syndrome, or psychosis 
210. 
Evidence of CNS involvement by NHL 
211. 
Known infection with human immunodeficiency virus (HIV) 
212. 
Exclusion of hepatitis infection based on the following results and/or criteria: 
• 
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: Assay for 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): Assay for hepatitis C virus RNA 
by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic 
hepatitis C 
213. 
History of malignancy other than B-NHL within the past 3 years with the 
exception of: 
• 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years before enrollment and felt to be at low risk for 
recurrence by the treating physician 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
• 
Adequately treated cervical carcinoma in situ without evidence of disease 
• 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease 
• 
Prostatic intraepithelial neoplasia without evidence of prostate cancer 
• 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ 
214. 
Major surgery within 28 days of first dose AMG 562 
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215. 
History of arterial thrombosis (eg, stroke or transient ischemic attack) within 
12 months of first dose of AMG 562 
216. 
Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials 
for management within 7 days of first dose AMG 562 
NOTE: Simple UTI and uncomplicated bacterial pharyngitis are permitted after 
consultation with sponsor  and if responding to active treatment  
217. 
Subject has known sensitivity to immunoglobulins or any of the products or 
components to be administered during dosing. 
218. 
Males and females of reproductive potential who are unwilling to practice highly 
effective method(s) of birth control while on study through 110 days (females) 
and 170 days (males) after receiving the last dose of study drug. Highly effective 
methods of birth control include sexual abstinence (males, females); vasectomy; 
bilateral tubal ligation/occlusion; or a condom with spermicide (males) in 
combination with hormonal birth control or intrauterine device (IUD) (females) 
219. 
Females who are lactating/breastfeeding or who plan to breastfeed while on 
study through 110 days after receiving the last dose of study drug 
220. 
Females with a positive pregnancy test 
221. 
Females planning to become pregnant while on study through 110 days after 
receiving the last dose of study drug 
222. 
Males who are unwilling to abstain from sperm donation while on study through 
170 days after receiving the last dose of study drug 
223. 
Subjects likely to not be available to complete all protocol- required study visits or 
precedures including BM aspirates/biopsies, and/or to comply with all required 
study procedures to the best of the subject and investigator’s knowledge 
224. 
History or evidence of any other clinically-relevant concurrent disorder, condition 
or disease (eg, symptomatic congestive heart failure, unstable angia pectoris, 
cardiac arrythmia requiring therapy at time of screening) with the exception of 
those outlined above that, in the opinion of the investigator or Amgen Medical 
Monitor, if consulted, would not 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 activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the IRB/IEC and Amgen approved informed 
consent form before commencement of study-specific activities/procedures.   
A subject is considered enrolled when the Investigator decides that the subject has met 
all eligibility criteria. The Investigator is to document the enrollment decision and date, in 
the subject’s medical record and in/on the enrollment case report form (CRF). 
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Each subject who enters into the screening period for the study (defined when the 
subject signs the informed consent form) 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 subject identification number will consist of 11 digits. The first 3 digits will 
represent the last 3 digits of the protocol number (ie, 445). 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 
are screened (eg, 001, 002, or 003). For example, the first subject to enter screening at 
site 66001 will receive the number 44566001001, and the second subject at the same 
site will receive the number 44566001002.   
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.   
Subjects who do not meet all eligibility criteria may be rescreened up to 2 times at the 
discretion of the Investigator.  If a subject is being rescreened, he or she may need to 
reconsent to the study to ensure that the IRB/IEC approved main informed consent form 
is signed within 21 days of enrollment. Subjects who are determined not eligible after 
rescreen must be screen-failed and the reason for the screen-failure provided.  Subjects 
may only be enrolled once into this study. 
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 the sponsor or designee.  The Amgen 
representative will acknowledge receipt and return confirmation of dose cohort (dose 
exploration part) or group (dose expansion part), respectively, to the site.   
5.1 
Treatment Assignment 
An Amgen representative will notify the site(s) in writing when a dose cohort (dose 
exploration part) or the dose expansion part, respectively, are open to screen and enroll 
new subjects.  The treatment assignment date is to be documented in the subject’s 
medical record.  
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6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products, and/or Medical Devices 
The Amgen Investigational Product (IP) used in this study is AMG 562. 
Other protocol-mandated medication (eg, dexamethasone used for pre-dose treatment 
or for treatment of adverse events) are commercially available and are not provided or 
reimbursed by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-specified therapies. 
6.2 
Investigational Product 
The investigational product will be administered at the research facility by a qualified 
staff member.  
A physician or nurse trained in emergency medicine must be available at the time of 
administration of investigational product for immediate intervention in case of 
complications. 
6.2.1 
Amgen Investigational Product AMG 562 
AMG 562 will be manufactured and packaged by Amgen and distributed using Amgen 
clinical study drug distribution procedures. AMG 562 will be supplied as lyophilized drug 
product in glass vials.   
6.2.1.1 
Dosage, Administration, and Schedule 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 562. AMG 562 will be delivered using infusion pumps (for the 
higher doses) and syringe pumps (for the lower doses)respectively, which are approved 
for use by the appropriate regulatory authority for the country in which the subject is 
undergoing treatment.   
AMG 562 solution for infusion will be prepared in bags for IV infusion and delivered 
intraveneously. AMG 562 may be administered through a peripheral venous line or a 
central venous access if available.  The drug should not be administered as a bolus.  
Details on the dose calculation, preparation, and administration are provided in the IPIM. 
The duration of infusion will be 
 for all doses. The DLRT may 
recommend to modify infusion rates based on emerging PK and safety.  Changes to the 
infusion rate will not be less than 1 hour and will apply to all subjects of the same dose 
cohort. Please note:  for infusion delays due to related adverse events, the instructions 
in Section 6.2.1.4.2 apply.   
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For further details on planned dosing see Section 3.1. 
The planned dose levels for the dose exploration cohorts are shown in Part 1 Study 
Design and Schema.  In the expansion part, the estimated MTD/RP2D and dosing 
schedule from the dose exploration part of the study will apply to all groups.  For each 
group, a BLRM design may be used to update the estimate of the RP2D/MTD  
(see Section 3.1 for details). 
Treatment can be administered as long as the subject is deriving benefit in the judgment 
of the investigator, unless 1 of the criteria for permanent discontinuation of treatment are 
met (see Section 6.2.1.4).  In no case may treatment be continued beyond the end of the 
LTFU period of the last subject in the study.   
Minimum hospitalization times for subjects will be as follows: 
Without step-up dosing: 
• 
72 hours after infusion at C1D1 and C1D8 
• 
48 hours after infusion at C1D15 and C1D22 if there are no adverse events  grade 
≥1 up to day 15, otherwise 72 hours.  
• 
For all subsequent infusions subjects should be monitored in hospital or outpatient 
clinic for at least 4 hours after start of each infusion with hospitalization at the 
discretion of the investigator 
With step-up dosing:  
• 
72 hours after infusion at day 1, after every step dose infusion and for the first two 
infusions at target dose (similar to C1D1 and C1D8 without step-dosing)  
• 
48 hours after the 3rd and 4th infusion at target dose if there are no adverse 
events  grade ≥ 1, otherwise 72 hours.  
• 
For all subsequent infusions, subjects should be monitored in hospital or outpatient 
clinic for at least 4 hours after start of each infusion with hospitalization at the 
discretion of the investigator 
In case of intra-subject dose escalation, subjects will be hospitalized as per the guidance 
for treatment initiation. 
The DLRT may recommend changes in hospitalization requirements after review of 
available safety data.  The hospitalization period for individual subjects may be extended 
at the discretion of the investigator. Any shortening of hospitalization period can only be 
implemented with the official approval of a substantial amendment of the protocol. 
Study sites must have immediate access to a medical intensive care unit staffed by 
critical care providers.  Prior to hospital discharge, vital signs will be measured in order 
to detect possible signs and symptoms of infusion reactions or CRS.  If required for 
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logistical reasons (eg, long travel times), subjects may be hospitalized the day before 
start of dosing, as well as during the treatment period for required PK samples. 
The start time of infusion should be chosen carefully so as to avoid any interference or 
inconvenience with time points of safety assessments or PK/pharmacodynamic 
measurements.  
The planned dose, quantity administered (amount and concentration), start date/time, 
stop date/time, and lot number of investigational product are to be recorded on each 
subject’s electronic case report form (eCRF). 
6.2.1.2 
Overdose 
The effects of overdose of this product are not known.  The administered AMG 562 dose 
may be up to 10% lower or higher than specified in the protocol.  A dose of up to 
10% higher than the intended dose may not require specific intervention.    
In any case of overdose, consultation with the Amgen medical monitor is strongly 
recommended for prompt reporting of clinically apparent or laboratory adverse events 
possibly related to overdosage.  Consultation with the Amgen Medical Monitor is also 
strongly recommended even if there are no adverse events, in order to discuss further 
management of the subject.  If the overdose results in clinically apparent or symptomatic 
adverse events, the subject should be followed carefully until all signs of toxicity are 
resolved or returned to baseline and the adverse event(s) should be recorded/reported 
per Section 9.2.2.2. 
6.2.1.3 
Dose Limiting Toxicities (DLTs) 
The DLT window (ie, DLT evaluable period) will start on Day 1 (start of the 
administration of the first infusion).  The duration of the DLT window is 28 days from 
infusion Day 1. 
The DLT window may also be extended to assess events starting within the window in 
case the DLT definition is time dependent. 
See Section 3.4 for description of DLT evaluability and replacement of subjects.  
All available safety data for subjects who are not DLT evaluable will still be evaluated 
and considered in DLRT recommendations. 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT window unless clearly attributable to causes other than AMG 562 treatment.  
The CTCAE version 4.0 (see Appendix A) will be used to assess toxicities/adverse 
Approved 
 
 


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events with the exception of CRS and tumor lysis syndrome (TLS).  See Section 6.2.1.4 
and Appendix K for grading criteria of CRS, neurotoxicity and TLS respectively. 
1. Death not clearly due to the underlying disease or extraneous causes. 
2. Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver 
injury [DILI]) 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 (TBIL) level of > 2x ULN 
or INR > 1.5 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) 
3. Non-hematologic DLTs: 
• 
Non-hematological adverse event grade 3 or higher, EXCEPT: 
− 
infection responding to antibiotic/anti-infective treatment within 48 hours 
− 
grade 3 fatigue or asthenia 
− 
grade 3 headache that improves to grade ≤ 2 within 72 hours 
− 
grade 3 insomnia that improves to grade ≤ 2 within 72 hours 
− 
grade 3 fever that improves to grade ≤ 2 within 72 hours 
− 
grade 3 nausea, vomiting or diarrhea responding if managed with optimal 
medical support and resolves within 72 hours 
− 
laboratory parameters of grade ≥ 3, not considered clinically relevant , 
and improved to grade ≤ 2 within 72 hours 
4. Hematologic DLTs: 
• 
Febrile neutropenia grade 3 or higher unless responding to 
antibiotic/anti-infective treatment within 48 hours 
• 
Grade 4 neutropenia lasting more than 5 days 
• 
Grade 4 thrombocytopenia lasting more than 7 days 
• 
Grade 3 thrombocytopenia with hemorrhage or required platelet transfusion 
• 
Grade 3 anemia with symptoms or required intervention (eg, transfusion) 
• 
Grade 4 anemia in the absence of detectable lymphoma as it may reflect a 
marrow toxic effect of AMG 562 
Any adverse event, that meets the DLT definition, occurring outside the DLT evaluation 
period that is determined by the investigator to be possibly related to AMG 562, 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. 
Approved 
 
 


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An event should be considered related to treatment if, in the investigator’s medical 
judgement, there is a reasonable possibility that the event may have been caused by 
AMG 562. 
The dosing schedule is described by Part 1 Study Design and Schema and also in the 
protocol synopsis.  
6.2.1.4 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.1.4.1 
Infusion Interruptions/Delays/Withholding and Re-Start in Case of 
Technical/Logistical Issues 
Events leading to infusion interruption or delay for technical/logistical reasons may 
include: technical problem with the infusion pump or the investigational product is 
incorrectly prepared or administered. 
Infusion Interruptions due to Technical/Logistical Issues 
The administration of AMG 562 should not be interrupted, if possible. In case of infusion 
interruption, due to any technical or logistic reason, the interruption should be as short 
as possible and the infusion continued at the earliest time possible. 
In case of infusion interruption, immediately consult with Amgen Medical Monitor to 
determine if  
• 
AMG 562 stability is sufficient to administer the remaining infusion or  
• 
a new infusion can be administered or  
• 
the dose should be withheld  
If the remaining infusion can be administered, no specific precautions have to be taken.  
If a new infusion can be administered, follow the procedures in the schedule of 
assessments (Table 8 through Table 11) for the day on which the original (interrupted) 
infusion was administered.  Premedication as described in Section 6.3 for the first 
infusion of the treatment should be administered.  If the infusion will need to be withheld, 
follow the instructions for re-start after interruptions due to adverse events described 
below for the next infusion. 
Infusion Delay due to Technical/Logistical Issues 
If the infusion delay was up to 72 hours, the dose can be administered without specific 
precautions. Procedures performed will follow the schedule of assessments for the 
treatment day on which the infusion was originally planned.  The following infusion 
should then be administered after 7 (± 1) days; eg, if the Day 8 infusion needs to be 
Approved 
 
 


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delayed for logistical issues, and could only be administered on Day 10, the next infusion 
should be administered on Day 17 (± 1 day) rather than the regular Day 15.  The ± 1 day 
window is allowed until the original dosing schedule is met again (in the example above, 
the third infusion could be administered on Day 16, and the fourth infusion on Day 22, if 
preferred for logistical reasons).  
If the delay of the next infusion was > 72 hours, the dose will need to be skipped and the 
instructions for re-start after interruptions due to adverse events described below should 
be followed. 
6.2.1.4.2 
Infusion Interruptions/Delays/Withholding and Re-Start due to 
Adverse Events 
6.2.1.4.2.1 
General Guidelines 
Subjects should be assessed for toxicity before each infusion of AMG 562. The severity 
of the toxicity will be graded using the CTCAE version 4.0 (Appendix A), with the 
exception of CRS, which must be graded using the criteria referenced in the publication 
by Lee et al, 2014 (see Table 7) and TLS, which must be graded according to the Cairo 
Bishop criteria referenced in the publication by Coiffier et al, 2008 (see Appendix K).  
Infusion modification and dose reduction due to a toxicity will be performed according to 
the instructions described below and outlined in Table 6 and Table 7. 
 
Approved 
 
 


Product:  AMG 562 
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Date:  07 August 2019 
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Table 6.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuations and Management of Adverse Events Including 
Dose Reductions 
 
Interruption/Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction 
Grade 1 
n/a 
Consider medication 
to control infusion 
reaction as deemed 
appropriate by the 
investigator according 
to local standard of 
care and institutional 
guidelines.  
Increase monitoring of 
vital signs as 
medically indicated 
until the subject is 
deemed medically 
stable 
n/a 
n/a 
Grade 2 
Immediate 
interruption/delay until 
event has improved to 
grade ≤ 1 
• 
Re-start possible, if successfully managed and 
improvement to ≤ grade 1 in ≤ 14 days. 
• 
In case of infusion interruption, continue 
treatment with next scheduled infusion, do not 
resume prior infusion or administer delayed 
infusion. 
• 
If the next infusion is delayed: 
− 
up to 72 hours:  follow the schedule of 
assessments for the treatment day on which 
the infusion was originally planned.  The 
following infusion should then be 
administered after 7 (± 1) days 
− 
> 72 hours:  skip the infusion and resume 
schedule of assessments for the next 
scheduled infusion  
• 
Hospitalization: 48 hours 
• 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated  
• 
Additional measures:  premedication and 
additional assessments as indicated in 
Section 6.2.1.4.2.4 above 
If subject missed more 
than 2 consecutive 
doses 
Page 1 of 5 
Footnotes defined on last page of table 
 
Approved 
 
 


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Table 6.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuations and Management of Adverse Events Including 
Dose Reductions 
 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (continued) 
Grade 3 
Immediate 
interruption/ delay 
until event has 
improved to grade 
≤ 1 
Consider supportive 
therapy including 
steroids as clinically 
indicated. 
Increase monitoring of 
vital signs as 
medically indicated 
until the subject is 
deemed medically 
stable.  
• 
As for grade 2 infusion-related reaction, with the 
exception of mandatory dose modification:  
reduce to next lower dose 
If subject missed more 
than 2 consecutive 
doses 
 
If recurrent grade 3 
Recurrent 
Grade 3 
despite 
reduction of 
infusion rate & 
other measures 
Immediate 
interruption 
As for grade 3 
infusion-related 
reaction 
• 
n/a 
Immediately stop the 
infusion (if applicable) 
and permanently 
discontinue AMG 562 
therapy 
Grade 4 
Immediate 
interruption 
As for grade 3 
infusion-related 
reaction 
n/a 
Immediately stop the 
infusion (if applicable) 
and permanently 
discontinue AMG 562 
therapy 
Cytokine Release Syndrome 
For Grading, Stopping and Re-challenge Rules please refer to Table 7. 
Page 2 of 5 
Footnotes defined on last page of table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
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Table 6.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuations and Management of Adverse Events Including 
Dose Reductions 
 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any other adverse events including those not meeting DLT criteria 
≥ Grade 3 
Interruption/ delay 
required if deemed 
intolerable by the 
subject and not 
responding to 
appropriate medical 
management until 
event has improved 
to grade ≤ 1  
n/a 
• 
Re-start possible if successfully managed and 
improvement to ≤ grade 1 in ≤ 14 days. 
• 
In case of infusion interruption, continue treatment 
with next scheduled infusion, do not resume prior 
infusion or administer delayed infusion. 
• 
If next infusion is delayed: 
− 
up to 72 hours:  follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned.  The following 
infusion should then be administered after 
7 (± 1) days 
− 
> 72 hours:  skip the infusion and resume 
schedule of assessments for the next 
scheduled infusion  
• 
Hospitalization:  48 hours 
• 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
• 
Additional measures:  premedication and 
additional assessments as indicated in  
Section 6.2.1.4.2.4 above. 
If subject missed more 
than 2 consecutive 
doses 
 
In case of any event at 
grade 4 
Page 3 of 5 
Footnotes defined on last page of table 
 
Approved 
 
 


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Table 6.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuations and Management of Adverse Events Including 
Dose Reductions 
 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
CNS grade 3 
Interrupt AMG 562 
immediately  
Perform investigations 
per local practice 
including neuro exam, 
cerebral MRI and CSF 
analysis 
Dexamethasone 
should be 
administered at a 
dose of 3 x 8 mg /d 
over 3 days with 
step-wise dose 
reduction over up to 
4 days 
• 
Re-start possible within 2 weeks but not earlier 
than 3 days after infusion was stopped if 
successfully managed and improvement to 
≤ grade 1 in ≤ 7 days. 
• 
Hospitalization: 72 hours 
• 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
• 
 
• 
Additional measures:  premedication and 
additional assessments as indicated in 
Section 6.2.1.4.2.4 and Section 6.2.1.4.2.5 above. 
In case CNS event 
needed more than 
7 days after treatment 
interruption to resolve to 
grade ≤ 1  
CNS grade 4* 
Interrupt AMG 562 
immediately 
As for grade 3 
CNS-related event 
n/a 
Permanently 
discontinue AMG 562 
therapy 
Seizure grade 
≤ 2* 
Interrupt AMG 562, 
administer 
corticosteroids and 
antiseizure 
medication per local 
practice 
n/a 
• 
Do not re-initiate AMG 562 until 7 days after the 
last seizure and after therapeutic levels of 
antiseizure medication are likely to have been 
achieved 
Permanently 
discontinue if a 2nd  
seizure occurs with 
re-initiation of AMG 562  
Seizure grade 
≥ 3* 
Interrupt AMG 562 
immediately 
Administer 
corticosteroids and 
antiseizure medication 
per local practice 
n/a 
Permanently 
discontinue AMG 562 
therapy 
Page 4 of 5 
Footnotes defined on last page of table 
 
Approved 
 
 


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Table 6.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuations and Management of Adverse Events Including 
Dose Reductions 
 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any Non-AMG 562 related events 
Grade 4 
Interruption/ delay required if 
deemed intolerable by the 
subject and not responding to 
appropriate medical 
management until event has 
improved to grade ≤ 1, with 
exception of Grade 4 
neutropenia or 
thrombocytopenia, follow 
re-start guidance as indicated. 
n/a 
• 
Re-start possible if successfully managed and 
improvement to ≤ grade 1 in ≤ 14 days. 
• 
In case of infusion interruption, continue treatment 
with next scheduled infusion, do not resume prior 
infusion or administer delayed infusion. 
• 
If next infusion is delayed: 
− 
up to 72 hours:  follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned.  The following 
infusion should then be administered after 
7 (± 1) days 
− 
> 72 hours:  skip the infusion and resume 
schedule of assessments for the next 
scheduled infusion  
• 
Hospitalization:  48 hours 
• 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
• 
Additional measures:  premedication and additional 
assessments as indicated in Section 6.2.1.4.2.4 
above. 
If subject missed more 
than 2 consecutive 
doses 
In case of 
reappearance of same 
event at grade 4 
Hepatotoxicity 
For Stopping and Rechallenge Rules please refer to Section 6.4 
Page 5 of 5 
* Obtain brain MRI and perform cerebro spinal fluid (CSF) analysis, if there are no contraindications 
 
 
Approved 
 
 


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6.2.1.4.2.2 
Infusion Interruptions due to Adverse Events 
Events occurring during the infusion and requiring treatment interruption will be 
managed by immediate infusion interruption.  The site should record any unscheduled 
interruption of an infusion on the eCRF, and provide the start and stop date/time of the 
infusion.  
Events requiring infusion interruption or permanent discontinuation are listed in Table 6. 
6.2.1.4.2.3 
Delay of Subsequent Infusion due to Adverse Events 
Events occurring after the end of the infusion and requiring a delay of treatment will be 
managed by delay of the subsequent infusion.  The site should record any delay of an 
infusion on the eCRF, and provide the start and stop date/time of the infusion.  
Events requiring a delay of the subsequent infusion are listed in Table 6. 
Note:  For single subject cohorts, replace a subject if an infusion is delayed during the 
DLT evaluation period by > 7 days for a reason other than a DLT (ie, the subject will 
miss 1 out of the 4 planned doses and therefore is not evaluable for DLT). 
For multiple subject cohorts, replace a subject if an infusion is delayed during the DLT 
evaluation period by > 14 days for a reason other than a DLT (ie, the subject will miss at 
least 2 consecutive doses out of the 4 planned doses and therefore is not evaluable for 
DLT). 
After the end of the DLT period, subjects will not be replaced. 
Infusion interruptions or delays for other reasons need to be discussed with the Amgen 
Medical Monitor. 
6.2.1.4.2.4 
Re-Start of Infusion 
Re-starting treatment after an interruption/delay due to an adverse event or if the 
interruption/ delay was > 72 hours, regardless of the reason, should be performed under 
medical supervision. Premedication as described in Section 6.3 for the first infusion of 
the treatment should be considered prior to re-start.  The following assessments should 
be performed as for Days 1, 2, and 3 of the treatment (see Schedule of Assessments, 
Table 8): 
• 
vital signs, pulse oximetry,  
• 
physical examination (including neurological examination, if applicable) 
• 
weight 
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• 
ECOG 
• 
safety Labs (hematology, chemistry, coagulation, urinalysis) 
The subject should be hospitalized for at least 48 hours after re-start of the infusion. 
6.2.1.4.2.5 
Dose Adjustments and Re-Start at a Lower Dose Level 
For adverse events for which restart of treatment is allowed according to the guidelines 
outlined in Table 6 and Table 7, treatment may be resumed at the same dose or a lower 
dose. 
Re-start at a lower dose level: 
In the following cases, the next infusion administered should be at the previous (lower) 
dose level: 
• 
If the event occurred during the infusion and caused an interruption of the infusion for 
more than 72 hours and therefore the affected dose was withheld, or 
• 
If the event started after the end of an infusion and administration of the next infusion 
had to be delayed for more than 72 hours due to the event. 
• 
If grade 3 CRS, the next infusion should be restarted 1 dose level below the dose at 
which the event occurred. If this lower dose level is well tolerated (ie, absence of 
grade ≥ 2 CRS), then escalation to the subject’s target dose level can occur for the 
next planned dose 
• 
For specific events as outlined in Table 6. 
In either case, re-escalation to the target dose can be considered for the next infusion if 
treatment at the lower dose has been well tolerated with no events requiring dose 
interruption or delay as described in Table 6 and Table 7.  After the dose re-escalation, 
the following assessments should be performed as for Day 8 through Day 11 of the 
treatment per the Schedule of Assessments(with step-up dosing, Table 9): 
• 
vital signs, pulse oximetry 
• 
physical examination (including neurological examination, if applicable) 
• 
safety labs (hematology, chemistry, coagulation, urinalysis) 
The subject should be hospitalized for at least 48 hours after re-escalation. 
In case an additional dose de-escalation is required, permanently discontinue treatment. 
6.2.1.4.2.6 
Specific Guidance for Cytokine Release Syndrome 
Cytokine release syndrome is clinically defined and may have various manifestations.  
There are no established diagnostic criteria. Signs and symptoms of CRS may include: 
• 
constitutional: fever, rigors, fatigue, malaise 
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• 
neurologic: headache, mental status changes, dysphasia, tremors, dysmetria, gait 
abnormalities, seizure 
• 
respiratory: dyspnea, tachypnea, hypoxemia 
• 
cardiovascular: tachycardia, hypotension 
• 
gastrointestinal: nausea, vomiting, transaminitis, hyperbilirubinemia 
• 
hematology: bleeding, hypofibrinogenemia, elevated D-dimer 
• 
skin: rash 
Subjects may be at an increased risk for CRS during the first few days following the 
infusion of AMG 562.  CRS may be life threatening or fatal. Infusion reactions may be 
clinically indistinguishable from manifestations of CRS. Throughout the treatment with 
AMG 562, monitor subjects for clinical signs (eg, fever, tachycardia, dyspnea, tremors) 
and laboratory changes (eg, transaminase increase) which may be related to CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in Table 7 (based on the adopted grading system referenced in 
Lee et al, 2014). 
After grade 2 or 3 CRS, the next scheduled infusion may be administered if all of the 
following criteria are met: 
• 
The Amgen Medical Monitor must be consulted prior to re-starting treatment 
• 
If CRS occurred during AMG 562 infusion, infusion has been interrupted for at 
least 72 hours 
The event has resolved to grade ≤ 1 prior to re-starting treatment 
Please also refer to the general guidance for re-start of infusion after 
interruptions/delay/withholding and dose modifications in Section 6.2.1.4.2. 
For grade 3 and 4 CRS, please also see Section 6.2.1.3 for DLT considerations. 
 
Approved 
 
 


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Table 7.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Interruption/ 
Delay/ 
Withholding 
Minimum Expected Intervention 
Restart Guidance 
Permanent 
Discontinuation 
1 
Symptoms are not 
life threatening and 
require symptomatic 
treatment only, eg, 
fever, nausea, 
fatigue, headache, 
myalgias, malaise 
n/a 
Administer symptomatic treatment (eg, 
paracetamol/ acetaminophen for fever). 
Monitor for CRS symptoms including vital 
signs and pulse oximetry at least Q2 hours 
for 12 hours or until resolution, whichever is 
later. 
n/a 
n/a 
2 
Symptoms require 
and respond to 
moderate 
intervention 
• 
Oxygen 
requirement 
< 40%, OR  
• 
Hypotension 
responsive to 
fluids or low 
dose of 
1 vasopressor, 
OR 
• 
Grade 2 organ 
toxicity or grade 
3 transaminitis 
per CTCAE 
criteria 
Immediately 
interrupt/ delay 
AMG 562 until 
event improves 
to CRS 
grade ≤ 1. 
Administer:  
• 
Symptomatic treatment (eg, paracetamol/ 
acetaminophen for fever) 
• 
Supplemental oxygen when oxygen 
saturation is < 90% on room air 
• 
Intravenous fluids or low dose 
vasopressor for hypotension when 
systolic blood pressure is < 85 mmHg.  
Persistent tachycardia (eg, > 120 bpm) 
may also indicate the need for 
intervention for hypotension. 
Monitor for CRS symptoms including vital 
signs and pulse oximetry at least Q2 hours 
for 12 hours or until resolution to CRS grade 
≤ 1, whichever is earlier. 
Investigators may also consider use of 
tocilizumabc as an additional therapy in this 
setting at a dose of 8 mg/kg IV as a single 
dose. 
For subjects with extensive co-morbidities or 
poor performance status, manage per grade 
3 CRS guidance below. 
• 
Re-start possible if successfully 
managed and improved to ≤ grade 1 
within 7 days. 
• 
Consult with Amgen medical monitor 
first. 
• 
In case of infusion interruption, 
continue treatment with next scheduled 
infusion, do not resume prior infusion 
or administer delayed infusion. 
• 
If the next infusion is delayed: 
− up to 72 hours:  follow the schedule of 
assessments for the treatment day on 
which the infusion was originally 
planned.  The following infusion should 
then be administered after 7 (± 1) days 
− > 72 hours:  skip the infusion and 
resume schedule of assessments for 
the next scheduled infusion  
• 
Hospitalization: 48 hours 
• 
Dose modification:  reduce to next 
lower dose  
• 
Additional measures:  premedication 
and additional assessments as 
indicated in Section 6.2.1.4.2.4 above  
If there is no 
improvement to 
CRS ≤ grade 1 
within 7 days. 
In case of 2 
separate grade 2 
or 3 CRS events. 
Page 1 of 3 
Footnotes defined on last page of this table 
 
Approved 
 
 


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Table 7.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Interruption/ 
Delay/ 
Withholding 
Minimum Expected Intervention 
Restart Guidance 
Permanent 
Discontinuation 
3  
Symptoms require 
and respond to 
aggressive 
intervention 
• 
Oxygen 
requirement 
≥ 40%, OR 
• 
Hypotension 
requiring high 
doseb or 
multiple 
vasopressors, 
OR 
• 
Grade 3 
organ toxicity 
or grade 4 
transaminitis 
per CTCAE 
criteria 
Immediately 
interrupt / 
delay 
AMG 562 until 
event improves 
to CRS grade 
≤ 1. 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer dexamethasone (or equivalent) IV 
or PO at a dose maximum of 3 doses of 8 mg 
(24 mg/day).  The dose should then be 
reduced step-wise. 
Additionally, tocilizumabc should be 
administered at a dose of 8 mg/kg IV as a 
single dose and may be repeated once within 
24 to 48 hours based on clinical assessment. 
Re-start possible if successfully 
managed and improved to ≤ grade 1 
within 7 days. 
• 
Consult with Amgen medical 
monitor first. 
• 
In case of infusion interruption, 
continue treatment with next 
scheduled infusion, do not 
resume prior infusion or 
administer delayed infusion. 
• 
If the next infusion is delayed: 
- 
up to 72 hours: follow the 
schedule of assessments 
for the treatment day on 
which the infusion was 
originally planned. The 
following infusion should 
then be administered after 
7 (± 1) days 
- 
> 72 hours: skip the 
infusion and resume 
schedule of assessments 
for the next scheduled 
infusion 
• 
Hospitalization: at least 48 hours 
after CRS resolves  to grade ≤ 2 
• 
Dose modification: reduce to 
next lower dose 
• 
Additional measures: 
premedication and additional 
assessments as indicated in 
Section 6.2.1.4.2.4 above 
If there is no 
improvement to CRS ≤ 
grade 2 within 5 days or 
CRS ≤ grade 1 within 
7 days. 
If CRS grade 3 occurs at 
the initial run in dose (ie, 
at MTD1), if applicable. 
In case of 2 separate 
grade 2 or 3 CRS events. 
Page 2 of 3 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
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Table 7.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Interruption/ 
Delay/ 
Withholding 
Minimum Expected Intervention 
Restart Guidance 
Permanent 
Discontinuation 
4 
Life-threatening 
symptoms 
• 
Requirement 
for ventilator 
support OR 
• 
Grade 4 
organ toxicity 
(excluding 
transaminitis) 
per CTCAE 
criteria 
 
Admit to intensive care unit for close clinical and 
vital sign monitoring per institutional guidelines. 
Administer dexamethasone (or equivalent) IV or 
PO at a dose maximum of 3 doses of 8 mg 
(24 mg/day).  Further corticosteroid use should 
be discussed with the Amgen medical monitor. 
Additionally, tocilizumabc should be 
administered at a dose of 8 mg/kg IV as a 
single dose and may be repeated once within 
24 to 48 hours based on clinical assessment. 
n/a 
Immediately stop the 
infusion (if applicable) 
and permanently 
discontinue AMG 562 
therapy 
Page 3 of 3 
CRS = Cytokine Release Syndrome, CTCAE = Common Terminology Criteria for Adverse Events, IV = Intravenous 
a Revised grading system for cytokine release syndrome (Lee et al, 2014) 
b High dose vasopressors (all doses are required for ≥3 hours):  Norepinephrine monotherapy ≥ 20 µg/min; Dopamine monotherapy ≥ 10 µg/kg/min, Phenylephrine 
monotherapy ≥ 200 µg/min, Epinephrine monotherapy ≥ 10 µg/min; If on vasopressin, vasopressin + norepinephrine equivalent of ≥ 10 µg/min; If on combination 
vasopressors (not vasopressin), norepinephrine equivalent of ≥ 20 µg/min 
c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and 2 doses of tocilizumab per study subject.  
 
 
Approved 
 
 


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6.2.1.4.3 
Specific Guidance for Neurotoxicity 
Neurotoxicity is a broad concept, including any adverse effect on the structure or 
function of the central and/or peripheral nervous system by a biological, chemical or 
physical agent. In this definition, neurotoxic effects may be permanent or reversible and 
result from direct or indirect actions on the nervous system (Erinoff, ‘Interagency 
Committee on Neurotoxicology’, 1995). 
In case of grade 3 or grade 4 neurotoxicity events, perform investigations per local 
practice including neurological exam, cerebral MRI and CSF analysis after interruption of 
infusion. 
Dexamethasone IV or PO should be administered at a dose of 3 x 8 mg /d over 3 days 
with step-wise dose reduction over up to 4 days. For seizures ≥ grade 2 administer 
corticosteroids and antiseizure medication per local practice. 
Re-start of IP is possible within 2 weeks but not earlier than 3 days after infusion was 
stopped and if successfully managed with improvement to ≤ grade 1 in ≤ 7 days. 
Subjects will remain hospitalized for 72 hours following re-start of IP. Following grade 2 
seizure, do not re-initiate AMG 562 until 7 days after the last seizure and after 
therapeutic levels of antiseizure medication are likely to have been achieved. 
6.2.1.4.4 
Permanent Discontinuation of AMG 562 
AMG 562 treatment will be permanently discontinued in the event of: 
• 
infusion-related reaction grade 4 (the infusion has to be stopped immediately, if 
applicable)  
• 
recurrent grade 3 infusion-related reaction despite reduction of infusion rate & other 
symptomatic measures 
• 
grade 4 CRS 
• 
grade 2 or 3 CRS meeting any of the criteria listed below: 
− 
grade 2 or 3 CRS that does not improve to grade ≤ 1 within 7 days 
− 
grade 3 CRS that does not improve to grade ≤ 2 within 5 days 
− 
if a subject experiences 2 separate grade 2 or grade 3 CRS events regardless  of 
dose 
− 
grade 3 CRS at the initial lower dose for treatment initiation (for cohorts with 
step-up dosing only) 
• 
Occurrence of acute kidney injury considered related to AMG 562 by the investigator 
and meeting one or more of the following criteria: 
− 
Creatinine > 3x baseline or > 4.0 mg/dL and not recovered to CTCAE grade 1 or 
≤ 0.3 mg/dL within 21 days 
− 
Hemodialysis required 
Approved 
 
 


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• 
DLT (separate guidance for CRS, IRR and Neurotoxicity) or other unmanageable 
toxicity unless a subject has a clear clinical benefit from treatment, the toxicity has 
resolved to  grade ≤ 1 or baseline and after consultation with the sponsor 
• 
in case of grade 4 non-hematologic adverse event 
• 
grade 3 neurotoxicity needing more than 7 days after treatment interruption to 
resolve to grade ≤1 
• 
Grade 4 neurotoxicity  
• 
Grade ≥ 3 seizure 
• 
In case of occurrence of more than one seizure of grade ≤ 2 
• 
treatment interruption:  if the subject misses at least 2 consecutive doses due to 
serious adverse events/adverse events  
• 
possible DILI requiring permanent withholding as per Section 6.4  
• 
subjects who require more than 1 dose reduction 
• 
clinically relevant disease progression 
• 
relapse of disease subsequent to response on protocol treatment 
• 
occurrence or progression of a medical condition which in the opinion of the 
investigator should preclude further participation of the subject in the study 
• 
administration of relevant non-permitted concomitant medications  
• 
requirement for alternative therapy  
• 
subject’s request 
• 
subject or investigator not compliant with the study protocol 
For grading of events, refer to Section 9.2.2.1. 
Females who become pregnant while on study through 120 days after receiving the last 
dose of study drug will not receive subsequent scheduled doses and will be followed for 
safety until the EOS visit. 
Males with pregnant partners or whose partners become pregnant while the subject is 
on study through 180 days after receiving the last dose of study drug must practice 
sexual abstinence or use a condom while on study through 180 days after receiving the 
last dose of study drug. 
All reasons for treatment discontinuation should be clearly and comprehensively 
documented in the eCRF.  If a subject has not continued to present for study visits, the 
investigator should determine the reason and circumstances as completely and 
accurately as possible. 
In any case of premature treatment discontinuation, the investigator should make every 
effort to perform all examinations scheduled for the EOT.  
Approved 
 
 


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6.3 
Other Protocol-required Therapies  
All other protocol-required therapies including glucocorticoids that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies.  
Premedication for Cycle 1: an 8 mg dose of IV or PO dexamethasone approximately  
1 hour prior to the start of the AMG 562 infusion is mandatory: 
o Prior to each infusion in Cycle 1 8 mg dexamethasone IV or PO as premedication 
Premedication for Cycle 2 and beyond: 
o Pre medication with 8 mg IV or PO dexamethasone for each subsequent cycle 
will be required for any subject who experienced grade ≥ 2 neurotoxicity or grade 
≥ 2 CRS in the preceding cycle 
o If CRS and neurotoxicity of grade 2 or higher did not occur in the prior cycle(s), 
premedication with dexamethasone can be reduced to 4 mg. If subjects tolerate 
AMG 562 well with reduced dose dexamethasone, premedication with 
dexamethasone can be discontinued for the next cycle in consultation with 
Amgen Medial Monitor. 
No additional premedication is permitted on the trial.. If the evaluation of available safety 
and laboratory data suggests that adjustment to the dexamentasone schedule are 
required or additional premedication is necessary the DLRT can recommend to adjust 
the current schedule and/or add additional premedication, eg, antihistamines and  
H2 blockers to the premedication regimen. In this case all future cohorts will receive this 
additional premedication. All subjects will be pre-treated unless a contraindication for this 
premedication exists. 
Premedication as described above for the first infusion also has to be administered after 
treatment interruptions / delays as described in Section 6.2.1.4.  
For administration of dexamethasone and tocilizumab after occurrence of CRS, follow 
guidance in Table 7.  All sites will ensure that CRS rescue medications are available 
on-site, including corticosteroids and 2 doses of tocilizumab per study subject. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 72 of 158 
CONFIDENTIAL 
 
 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], AST, 
ALT, TBIL) or INR or signs/symptoms of hepatitis may meet the criteria for withholding of 
investigational product.  Withholding is either permanent or conditional depending upon 
the clinical circumstances discussed below (as specified in the FDA Guidance for 
Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009). 
6.4.1 
Criteria for Permanent Withholding of AMG 562 due to Potential 
Hepatotoxicity 
AMG 562 should be permanently withheld and the subject should be followed according 
to the recommendations in Appendix A (Additional Safety Assessment Information) for 
possible 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 
> 3 x 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: 
− 
hepatobilliary tract disease  
− 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia  
− 
exposure to hepatotoxic agents/drugs including herbal and dietary supplements, 
plants, and mushrooms,  
− 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir)  
− 
alpha-one antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis 
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic fatty liver disease including steatohepatitis (NASH) 
− 
non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 73 of 158 
CONFIDENTIAL 
 
 
6.4.2 
Criteria for Conditional Withholding of AMG 562 due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of AMG 562 
outlined above and have no underlying liver disease and eligibility criteria requiring 
normal transaminases and TBIL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of Amgen investigational product and other protocol-required therapies:   
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT 
value 
AST or ALT elevation 
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
> 3x ULN with clinical signs or symptoms that are consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice. 
• 
OR:  TBIL > 3x ULN at any time 
• 
OR:  ALP > 8x ULN at any time 
AMG 562 should be withheld pending investigation into alternative causes of the 
laboratory elevations.  If AMG 562 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 the elevated liver enzymes (ALT, AST, ALP) and/or elevated 
TBIL, is discovered and the laboratory abnormalities resolve to normal or baseline 
(Section 6.4.3). 
Discontinuation of the product should be considered and the decision to rechallenge 
should be discussed with the Amgen Medical Monitor before reinitiating treatment with 
investigational product.  
6.4.3 
Criteria for Rechallenge of AMG 562 After Potential Hepatotoxicity 
If signs or symptoms recur with rechallenge, then AMG 562 should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.2.1.4) should not be rechallenged.  
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 74 of 158 
CONFIDENTIAL 
 
 
6.5 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
Concomitant therapies are to be collected from screening start through the SFU period.  
All concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter, herbal supplements, and IV medications and fluids and blood 
products. 
For all concomitant medication collect therapy name, indication, dose, unit, frequency, 
route, start date, and stop date.  
6.5.1 
Supportive Care 
Subjects should receive supportive care according to local guidelines for blood product 
support, antibiotics, antivirals, analgesics, etc.   
Throughout the study, subjects should be encouraged to remain well hydrated 
throughout the treatment period.   
Please refer to Sections 6.2.1.4.2.2 and 6.2.1.4.2.6 for management of CRS and 
infusion related reaction. 
Oxygen administration as supportive measure is permitted during study treatment.   
6.5.2 
Growth Factors 
The use of growth factors such as erythropoiesis-stimulating proteins as well as G-CSF 
will be allowed during therapy. However, growth factors are not allowed at inclusion 
(within 7 days of applicable screening assessment) and should be avoided, if subject`s 
condition allows, in the first four weeks of treatment for better assessment of safety 
parameters.  
6.5.3 
Infections 
Prophylactic antibiotics, antifungal and antivirals are allowed and should be given as per 
institutional standards and as per recommendation below. Subjects who experience 
neutropenia for 7 days or longer are at a high risk for infectious complications. Therefore 
if ANC < 0.5 x 10^9, all patients should have anti-bacterial and anti-fungal prophylaxis 
started using agents according to institutional standard. These subjects should be 
monitored for early signs of breakthrough infections after the initiation of antibacterial 
therapy to prompt additional evaluation and possible therapy modification.   
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 75 of 158 
CONFIDENTIAL 
 
 
Subjects with evidence of existing infection after the start of AMG 562 treatment should 
be closely monitored while being treated with AMG 562.  Subjects with active systemic 
infections requiring IV antibiotics, antivirals, or antifungals should not be dosed with 
AMG 562 until infection has resolved and if being treated with an IV 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. 
6.6 
Medical Devices 
Investigational product must be administered using infusion pumps approved for use by 
the appropriate regulatory authorities for the country in which the subject is undergoing 
treatment.  Investigational product infusion for solution will be prepared in bags for 
IV infusion and delivered through infusion lines that are compatible with the 
investigational product. Additional medical devices (eg, syringes, sterile needles, alcohol 
prep pads), that are commercially available are not provided or reimbursed by Amgen 
(except, if required by local regulation).  The investigator overseeing the conduct of the 
study at each respective institution will be responsible for obtaining these supplies.   
6.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.   
This includes any drug(s), device(s), or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 76 of 158 
CONFIDENTIAL 
 
 
6.8 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period  
The following treatments and/or procedures are excluded during the treatment period of 
the study (until SFU):  
• 
any antitumor therapy other than AMG 562, such as: 
− 
cytotoxic and/or cytostatic drugs 
− 
radiation therapy (with the exception of radiotherapy for palliative care such as 
bone pain; this is only permitted after discussion with Amgen Medical Monitor) 
− 
immunotherapy  
• 
any other immunosuppressive therapies (except for the management of acute, 
treatment–related toxicities such as transient – ie, for up to 2 weeks - use of 
corticosteroids and tocilizumab) 
− 
high-dose corticosteroid therapy (dexamethasone > 24 mg/day or equivalent) is 
only allowed for up to 7 days 
• 
any other investigational agent 
• 
treatment with growth factors, IV antibiotics, antivirals, or antifungals during DLT 
window unless discussed with the Amgen Medical Monitor 
• 
treatment with medications known to cause QTc interval prolongation unless 
approved by the Amgen Medical Monitor (see Appendix E) 
• 
treatment with medications that are CYP450 substrates with a narrow therapeutic 
index in cycles 1 and 2 unless approved by the Amgen Medical Monitor (see 
Appendix G for examples). In case use of these substrates is approved, appropriate 
monitoring for potentially increased toxicity should be implemented. 
• 
any major surgery 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 77 of 158 
CONFIDENTIAL 
 
 
Table 8.  Schedule of Assessments for Screening and Treatment Cycle 1 
 
SCR 
Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
1b 
2 
3 
4 
 
8a 
9 
10 
11 
15a 
16 
17 
18 
20 
22a 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
  
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
ICF 
X 
  
  
  
                    
  
  
  
                          
  
                                                   
Hospitalizationc 
 
  
 
---------------------------------------> 
  
  
---------------------------------------> 
  
------------------------------------> 
    
------------------------------------>  
Demographics 
X 
  
  
  
                    
  
  
  
                          
  
                                                  
  
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds 
X X 
 
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
SAE review 
X X 
 
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
AE/DRE review 
  
  
X 
<-----------------------------------------------------------------      continually throughout treatment      -----------------------------------------------------------------> 
Physical exam 
X X 
X X 
X 
X 
X X X X 
X X X 
X 
X 
Neurological exam 
X X 
xt 
xt xt 
xt 
X 
xt 
xt xt xt X 
xt 
xt xt xt 
X 
xt xt 
xt 
ECOG 
X X 
X 
Weight 
X X 
Vitals/pulse oxd 
X X 
  
X X X X X X X X X X X 
X 
  
X   X X X X X X X X X X X X X   X X X X X X X X X X X   X   X X X X X X X X X X 
X 
ECG triplicated 
X X 
  
X 
      X   X     X X 
X 
  
X   X                 
X   X   X 
            
X     X   X 
  X   X     X X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 562 IVb 
 
  
X 
  
                    
  
  
  X                         
  X                           X                     
  
Premedicatione 
 
X 
  
  
                    
  
  
X                           X                           X                       
   
Page 1 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 78 of 158 
CONFIDENTIAL 
 
 
Table 8.  Schedule of Assessments for Screening and Treatment Cycle 1 
 
SCR 
Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
1b 
2 
3 
4 
8a 
9 
10 
11 
15a 
16 
17 
18 
20 
22a 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
  
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
LABORATORY ASSESSMENTS 
Pregnancy testf 
X X 
  
  
                    
  
  
  
                          
  
                                                   
Coagulationq 
X X 
  
  
        X       X X 
  
  
X                     X X   X                   X X     X                   X X 
X 
Hem, chemq 
X X 
  
  
        X       X X 
  
  
X                     X X   X                   X X     X                   X X 
 X 
Ferriting 
  
X 
<-------------------------------------------     at onset of CRS, and daily until values are back to baseline/event is resolved -------------------------> 
CSF analysis m, p 
Collect if grade ≥3 neurologic event  or seizure grade ≤ 2p 
C-reactive protein 
 
X 
 
 
 
 
 
 
 
 
 
 X X 
 
X 
 
 
 
 
 
 
 
 
 
 X X  
X 
 
 
 
 
 
 
 
 
 X X  
 X  
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
X 
  
  
  
                    
  
  
  
                          
  
                                                  
  
Urinalysis  
X X 
  
  
                  X 
  
  
X                       X   X                     X     X                     X 
 X 
Ig:  IgA, IgM, IgG 
X X 
  
  
                    
  
  
  
                          
  
                                                  
X 
Anti-AMG 562-Ab 
 
Xh   
  
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER ASSESSMENTS 
Page 2 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 79 of 158 
CONFIDENTIAL 
 
 
Table 8.  Schedule of Assessments for Screening and Treatment Cycle 1 
 
SCR 
 
Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
 
8a 
9 
10 
11 
15a 
16 
17 
18 
20 
22a 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2 
 
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
  
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
BIOMARKER ASSESSMENTS (continued)  
PK ASSESSMENTS 
AMG 562 PKn, r 
  X*   
X 
  
X 
X     X X 
X 
X*   X 
X*   X 
X*   X 
X 
X 
X X 
X 
Page 3 of 4 
Footnotes defined on last page of this table 
 
ed 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 80 of 158 
CONFIDENTIAL 
 
 
Table 8.  Schedule of Assessments for Screening and Treatment Cycle 1 
 
SCR 
 
Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
8a 
9 
10 
11 
15a 
16 
17 
18 
20 
22a 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion  
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2  
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
  
  
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
DISEASE ASSESSMENTS 
BM aspirate/ biopsyj 
X  
<------------------      Optional at week 5 (C2D1)      ----------------> 
COO/FISH lymph node 
biopsyk 
X  
 
LN biopsy for DLBCL 
following prior CD19-
targeted treatment 
failureI 
X 
 
<------------------      Optional at relapse, post AMG 562 treatment, in responders      ----------------> 
RADIOGRAPHIC ASSESSMENTS 
MRIs/PET/CTo 
x 
 
 
Page 4.of 4 
Ab = antibody, AE = adverse event; BM = bone marrow, chem = chemistry, con meds = concomitant medications, COO = cell of origin, CR = complete response, 
CRS = Cytokine Release Syndrome, ctDNA = circulating tumor DNA, CT = computed tomography, demo = demographics, DRE = disease-related event; 
ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, Expl = exploratory, FISH = fluorescent insitu hybridization, 
hem = hematology, ICF = informed consent form, Ig = immunoglobulins, LN= lymph node, LTFU =  long-term follow-up, med hist = medical history, MRD = minimal 
residual disease, MRI = magnetic resonance imaging, neuro = neurological, NGS = next generation sequencing, ox = oximetry, PB = peripheral blood, PD = 
progressive disease, periph. = peripheral, PET = positron emission tomography, PG = pharmacogenomic, PK = pharmacokinetics, PR = partial response, SAE = 
serious adverse event, SCR = screening, SFU = safety follow-up,  
a The Dose Level Review Team (DLRT) may recomend to change timing of D8/D15/D22 within a window of ± 1 day.  In this case, timing of the following visits would be 
adjusted accordingly.   
b In case of step-dosing, the subsequent treatments will be at weekly intervals after the target dose is administered. 
c See Section 6.2.1.1 for details on hospitalization requirements. 
d ECGs and vital signs should be performed prior to any invasive procedures.  ECGs are only required in treatment cycle 1 and 2.  In case of intra-subject dose 
escalation:  conduct ECGs as in cycle 1 during the first cycle after dose escalation. 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 81 of 158 
CONFIDENTIAL 
 
 
e For premedication details see Section 6.3. 
f Serum pregnancy test required at screening.  For later time points, urine pregnancy test is allowed.  In case of a positive result, serum pregnancy test should be 
repeated.  Pregnancy tests will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal.  
g Ferritin assessment to be performed at onset of CRS, and daily until values are back to baseline/event is resolved. 
h Predose anti-AMG 562 antibody sample in every 2nd cycle after cycle 1 (C1D1, C1D15, C3D1, C5D1, ..). 
o PET/CT will be performed at screening, week 5, week 15, week 25 and  and at end of treatment if end of treatment is at week 35 or beyond. Clinical tumor 
assessments will be performed at screening, week 5, week 15, week 25 and at end of treatment if end of treatment is at week 35 or beyond. Every attempt should be 
made to complete PET and CT within 3 days of each other, particularly during treatment. If subject discontinues study treatment for any reason, including toxicity or 
clinical evidence of disease progression, PET/CT should be conducted 14 (+ 3) days following the last dose of AMG 562.  
p In case of seizure of any grade perform brain MRI and cerebro spinal fluid (CSF) analysis, if there are no contraindications.  
q As indicated in Section 7.3.10, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests. Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer 
r PK samples should be collected at the exact nominal time point specified; all times are relative to the start of infusion. The 
hour sample is the same as the end of 
infusion and should be collected as close as possible to the end of infusion of AMG 562. If unable to collect a PK sample at the specified nominal time point, then 
collect the sample as close as possible and record the actual collection time. The exact date and time of IP administration and PK sample collection should be 
documented. Additional PK samples may be collected per the discretion of the PI as clinically indicated. 
s MRI of the brain to be performed at screening. To be repeated during treatment in case of seizure  
t Limited neurological examinations to be performed at these timepoints when hospitalized or in clinic as described in Section 7.3.9.2. Writing test to be performed on 
mornings and evenings on C1D1, C1D2 and after step-up dose treatment initiation 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 82 of 158 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Screening and Treatment Cycle 1 With 24 hour Step-up Dosing Intervals 
 
SCR 
 
 Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
5 
8a 
9 
10 
11 
15a  
16 
17 
18 
20 
22a  
23 
24 
25 
Hours 
 
Predose 
 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
 
0 
1.5 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
 
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
GENERAL AND SAFETY ASSESSMENTS 
ICF 
X 
Hospitalizationc 
 
---------------------------------------> 
---------------------------------------> 
---------------------------------------> 
--------------------------------------> 
Demo/med hist 
/height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds 
X X  
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
SAE review 
X X  
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
AE/DRE review 
X  
<-----------------------------------------------------------------      continually throughout treatment      -----------------------------------------------------------------> 
Physical exam 
X X 
X X X 
X 
X X X X 
X X X 
X 
X 
Neurological exam X X 
xt 
xt xt xt 
X 
xt 
xt xt xt X 
xt 
xt xt xt 
X 
xt xt 
xt 
ECOG 
X X 
Weight 
X X 
Vitals/pulse oxd 
X X 
X X 
X X X X X X X X X X 
X 
X X X X X X X X X X X X X 
X X X X X X X X X X X 
X 
X X X X X X X X X X 
X 
ECG triplicated 
X X 
X 
 
 
 X  
 X  
 X X 
X 
X  
 
 
 
 
 
 
 
X 
X 
X  
 
 
 
 
 
 
 X 
X 
X 
X 
X 
X X 
X 
Page 1 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 83 of 158 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Screening and Treatment Cycle 1 With 24 hour Step-up dosing Intervals 
 
SCR 
 
Treatment Period (Cycle 1) 
  
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
 
8a 
9 
10 
11 
15a  
16 
17 
18 
20 
22a  
23 
24 
25 
Hours 
 
Predose 
 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
 
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
INVESTIGATIONAL PRODUCT DOSING 
AMG 562 IVb 
 
 X 
 
X 
 
X  
 
 
 
 
 
X  
  
 
X  
 
 
Premedicatione 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Pregnancy 
X X 
 
Coagulationq 
X X 
X 
X X 
X 
X 
X X 
X 
X X 
X 
X X 
Hem, chemq 
X X 
X 
X X 
X 
X 
X X 
X 
X X 
X 
X X 
Ferriting 
X  
<-------------------------------------------     at onset of CRS, and daily until values are back to baseline/event is resolved -------------------------> 
CSF analysism, p 
 
 
Collect if grade ≥3 neurologic event  or seizure grade ≤ 2p 
C-reactive protein 
 
X  
 
 
 
 
 
 
 
 
 X X X  X  
 
 
 
 
 
 
 
 
 X X  X  
 
 
 
 
 
 
 
 X X  
 X  
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology X 
Urinalysis  
X X 
X 
X 
X 
X 
X 
X 
X 
Ig:  IgA, IgM, IgG 
X X 
Anti-AMG 562-Ab 
Xh 
X 
Page 2 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 84 of 158 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Screening and Treatment Cycle 1 With 24 hour Step-up dosing Intervals 
 
SCR 
 
Treatment Period (Cycle 1) 
  
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
 
8a 
9 
10 
11 
15a  
16 
17 
18 
20 
22a  
23 
24 
25 
Hours 
 
Predose 
 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
BIOMARKER ASSESSMENTS 
Page 3 of 4 
Footnotes defined on last page of this table 
 
ed 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 85 of 158 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Screening and Treatment Cycle 1 With 24 hour Step-up dosing Intervals 
 
SCR 
 
Treatment Period (Cycle 1) 
Cycle Day 
-21 to -1 
 
1b 
2 
3 
4 
 
8a 
9 
10 
11 
15a  
16 
17 
18 
20 
22a  
23 
24 
25 
Hours 
 
Predose 
 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
 
 
Predose 
Relative to start of infusion 
 
 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
PK ASSESSMENTS 
AMG 562 PKn, r  
  
X*   X* 
  
X 
X     X X X 
X*   X 
X*   X 
X*   X 
X 
X 
X X 
X 
DISEASE ASSESSMENTS 
BM aspirate/ 
biopsyj 
X 
 
<------------------      Optional at week 5 (C2D1)      ----------------> 
COO/FISH 
Lymph node 
biopsyk 
X 
 
 
LN biopsy for 
DLBCL following 
prior CD19-
targeted 
treatment failures 
X 
 
<------------------      Optional at relapse, post AMG 562 treatment, in responders      ----------------> 
 
RADIOGRAPHIC ASSESSMENTS 
PET/CTo 
x 
 
 
Page 4 of 4 
Ab = antibody, AE = adverse event, BM = bone marrow, chem = chemistry; con meds = concomitant medications, CR = complete response, CRS = Cytokine Release 
Syndrome, ctDNA = circulating tumor DNA, CT = computed tomography, demo = demographics, DRE = disease-related event, ECG = electrocardiogram, 
ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, Expl = exploratory,  hem = hematology, ICF = informed consent form, Ig = immunoglobulins, 
LN= lymph node, LTFU = long-term follow-up, med hist = medical history, MRD = minimal residual disease, MRI = magnetic resonance imaging, neuro = neurological, 
NGS = next generation sequencing, ox = oximetry, PB = peripheral blood, PD = progressive disease, periph = peripheral, PET = positron emission tomography, 
PG = pharmacogenomics, PK = pharmacokinetics, PR = partial response, SAE = serious adverse event, SCR = screening, SFU = safety follow-up,  
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 86 of 158 
CONFIDENTIAL 
 
 
a The Dose Level Review Team (DLRT) may recommend to change timing of D8/D15/D22 within a window of ± 1 day.  In this case, timing of the following visits would 
be adjusted accordingly.  The DLRT may also recomend to move the dose step to D5.  In this case, the following infusions would be administered on D12 and D19 
(and not on D15 and D22), and the following cycle days would move in accordingly.   
b In case of step-dosing, the subsequent treatments will be at weekly intervals after the target dose is administered.  
c See Section 6.2.1.1 for details on hospitalization requirements  
d ECGs and vital signs should be performed prior to any invasive procedures.  ECGs are only required in treatment cycle 1 and 2.  In case of intra-subject dose 
escalation: conduct ECGs as in cycle 1 during the first cycle after dose escalation.  
e For premedication details see Section 6.3. 
f Serum pregnancy test required at screening.  For later time points, urine pregnancy test is allowed.  In case of a positive result, serum pregnancy test should be 
repeated.  Pregnancy tests will be performed for all females unless surgically sterile or > 2 years postmenopausal. 
g Ferritin assessment to be performed at onset of CRS, and daily until values are back to baseline/event is resolved 
h Predose anti-AMG 562 antibody sample in every 2nd cycle after cycle 1 (C1D1, C1D15, C3D1, C5D1, ..).  
o PET/CT will be performed at screening, week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or beyond. Clinical tumor assessments 
will be performed at screening, week 5, week 15, week 25 and at end of treatment if end of treatment is at week 35 or beyond. Every attempt should be made to 
complete PET and CT within 3 days of each other, particularly during treatment. If subject discontinues study treatment for any reason, including toxicity or clinical 
evidence of disease progression, PET/CT should be conducted 14 (+ 3) days following the last dose of AMG 562.  
p In case of seizure of any grade perform brain MRI and cerebro spinal fluid (CSF) analysis, if there are no contraindications. 
q As indicated in Section 7.3.10, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests. Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer 
r PK samples should be collected at the exact nominal time point specified; all times are relative to the start of infusion. The 
hour sample is the same as the end of 
infusion and should be collected as close as possible to the end of infusion of AMG 562. For step dosing, intermediate doses will only require PK collection at predose 
and
hour (EOI). PK samples should be collected at the following time points after administration of the first target dose: predose, 
(EOI), 6, 12, 24, 48, 72 hr 
relative to the start of infusion at the target dose. 
s For DLBCL subjects who failed prior CD-19 therapy;  a LN biopsy at screening is  (mandatory) to test for CD19 expression unless no lesion is accessible or the 
investigator deems the risk of the biopsy too high. For patients responding to AMG 562 treatment an optional LN biopsy at relapse, post AMG 562 treatment in 
responders may be collected. 
t Limited neurological examinations to be performed at these timepoints when hospitalized or in clinic as described in Section 7.3.9.2. Writing test to be performed on 
mornings and evenings on C1D1, C1D2 and after step-up dose treatment initiation 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 87 of 158 
CONFIDENTIAL 
 
 
Table 10.  Schedule of Assessments for Treatment Cycle 2 
  
Treatment Period (Cycle 2) 
Cycle Day 
1b 
2 
3 
4 
8a 
 
 
9 
10 
11 
15a 
 
 
16 
17 
18 
22a 
 
 
23 
24 
25 
Hours 
Predose 
 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
0 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
GENERAL AND SAFETY ASSESSMENTS 
Con meds 
X  
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
SAE review 
X  
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
AE/DRE review 
X X 
<-------------------------------------------------------------------      continually throughout treatment      -------------------------------------------------------------------> 
Hospitalizationc 
 
 
--------------> 
 
 
 
 
 
 
 
 
 
--------------> 
 
 
 
 
 
 
 
 
 ----------->  
 
 
 
 
 
 
 
 
----------->  
 
 
 
 
 
 
 
Physical exam 
X 
X X 
X 
X 
X 
X 
X 
 
 
Neurological exam X  
<-----------------------------------------------   to be performed prior to discharge from clinic from cycle 2 and beyond   ----------------------------------------> 
ECOG 
X 
Weight 
X 
Vitals, pulse oxd 
X 
X 
X X X X X X X X X X X X 
X X X X X X X X X X 
X X 
X X X X X X X X X 
X X 
X X X X X X X X X 
X 
ECG triplicated  
X 
X 
X 
X 
X 
X 
X 
X 
INVESTIGATIONAL PRODUCT DOSING 
AMG 562 IVb 
X 
X 
X 
X 
Premedicatione 
X 
X 
X 
X 
Page 1 of 3 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 88 of 158 
CONFIDENTIAL 
 
 
Table 10.  Schedule of Assessments for Treatment Cycle 2 
  
Treatment Period (Cycle 2)  
Cycle Day 
1b 
2 
3 
4 
8a 
 
 
9 
10 
11 
15a 
 
 
16 
17 
18 
22a 
 
 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
7
2 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
LABORATORY ASSESSMENTS 
Pregnancy testf 
X 
Coagulationp 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
Hem, chemp 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
Ferriting 
 
<-------------------------------------------     at onset of CRS, and daily until values are back to baseline/event is resolved -------------------------> 
CSF analysis l, o 
 
Collect if grade ≥3 neurologic event  or seizure grade ≤ 2o 
Urinalysis  
X 
X 
X 
X 
Ig:  IgA, IgM, IgG 
X 
BIOMARKER ASSESSMENTS 
Page 2 of 3 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 89 of 158 
CONFIDENTIAL 
 
 
Table 10.  Schedule of Assessments for Treatment Cycle 2 
  
Treatment Period (Cycle 2)  
Cycle Day 
1b 
2 
3 
4 
8a 
 
 
9 
10 
11 
15a 
 
 
16 
17 
18 
22a 
 
 
23 
24 
25 
Hours 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
0 
 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
BIOMARKER ASSESSMENTS (Continued) 
PK ASSESSMENTS 
AMG 562 PKm, r 
X*   X* 
   
 
 
 
 
 
  
 
 
 
X* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X* 
 
X  
 
 
 
 
 
 
 
 
 
X* 
 
X  
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENTS and RADIOGRAPHIC ASSESSMENTS 
PET/CTq 
X 
 
x 
BM aspirate/ 
biopsyi 
 
<------------------      Optional at week 5 (C2D1)      ----------------> 
Page 3 of 3 
Ab = antibody, AE = adverse event, BM = bone marrow, chem = chemistry; con meds = concomitant medications, CR = complete response, CRS = Cytokine Release 
Syndrome, ctDNA = circulating tumor DNA, CT = computed tomography, demo = demographics, DRE = disease-related event, ECG = electrocardiogram, 
ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, Expl = exploratory, hem = hematology, Ig = immunoglobulins LTFU =  long-term follow-up, 
MRD = minimal residual disease, MRI = magnetic resonance imaging,  NGS = next generation frequencing, ox = oximetry, PB = peripheral blood, PD = progressive 
disease, periph = peripheral, PET = positron emission tomography, PG = pharmacogenomic, PK = pharmacokinetics, PR = partial response, SAE = serious adverse 
event, SFU = safety follow-up 
a The Dose Level Review Team may decide to change timing of D8/D15/D22 within a window of ± 1 day.  In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of step-dosing, the subsequent treatments will be at weekly intervals after the target dose is administered. 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 90 of 158 
CONFIDENTIAL 
 
 
c See Section 6.2.1.1 for details on hospitalization requirements 
d ECGs and vital signs should be performed prior to any invasive procedures. ECGs are only required in treatment cycle 1 and 2.  In case of intra-subject dose 
escalation:  conduct ECGs as in cycle 1 during the first cycle after dose escalation. Vital Signs at hour 4 and beyond after each IP administration from cycle 2 will be 
performed if patient is hospitalized. 
e For premedication details see Section 6.3. 
f Serum pregnancy test required at screening.  For later time points, urine pregnancy test is allowed, in case of a positive result, serum pregnancy test should be 
repeated.  Pregnancy tests will be performed for all females unless surgically sterile or > 2 years postmenopausal. 
g Ferritin assessment to be performed at onset of CRS, and daily until values are back to baseline/event is resolved. 
 
o In case of seizure of any grade perform brain MRI and cerebro spinal fluid (CSF) analysis, if there are no contraindications. 
p As indicated in Section 7.3.10, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests. Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer 
q PET/CT will be performed at screening, week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or beyond. Clinical tumor assessments 
will be performed at screening, week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or beyond. Every attempt should be made to 
complete PET and CT within 3 days of each other, particularly during treatment. If subject discontinues study treatment for any reason, including toxicity or clinical 
evidence of disease progression, PET/CT should be conducted 14 (+ 3) days following the last dose of AMG 562.  
r PK samples should be collected at the exact nominal time point specified; all times are relative to the start of infusion. The 
 hour sample is the same as the end of 
infusion and should be collected as close as possible to the end of infusion of AMG 562. If unable to collect a PK sample at the specified nominal time point, then 
collect the sample as close as possible and record the actual collection time. The exact date and time of IP administration and PK sample collection should be 
documented. Additional PK samples may be collected per the discretion of the PI as clinically indicated. 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 91 of 158 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Treatment Cycle 3 and Following to End of Study 
 
Treatment Period (Cycle 3 and following)  
EoT 
SFU 
LTFUc 
Cycle Day 
1b 
2 
3 
4 
8a  
9 
10 
11 
15a  
16 
17 
18 
22a 
23 
24 
25 
    
Up to  
2 yrs 
after 1st 
IP dose  
Hours 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
  
  
  
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
0 
2 
4 
6 
8 
12 
24 
48 
0 
4 
6 
8 
12 
24 
48 
 
0 
4 
6 
8 
12 
24 
48 
  
  
  
  
  
GENERAL AND SAFETY ASSESSMENTS 
 
 
Hospitalizationd 
 
--------------> 
-------> 
---> 
----> 
Con meds 
X 
 
<---------------------------------------------------------------      continually throughout treatment      ----------------------------------------------------------------> 
Subsequent 
anti-lymphoma 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SAE review 
X 
 
<--------------------------------------------------------------      continually throughout treatment      ----------------------------------------------------------------> 
Xe 
AE/DRE review 
X X 
<------------------------------------------------------------      continually throughout treatment      --------------------------------------------------------------> 
Physical exam 
X 
X X 
Neurological exam X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
ECOG 
X 
X X 
Weight 
X 
X X 
Vitals, pulse oxf 
X 
X 
X 
X X X X X X X X X X 
X X 
X X X X X X 
X 
X X X 
X 
X 
X 
X 
X X X X X 
X X 
ECG triplicatef  
X X 
Page 1 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 92 of 158 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Treatment Cycle 3 and Following to End of Study 
 
Treatment Period (Cycle 3 and following) 
  
EoT 
SFU 
LTFUc 
Cycle Day 
1b 
2 
3 
4 
8a  
9 
10 
11 
15a  
16 
17 
18 
22a 
23 
24 
25 
    
Up to  
2 yrs 
after 1st 
IP dose  
Hours 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
  
  
  
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
0 
2 
4 
6 
8 
12 
24 
48 
0 
4 
6 
8 
12 
24 
48 
 
0 
4 
6 
8 
12 
24 
48 
  
  
  
  
  
INVESTIGATIONAL PRODUCT DOSING 
AMG 562 IVb  
X 
X 
X 
X 
Premedicationg 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Pregnancy testh 
X 
X 
Coagulations 
X 
X 
X 
X 
X X 
Hem, chems 
X 
X 
X 
X 
X X 
Ferritini 
 
<-------------------------------------------     at onset of CRS, and daily until values are back to baseline/event is resolved -------------------------> 
CSF analysis o, r 
 
Collect if grade ≥3 neurologic event  or seizure grade ≤ 2r 
 
Urinalysis  
X 
X 
X X 
Ig:  IgA, IgM, IgG 
X 
X 
Anti-AMG 562-Ab 
Xj 
X 
Page 2 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 93 of 158 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Treatment Cycle 3 and Following to End of Study 
 
Treatment Period (Cycle 3 and following) 
  
EoT 
SFU 
LTFUc 
Cycle Day 
1b 
2 
3 
4 
8a  
9 
10 
11 
15a  
16 
17 
18 
22a 
23 
24 
25 
    
Up to  
2 yrs 
after 1st 
IP dose  
Hours 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
  
  
  
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
0 
2 
4 
6 
8 
12 
24 
48 
0 
4 
6 
8 
12 
24 
48 
 
0 
4 
6 
8 
12 
24 
48 
  
  
  
  
  
BIOMARKER ASSESSMENTS 
Page 3 of 4 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 94 of 158 
CONFIDENTIAL 
 
 
Table 11.  Schedule of Assessments for Treatment Cycle 3 and Following to End of Study 
 
Treatment Period (Cycle 3 and following) 
  
EoT 
SFU 
LTFUc 
Cycle Day 
1b 
2 
3 
4 
8a  
9 
10 
11 
15a  
16 
17 
18 
22a 
23 
24 
25 
    
Up to  
2 yrs 
after 1st 
IP dose  
Hours 
Predose 
Relative to start of infusion 
 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
Predose 
Relative to start of infusion 
  
  
  
0 
 
2 
3 
4 
6 
8 
12 
16 
20 
24 
48 
72 
0 
2 
4 
6 
8 
12 
24 
48 
0 
4 
6 
8 
12 
24 
48 
 
0 
4 
6 
8 
12 
24 
48 
  
  
  
  
  
BIOMARKER ASSESSMENTS (Continued) 
PK ASSESSMENTS 
AMG 562 PKp, t 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 X X 
  
DISEASE ASSESSMENTS and RADIOGRAPHIC ASSESSMENTS 
PET/CTq 
 
 
 
X  
 
BM aspirate/ 
biopsyl 
 
<------------------      at EOT to confirm CRl      ----------------> 
Page 4 of 4 
Ab = antibody, AE = adverse event, BM = bone marrow, chem = chemistry; con meds = concomitant medications, CR = complete response, CRS = Cytokine Release 
Syndrome, ctDNA = circulating tumor DNA, CT = computed tomography, demo = demographics, DRE = disease-related event, ECG = electrocardiogram, 
ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, Expl = exploratory, hem = hematology, Ig = immunoglobulins, LTFU =  long-term follow-up, 
MRD = minimal residual disease, MRI = magnetic resonance imaging, neuro = neurological, NGS = next generation sequencing, ox = oximetry, PB = peripheral blood, 
PD = progressive disease, periph = peripheral, PK = pharmacokinetics, PR = partial response, SAE = serious adverse event, SFU = safety follow-up,  
a The Dose Level Review Team may decide to change timing of D8/D15/D22 within a window of ± 1 day.  In this case, timing of the following visits would be adjusted 
accordingly.   
b In case of step-dosing, the subsequent treatments will be at weekly intervals after the target dose is administered. 
c LTFU via on-site visit every 6 weeks until progression of disease.  Afterwards, LTFU frequency will be 3 months for collecting information on survival and subsequent 
anti-lymphoma treatment only, without the requirement for on-site visitsThe procedures or assessments as mentioned in section 7.2.4  are applicable only if on-site 
visits apply. 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 95 of 158 
CONFIDENTIAL 
 
 
d See Section 6.2.1.1 for details on hospitalization requirements. 
e See Section 9.2.2.1 and Section 9.2.2.3 for SAE reporting requirements during LTFU. 
f ECGs and vitals should be performed prior to any invasive procedures.  ECGs are only required in treatment cycle 1 and 2.  In case of intra-subject dose escalation:  
conduct ECGs as in cycle 1 during the first cycle after dose escalation.  Starting with cycle 3, time points for vital sign measurement > 4 h after each infusions apply if 
the subject is still hospitalized at the time. 
g For premedication details see Section 6.3  
h Serum pregnancy test required at screening.  For later time points, urine pregnancy test is allowed.  In case of a positive result, serum pregnancy test should be 
repeated.  Pregnancy tests will be performed for all females unless surgically sterile or > 2 years postmenopausal. 
i Ferritin assessment to be performed at onset of CRS, and daily until values are back to baseline/event is resolved. 
j Predose anti-AMG 562 antibody sample in every 2nd cycle after cycle 1 (C1D1, C1D15 C3D1, C5D1, ..). 
q PET/CT will be performed at screening, week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or beyond. Clinical tumor assessments 
will be performed at screening, week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or beyond. Every attempt should be made to 
complete PET and CT within 3 days of each other, particularly during treatment. If subject discontinues study treatment for any reason, including toxicity or clinical 
evidence of disease progression, PET/CT should be conducted 14 (+ 3) days following the last dose of AMG 562. 
r  In case of seizure of any grade perform brain MRI and cerebro spinal fluid (CSF) analysis, if there are no contraindications. 
s As indicated in Section 7.3.10, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests. Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer 
t PK samples should be collected at the exact nominal time point specified; all times are relative to the start of infusion. The 
 hour sample is the same as the end of 
infusion and should be collected as close as possible to the end of infusion of AMG 562. If unable to collect a PK sample at the specified nominal time point, then 
collect the sample as close as possible and record the actual collection time. The exact date and time of IP administration and PK sample collection should be 
documented. Additional PK samples may be collected per the discretion of the PI as clinically indicated.  
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 96 of 158 
CONFIDENTIAL 
 
 
Table 12.  Dosing Schedule with 48, 72, and 96 hour Step-up dosing Intervals 
 
Treatment Period  
Cycle Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
No 
Intermediate 
doses 
X 
 
T2 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
X 
 
 
T2 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
One 
Intermediate 
dose 
X 
 
X1 
 
T2 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
X 
 
 
 
X1 
 
 
 
 T2 
 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
Two 
Intermediate 
doses 
X 
 
 
X1 
 
 
X1 
 
 
T2 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
Three 
Intermediate 
doses 
X 
 
X1 
 
X1 
 
X1 
 
T2 
 
 
 
 
 
T2 
 
 
 
 
 
 
T2 
 
 
 
 
 
 
X 
 
 
 
X1 
 
 
 
X1 
 
 
 
X1 
 
 
 
T2 
 
 
 
 
T2 
 
 
 
 
 
 
1 Intermediate dose 
2 Target dose 
 
 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 97 of 158 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
A signed and dated IRB/IEC approved informed consent form (ICF) must be obtained 
prior to performing any study specific procedures, including discontinuing standard 
therapy for observing study specific washout periods.  
Subjects will be seen in the clinic for study evaluations.  When ECGs, vital signs, and 
invasive procedures like blood or BM sampling occur on the same visit, ECGs and vital 
signs should be collected prior to performing any invasive procedures.  
Blood samples for biomarker and PK assessments should be drawn from a peripheral 
vein and not from a central venous catheter.  The study specific lab manual will provide 
additional detail on lab sampling and handling requirements.  
Study procedures should be performed and samples obtained at the time points 
stipulated in the Schedules of Assessments (Table 8 through Table 11).  
Acceptable deviation windows for study procedures are listed below:  
• 
ECGs, 
, safety labs, vital signs (incl. pulse oximetry):   
− 
± 15 minute window if collected within the first 24 hours (excluding the 24 hour 
sample) after the start of an infusion 
− 
± 1 hour window if collected 24 or 48 hours after the start of an infusion    
• 
PK blood draws see Appendix I. 
Starting with Day 4 post infusion, assessments should be performed on the indicated 
study day prior to infusion.   
Acceptable deviation windows for study visits are listed below: 
• 
Visits during treatment-free interval, if applicable:  ± 1 day 
• 
SFU:  + 7 days 
• 
LTFU: ± 7 days for on-site visits, ± 2 weeks for remote survival follow-up 
Furthermore, start of a treatment can be delayed for administrative/logistical reasons for 
up to 7 days to allow for appropriate scheduling after discussion with and final approval 
by sponsor.  
The DLRT may recommend a ± 1 day window for infusions following the day 1 infusion. 
The DLRT may also recommend to reduce the number of infusions for a dose cohort.  If 
no infusion was administered on Day 8, 15, and/or 22, all assessments that occur  
> 1 time on the respective day only have to be performed once, at any time during that 
day.  Also, the following assessments scheduled for 24 hours, 48 hours, and 3 days  
post infusion would not be mandatory in that case:  physical examination, vital signs, 
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ECG, hematology, chemistry, coagulation, urinalysis, PK and the following 
 
   
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the eCRFs. Subsequent study visits should resume on the original 
schedule. Missed assessments at prior visits should not be duplicated at subsequent 
visits. Every effort should be taken to collect all biomarker and PK samples as described 
in the schedule of assessments. However, if sample processing/shipment on a 
weekend/holiday is not logistically feasible for a site, this needs to be documented and 
will not be considered a deviation from the protocol.  
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.1 
Screening  
After written consent has been obtained, subjects will be screened in order to assess 
eligibility for study participation. All screening procedures must be performed within 
21 days prior to start of investigational product administration, unless otherwise noted.  
The ICF may be signed earlier than 21 days prior to start of investigational product in 
case of washout times that have to be observed to meet eligibility criteria.  
Subjects who meet the inclusion and exclusion criteria will be eligible to be enrolled in 
the study. If a subject has not met all eligibility criteria at the end of the 21-day window, 
the subject will be registered as a screen failure. Subjects who screen fail may be 
eligible for re-screening at the investigator’s discretion after consultation with Amgen 
(see also below for details on re-screening). 
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation during each 21-day screening period before the subject is considered a 
screen failure. If laboratory assessments are repeated during the screening period, the 
result of the last sample taken prior to start of treatment with AMG 562 will be taken into 
account for determination of subject eligibility.  
The following procedures are to be completed during the screening period at the time 
points designated in the Schedules of Assessments (Table 5 through Table 8).  
Assessments that were performed as standard of care prior to signature of informed 
consent, but within 21 days prior to start of treatment with AMG 562 can be used as 
screening assessments and do not need to be repeated to confirm subject eligibility. 
• 
confirmation that the ICF has been signed  
• 
demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness  
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• 
medical history (including surgical history) 
• 
physical examination (including neurological exam) 
• 
ECOG performance status 
• 
height and weight 
• 
vital signs (ie, blood pressure, heart rate, respiratory rate, temperature) 
• 
pulse oximetry 
• 
ECG triplicate measurement  
• 
MRI of the brain 
• 
Bone marrow biopsy. See Section 7.3.12.4 
• 
Lymph node biopsy. Exceptions can be made based on site accessibility upon 
consultation with the Amgen Medical Monitor 
• 
laboratory assessments: hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test (females only and not required if surgically sterile or ≥ 2 years 
postmenopausal), hepatitis serology, immunoglobulins  
• 
• 
disease assessments:  
− 
for all subjects: Clinical tumor and radiographic assessment (PET/CT) at 
screening and re[peated at week 5, week 15, week 25, and at end of treatment if 
end of treatment is at week 35 or beyond 
• 
serious adverse event reporting 
• 
documentation of concomitant medication  
Re-Screening: 
Subjects may be re-screened up to 2 times at the discretion of the investigator, after 
consultation with Amgen.  The subject must be re-consented if a re-screening attempt 
occurs more than 30 days after the original signing of the ICF. 
Re-screened subjects must be documented as screen failed in the subject’s medical 
record and subsequently documented as re-screened.  Subjects will retain the same 
subject identification number assigned at the time of initial screening.  Once the subject 
is recorded as re-screened, a new 21-day screening window will begin.  The following 
assessments do not have to be repeated during re-screening, if they were performed as 
standard of care or during the initial screening attempt within the time frames specified 
below: 
• 
Hepatitis serology does not need to be repeated if it was performed within 6 weeks 
prior to start of treatment with AMG 562. 
• 
Imaging assessments do not need to be repeated if they were performed within 
4 weeks prior to start of treatment with AMG 562. 
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• 
Any other assessments do not need to be repeated if they were performed within 
21 days prior to start of treatment with AMG 562. 
7.2.2 
Treatment 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 5 through Table 8).   
Subjects will be hospitalized as outlined in Section 6.2.1.1. 
Treatment begins on Day 1 when the first investigational product infusion is administered 
to a subject. 
Prior to each start of investigational product infusion all protocol-required predose 
assessments including premedication have to be performed. 
Results of any predose laboratory tests will not have to be available before starting the 
infusion with AMG 562. Laboratory assessments that were done within 24 hours prior to 
infusion start do not need to be repeated prior to infusion. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedules of Assessments (Table 5 through Table 8): 
• 
hospitalization 
• 
physical examination  
• 
ECOG performance status 
• 
weight 
• 
vital signs (ie, blood pressure, heart rate, respiratory rate, temperature) 
• 
pulse oximetry 
• 
ECG triplicate measurement 
• 
laboratory assessments:  hematology, chemistry, coagulation, urinalysis, urine/serum 
pregnancy test (females only and not required if surgically sterile or ≥ 2 years 
postmenopausal), ferritin, immunoglobulins, anti-AMG 562 antibody sample 
collection 
• 
AMG 562 PK sample collection  
• 
• 
serious adverse event reporting 
• 
disease assessments:  
− 
for all subjects: Clinical tumor and radiographic assessment (PET/CT) at week 5, 
week 15, week 25, and at end of treatment if end of treatment is at week 35 or 
beyond 
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• 
adverse event reporting 
• 
disease-related event reporting 
• 
documentation of concomitant medication 
• 
administration of protocol-required therapies  
• 
For subjects to whom intra-subject dose escalation applies: 
• 
Subjects should be hospitalized  as outlined in schedule of assessment section 7.1.  
Hospitalization may also be required at other times (eg, intra-subject dose 
escalation). 
• 
All other assessments should be performed as per the schedule of assessments 
applicable to the actual cycle 
In case of CRS:  
• 
Ferritin should be repeated until values are back to baseline or the event is resolved 
7.2.3 
Safety Follow-up Visit(s)/End of Study Visit  
The SFU visit should occur approximately 30 (+7) days after the last dose of AMG 562.  
Every effort should be made to conduct this visit for all subjects enrolled into the study, 
including subjects who withdraw from treatment early.  The following procedures will be 
completed during the SFU visit as designated in the Schedules of Assessments 
(Table 8). 
• 
physical examination (including neurological exam) 
• 
ECOG performance status 
• 
weight 
• 
vital signs (ie, blood pressure, heart rate, respiratory rate, temperature) 
• 
pulse oximetry 
• 
ECG triplicate measurement  
• 
laboratory assessments:  hematology, chemistry, coagulation, urinalysis, urine/serum 
pregnancy test (females only and not required if surgically sterile or ≥ 2 years 
postmenopausal), anti-AMG 562-antibody sample collection 
• 
AMG 562 PK sample collection 
• 
disease assessments  
• 
• 
serious adverse event reporting 
• 
adverse event reporting 
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• 
disease-related event reporting 
• 
documentation of concomitant medications 
perform assessments driven by observation of CR/progression/relapse, or CRS as listed 
in Section 7.2.2.   
7.2.4 
Long-term Follow-up 
Following the SFU visit, there will be a LTFU period for clinical evaluation of disease 
status and survival.  Subjects will be followed via on-site visit every 6 weeks (± 3 days) 
for assessments of disease status and documentation of anti-lymphoma treatment until 
progression of disease.  From this time point onwards subjects will be followed every 
3 months (± 2 weeks) for survival and anti- lymphoma treatment (on-site visits are not 
required, if needed also interrogation of public databases is acceptable).  Subjects will 
be followed for a maximum of 2 years from the first dose of AMG 562, or until subject 
death, whichever occurs first.  
Subjects will allow Amgen continued access to medical records so that information 
related to subjects’ health condition, including disease status and survival, may be 
obtained. 
The following procedures will be performed during the LTFU as designated in the 
Schedules of Assessments (Table 8) as long as on-site visits apply. 
• 
laboratory assessments: immunoglobulins 
• 
disease assessments 
• 
serious adverse event reporting (see Sections 9.2.2.2 and 9.2.2.3 for reporting 
requirements during the LTFU period) 
perform assessments driven by observation of CR/progression/relapse, or CRS as listed 
in Section 7.2.2. 
7.2.5 
End of Study 
End of study is defined as the date of the final study visit (eg, LTFU) when assessments 
and/or procedures are performed. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures listed in 
Section 7.2.  
7.3.1 
Informed Consent 
A signed ICF must be obtained from each subject prior to any study-mandated 
procedures.  All subjects who are enrolled and receive investigational product treatment 
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should be reconsented with any updated versions of IRB/IEC approved informed 
consents during study participation as applicable and per institutional guidelines. 
7.3.2 
Demographic Data 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact of the protocol-required 
therapy on biomarker variability and PK. 
7.3.3 
Medical History  
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject’s concurrent medical conditions.  
Relevant medical history, including renal/urinary history (eg, subjects’ reports of 
subjective urine output trend),  antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, polyneuropathy, and infection (resolved and 
ongoing) will be collected.  The current toxicity grade will be collected for each condition 
that has not resolved.  
In addition to the medical history noted above, all history related to the subject’s  
diagnosis of B-NHL (eg, date of initial diagnosis, international prognostic index and 
additional risk factors at diagnosis, stage at diagnosis, COO at any timepoint ifavailable 
[immunohistochemistry pattern, GEP/other], BCL-2 [Fluorescent in-situ.  
hybridization [FISH]: translocation, immunohistochemistry expression levels], c-myc.  
[FISH: translocation, immunohistochemistry expression levels]) will be recorded 
Lymphoma history must date back to the initial diagnosis and any response duration 
must be recorded.   
All findings will be recorded on the medical history eCRF. 
7.3.4 
Prior Therapy 
For prior therapies being taken for lymphoma the therapy line, name of therapeutic 
agent, regimen, type of therapy, start date and stop date will be collected, as well as 
best responses.  
For radiotherapy the type of therapy, dose, site, start date and stop date will be 
collected. 
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For prior autologous HSCT, hematopoietic stem cell mobilization source, conditioning 
regimen, number of cells infused (CD34+/kg) on day 0, date of neutrophil engraftment 
(first day that ANC > 0.5 x 10^9/L for 3 consecutive days), date of platelet engraftment 
(first day that platelets > 20 x 10^9/L), and complications need to be collected.  
7.3.5 
Concomitant Medication 
Concomitant therapies are to be collected from informed consent until the SFU visit.  
After the SFU visit until EOS only anti- lymphoma therapy is to be recorded.   
Collect therapy name, indication, dose, unit, frequency, route, start date, and stop date. 
7.3.6 
Clinical Evaluation 
7.3.6.1 
Physical Examination 
A complete physical examination as per standard of care will be performed by the 
investigator or designee at screening and at the time points specified in the Schedules of 
Assessments (Table 5 through Table 8).  The physical examination will include general 
appearance, including examination of the skin, spleen, and respiratory, cardiovascular, 
musculoskeletal, and neurological systems.  The individual performing the physical 
examination will characterize their findings as either normal or abnormal.  Abnormal 
physical examination findings found during screening should be reported on the Medical 
History eCRF.  Abnormal physical examination findings found after the subject has 
received investigational product will be reported on the Event eCRF.  
7.3.6.2 
ECOG Performance Status 
The performance status will be assessed at the time points indicated in the Schedules of 
Assessments (Table 5 through Table 8) using the ECOG performance status scale (see 
Appendix F). 
7.3.6.3 
Height Measurements 
Height (in centimeters) will be measured without shoes at screening. 
7.3.6.4 
Weight Measures 
Weight (in kilogram) without shoes will be measured at screening and at Safety-Follow 
Up. 
7.3.7 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Record all measurements on the vital signs 
eCRF. 
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Subject must be in a supine position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted.  If the subject is unable to be in the 
supine position, the subject should be in the most recumbent position possible.  The 
position selected for a subject should be the same throughout the study and 
documented on the vital signs eCRF.   
The temperature location selected for a subject should be the same throughout the study 
and documented on the vital signs eCRF.  If abnormalities are found and they are 
considered an adverse event, record on the Event eCRF. 
7.3.8 
Pulse Oximetry 
Oxygen saturation will be measured using a standard pulse oximeter.  The subject must 
be in a rested and calm state for at least 5 minutes before pulse oximetry assessments 
are completed. 
7.3.9 
Neurological Examination 
7.3.9.1 
Extended Neurological Examination 
An extended neurological examination will be performed during screening, on day 1, 
day 8, day 15 and day 22 of the first cycle, on the first day of each cycle, and at the EOS 
as well as in case of grade ≥ 2 neurotoxicity event daily until resolution or grade  
≤ 1. Subjects will be specifically queried for neurological symptoms observed in the 
interval since the last extended neurological examination. Abnormalities of the following 
should be recorded: level of consciousness, orientation, vision, cranial nerves and brain 
stem functions, pyramidal and extra pyramidal motor system, reflexes, muscle tone and 
trophic findings, coordination, sensory system, neuropsychological findings (eg, speech, 
cognition and emotion). Neurological examinations will include a writing test to detect 
cerebral signs. For the writing tests, patients will be asked to write down the current date 
and time as well as an arbitrary sentence (this should be the same sentence throughout 
the study). Additional neurological examinations can be performed at the discretion of 
the Investigator. Neurologic examination findings should be recorded on the appropriate 
eCRF. 
7.3.9.2 
Limited Neurological Examination 
 A limited neurological examination will be performed at time points indicated in the 
schedule of assessment when the patient is in clinic. The limited neurological 
examinations will assess impairment of orientation to time and place, occurrence of 
tremors as well as writing test in Section 7.3.9.1.  
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Patients should be instructed to perform writing tests daily and to bring the writing tests 
to the clinic during study visit days. 
7.3.10 
Electrocardiogram (ECG) Performed in Triplicate 
The subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. 
ECGs should be performed in a standardized method, as triplicate single-reads, run 
consecutively (ie, approximately 30 seconds apart but not greater than 3 minutes apart.), 
and prior to blood draws or other invasive procedures.  Each ECG must include the 
following measurements: QRS, QT, QTc, RR, and PR intervals.  
The investigator or designated site physician will review all ECGs. Once signed, the 
original ECG tracing will be retained with the subject’s source documents. At the request 
of the sponsor, a copy of the original ECG will be made available to Amgen.  Standard 
ECG machines should be used for all study-related ECG requirements. 
7.3.11 
Clinical Laboratory Tests 
Table 13 outlines the specific analytes that will be assessed during the study at time 
points outlined in the Schedules of Assessments (Table 8 through Table 11).  All 
screening and on-study samples will be collected, processed and sent to the investigator 
local laboratory or central laboratory as applicable (see Table 13) to be analyzed by 
standard laboratory procedures. 
The date and exact time of sample collection will be recorded in the source documents 
at the site (do not use the time that the samples were frozen or any other time point). 
The test results are to be recorded on the eCRFs. Missed test(s) that are not done must 
be reported as such on the eCRFs. 
Refer to the laboratory manual and/or Amgen-provided training materials for detailed 
collection, processing, and shipping instructions. 
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Table 13.  List of Analytes 
Local Laboratory 
 
Central 
Laboratory 
Chemistry 
Hematology 
Coagulation Urinalysis 
Other  
Neurological 
Safety  
 
Sodium 
Potassium 
Chloride 
Bicarbonate 
(HCO3) or 
Total CO2 
Total protein  
Albumin  
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Creatininea 
clearance 
Uric acid 
Total 
bilirubin 
Direct 
bilirubin 
Alkaline 
phosphatase 
ALT (SGPT) 
AST (SGOT) 
Amylase 
Lipase 
LDH 
Ferritin 
CRP 
Haptoglobin 
ANC 
Hemoglobin 
Hematocrit 
MCH 
MCHC 
MCV 
Platelets 
RBC 
WBC  
Differential 
• Total 
neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
PT or INR 
PTT or 
aPTT 
Fibrinogen 
D-Dimer 
Specific 
gravity 
pH 
Blood 
Protein 
Ketones 
Glucose 
Bilirubin 
Leucocytes 
esterase 
(WBC) 
Microscopic 
exam (only 
needed for 
positive 
dipstick and 
should 
include the 
following): 
Epithelial, 
Bacteria, 
Casts, 
Crystal, 
RBC, WBC 
Serology 
(HBsAg, 
HBcAb, 
HCV Ab, 
HIV)  
Urine or  
serum 
pregnancy 
testb 
Immuno-
globulins  
(IgA, IgM, 
 IgG) 
BM biopsy  
CSF albumin 
CSF red blood 
cells 
CSF white 
blood cells 
CSF flow 
cytometry 
CSF glucose 
CSF protein 
CSF 
neutrophils 
percentage 
CSF 
lymphocytes 
percentage 
CSF 
eosinophils 
percentage 
CSF basophils 
percentage 
CSF 
monocytes 
percentage 
Additional CSF 
viral studies as 
clinically 
indicated 
Anti-AMG 562 
-Antibodies 
PK sampling 
BM and PB 
flow 
cytometry 
 
 
ctDNA 
 
 
 
 
Immune 
response 
Pharmaco-
genetic 
analyses 
(optional) 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; BM = bone marrow; BUN = blood urea nitrogen; CRP = C-reactive 
protein; ctDNA = circulating tumor DNA; Ig = immunoglobulins; INR = international normalized ratio; 
MRD = minimal residual disease; LDH = lactase dehydrogenase; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PB = peripheral 
blood; PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood 
cells; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; 
WBC = white blood cells; CSF = cerebral spinal fluid 
a Creatinine clearance will be calculated using the Cockcroft-Gault equation: 
(140 - age [years] x weight [kg] x 0.85 if female) / (72 x creatinine mg/dL), adjusted for BSA by 
1.73 m2/BSA  
b A pregnancy test will be performed locally at each site on all women unless they are surgically sterile or 
≥ 2 years postmenopausal.  
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Additional procedures (eg, collection of an unscheduled blood sample to measure 
cytokine levels) deemed necessary as part of standard of care or as required by local 
laws and regulations may be performed at the investigator’s discretion. 
7.3.11.1 
Pregnancy Test 
Pregnancy tests will be performed locally at each site on all women unless they are 
surgically sterile or ≥ 2 years postmenopausal.  A serum pregnancy test should be 
performed at screening.  During the course of the study a urine pregnancy test is 
allowed, a positive result should be confirmed by a serum pregnancy test.  
Pregnancy tests must be performed prior to dosing with investigational product.  If the 
pregnancy test is positive at either time point, the subject should not be given 
investigational product. 
7.3.12 
Response Assessments 
The Lugano Classification will be used to assess treatment response as described in 
Appendix D. 
7.3.12.1 
Clinical Tumor Assessment 
Clinical tumor assessments will be performed as indicated in the schedule of 
assessments and are based on changes in the size of previously abnormal lymph node 
groups or extranodal sites, or the appearance of new lesions suspected to represent 
lymphoma progression or relapse.  Findings will be recorded on the clinical tumor 
assessment eCRF.   
7.3.12.2 
Radiographic Assessment 
PET/CT scans with whole body images, from base of skull to mid-thigh, will be 
conducted.  Examinations should be consistent across all timepoints at screening,  
week 5, week 15, week 25, and at end of treatment if end of treatment is at week 35 or 
beyond including: the amount of tracer, location of injection, arm location, and scan 
delay.  
PET images should be converted to standardized uptake values maps to support 
comparison across timepoints and to standardize viewing conditions CT anatomical 
coverage: chest, abdomen, and pelvis (and neck if not visualized with chest).  
If PET and CT are acquired on the same day, it is strongly recommended that PET is 
performed prior to the CT with IV contrast. CT only can be performed if PET is not 
feasible during dose escalation. PET and CT are mandatory during expansion.  
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PET/CT imaging data including documentation of target lesion size (s)will be entered in 
the eCRF during Part 1 (dose escalation) and Part 2 (dose expansion). During Part 2, 
PET/CT imaging data may also be sent to a central vendor. 
7.3.12.3 
Bone Marrow Biopsy for Disease Assessment 
Bone marrow evaluation (core biopsy with or without aspirate) should be performed 
for all subjects at screening and optional at week 5 (C2D1). 
7.3.13 
Events 
Adverse event and serious adverse event as well as disease-related event assessments 
will be made throughout the study and will be evaluated and recorded in the source 
documents and on the eCRF as specified in Section 9.  The severity of all events will be 
graded according to CTCAE, version 4.0 (Appendix A) unless specified otherwise.  
Exceptions:  CRS will be graded according to the adopted grading system referenced in 
Lee et al, 2014 and TLS according to Cairo-Bishop criteria (see Appendix K for details). 
7.3.14 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If the subject is 
deceased, the date and reported case of death should be obtained. 
7.3.15 
Pharmacokinetic Blood Sampling 
Blood samples will be obtained for determination of serum concentrations of AMG 562 
from all subjects at the time points specified in the Schedule of Assessments (Table 5 
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through Table 11).  Blood must not be drawn from the IV access or port catheter used 
for dosing AMG 562.  
Sample collection, processing, storage, and shipping instructions are provided in a 
separate laboratory manual. 
7.4 
Antibody Testing Procedures 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 5 
through Table 11).  Bioanalytical testing for anti-AMG 562 antibodies will be conducted 
on these samples only if there are unexpected PK findings or safety related concerns in 
the study population that warrant further investigation by characterizing drug 
immunogenicity. Samples testing positive may be further characterized. Additional blood 
samples may be obtained to rule out anti-drug antibodies during the study.  Subjects 
who test positive for binding antibodies at the final scheduled study visit and have clinical 
sequelae that are considered potentially related to an anti-AMG 562 antibody response 
may be asked to return for additional follow-up testing.  
Please see the laboratory manual for detailed sample collection and handling 
instructions. 
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7.7 
Sample Storage and Destruction 
Any blood or bone marrow sample collected according to the Schedule of Assessments 
(Table 8 through Table 11) can be analyzed for any of the tests outlined in the protocol 
and for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study. Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
disease, the dose response, and/or prediction of response to AMG 562 or other 
protocol-specified therapy, characterize antibody response, 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 
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made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the Investigator.  Following the request from the subject, the Investigator is to 
provide the Sponsor with the required study and subject number so that any remaining 
blood or bone marrow samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The Sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the Sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
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 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
(Table 8 through Table 11) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other treating 
physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events.  Subjects who have discontinued investigational product 
and/or protocol required therapies or procedures should not be automatically removed 
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from the study.  Whenever safe and feasible it is imperative that subjects remain 
on-study to ensure safety surveillance and/or collection of outcome data.  The 
investigator must document the level of follow-up that is agreed to by the subject.    
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, medical device(s), 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 protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
adverse event 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor  
• 
non-compliance 
• 
requirement for alternative therapy 
• 
disease progression 
• 
pregnancy 
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8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by Sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease, as summarized in Table 14 below.   
Table 14.  Disease-related Events by System Organ Class 
System Organ Class 
Term(s) 
Blood and lymphatic system disorders 
Lymphadenopathy 
General disorders and administration site 
conditions 
Disease progression, Fatigue 
Investigations 
Weight decreased 
Skin and subcutaneous tissue disorders 
Night sweats 
Disease-Related Events that do not qualify as Adverse Events or Serious Adverse 
Events: 
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
recorded as a Disease-Related Event. 
• 
Death due to the disease under study is to be recorded on the Event eCRF. 
Disease-Related Events that would qualify as an Adverse Event or Serious Adverse 
Event: 
• 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator for the subject’s condition, or if the investigator believes there is a 
causal relationship between the investigational product(s)/study 
treatment/protocol-required therapies and disease worsening, this must be recorded 
and reported as per section 9.1.3 as an Adverse Event or Serious Adverse Event. 
• 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious  
disease-related event data to the sponsor within 24 hours of it being available. 
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9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The Investigator is responsible for ensuring that any adverse events observed by the 
Investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected. A pre-existing condition that has not worsened more than 
anticipated (ie, more than usual fluctuation of disease) during the study, or involves an 
intervention such as elective cosmetic surgery or a medical procedure while on study, is 
not considered an adverse event.   
Every increase in severity of an adverse event needs to be recorded.  Record a single 
event for each increased level of severity on the Event eCRF.  Decrease in severity only 
has to be recorded for DLTs and adverse events that lead to interruption of 
treatment/delay of a subsequent infusion. 
For situations when an adverse event or serious adverse event is due to lymphoma, 
report all known signs and symptoms.  Death due to disease progression in the absence 
of signs and symptoms should be reported as the primary tumor type (eg, metastatic 
pancreatic cancer).  
Note:  The term “disease progression” should not be used to describe the 
disease-related event or 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 requests to 
withdraw from protocol-required therapies or the study due to an adverse event, refer to 
Section 8.1 for additional instructions on the procedures recommended for safe 
withdrawal from protocol-required therapies or the study.   
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9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease-Related Event as 
defined in Section 9.1.1): 
• 
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 
A Disease-Related event is to be reported as a serious adverse event if 
• 
the subject’s pre-existing condition becomes worse than what the Investigator 
would consider typical for a patient with the same underlying condition, or 
• 
if the Investigator believes a causal relationship exists between the 
investigational medicinal product(s)/protocol-required therapies and the event, 
• 
and the event meets at least 1 of the serious criteria above. 
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 
Reporting Procedures for Disease-related Events 
The Investigator is responsible for ensuring that all Disease-Related Events observed by 
the Investigator or reported by the subject that occur after the first dose of investigational 
medicinal product(s)/study treatment/protocol-required therapies through the Safety 
Follow-Up visit (ie, 30 [+7] days after the last dose of study treatment[s]) are recorded on 
the Event eCRF as a Disease-Related Event.   
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious disease-
related event data to the sponsor within 24 hours of it being available 
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Disease-Related Events assessed by the Investigator to be more severe than expected 
and/or related to AMG 562/study treatment/protocol-required therapies, and determined 
to be serious, must be recorded on the Event eCRF as Serious Adverse Events.   
Additionally, the Investigator is required to report a fatal Disease-Related Event on the 
Event eCRF as a Disease-Related Event.  
9.2.2 
Adverse Events 
9.2.2.1 
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(s) through the Safety Follow-Up visit (ie, 30 [+7] days after the last dose of study 
treatment[s]) are reported using the Event eCRF. 
The Investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Toxicity grade 
• 
Assessment of relatedness to investigational product(s) and 
• 
Action taken. 
The adverse event grading scale used will be the 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(s).  This 
relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by the investigational 
product(s)?   
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 procedure(s)).  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity (eg, administration of investigational product, 
protocol-required therapies, use of medical device[s]), and/or procedure”?  
The Investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
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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 
resolution.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The Investigator is responsible for ensuring that all serious adverse events observed by 
the Investigator or reported by the subject that occur after signing of the informed 
consent through the Safety Follow-Up visit (ie, 30 [+7] days after the cessation of all 
study treatement) are recorded in the subject’s medical record and are submitted to 
Amgen. 
All serious adverse events must be submitted to Amgen within 24 hours following the 
Investigator’s knowledge of the event via the Event eCRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
Investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The Investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  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/procedure?  Relatedness means that there are facts or 
reasons to support a relationship between investigational product and the event.  
The Investigator is expected to follow reported serious adverse events until stabilization 
or resolution. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
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requested, the Investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event eCRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, Investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The Investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), Investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
Investigator is to report them to Amgen within 24 hours following the Investigator’s 
knowledge of the event.  
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking protocol-required therapies, report the pregnancy to Amgen Global 
Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, Investigators should 
report pregnancies that occur through 110 days after the last dose of AMG 562 or in a 
male subject’s female partner through 110 days after the last dose of AMG 562.  
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The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the Investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the Investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
Investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, Investigators should report 
lactation cases that occur through 120 days after the last dose of protocol-required 
therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the Investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the Investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint: 
• 
Safety: Incidence of dose limiting toxicities (DLTs), treatment-emergent adverse 
events, treatment-related adverse events, disease-related events and 
clinically-significant changes in vital signs, physical examinations, 
electrocardiograms (ECG) and clinical laboratory tests 
Secondary Endpoints:   
• 
AMG 562 PK parameters including, but not limited to, maximum concentration (Cmax), 
minimum concentration (Cmin), time of maximum concentration (Tmax), area under the 
concentration-time curve (AUC), and if feasible, half-life (t1/2)  
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• 
Efficacy parameters:  
− 
ORR according to Lugano classification 
− 
Best overall response by category (response terminology reflects the response 
criteria used. The Lugano Classification response definitions for PET-CT 
evaluations of FDG-avid lymphomas uses the terminology CMR, PMR, NMR, or 
PMD. Corresponding designations from earlier response criteria include CR, PR, 
SD, or PD.) 
− 
Duration of response (DOR) 
− 
Progression free survival (PFS) 
− 
Overall survival (OS)  
Exploratory Endpoints: 
• 
Incidence of anti-AMG 562 antibody formation 
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 562.   
The analysis of DLT will be conducted on the DLT Analysis Set defined as all subjects 
who are DLT-evaluable (see Section 6.2.1.3). DLT-evaluable subjects are those who 1) 
experienced DLTs or 2) completed DLT observational period and did not experience 
DLTs 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
AMG 562 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 following subgroups will be used summarized safety data in part 2 of dose 
expansion: 
• 
Age 
• 
age group: <65, ≥65; and <75,  ≥75 
• 
Sex:  Male, Female 
• 
Race 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black ( or African American) 
• 
Native Hawaiian or Other Pacific Islander 
• 
White 
• 
Other 
• 
Geographic region  
• 
US/Canada 
• 
Europe 
• 
Rest of the world  
• 
Disease state: 
o Transformed disease 
o Primary refractory disease 
o Refractory to last treatment 
o GCB versus non-GCB (Hans algorithm) 
o Double or Triple hit, vs non-double or triple hit, by FISH 
• 
Prior treatments 
o Autologous HSCT 
o CD19-targeted treatment 
10.1.4 
Handling of Missing and Incomplete Data  
For efficacy data of overall response, subjects without tumor response assessments will 
be considered as nonresponders. Otherwise, only nonmissing data will be analyzed. 
Ineligible subjects and subjects enrolled in Part 1 who are not DLT evaluable may be 
replaced. 
10.2 
Sample Size Considerations 
It is anticipated that approximately 85 subjects will be enrolled in this study. 
Approximately 30 subjects will be enrolled in the dose escalation cohorts and up to 
55 additional subjects will be enrolled in the dose expansion cohort. The sample size in 
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the dose escalation is based on practical considerations and is consistent with 
conventional oncology studies with the objective to estimate the MTD. With 3 subjects 
per cohort, there is a 27-70% probability of observing at least one DLT if the true DLT 
rate is 10-33% and with 4 subjects per cohort, there is a 34-80% probability.  
In the dose expansion cohort, a subject number of 55 will provide a 43% probability of 
observing at least one adverse event with 1% incidence rate and 94% probability of 
observing at least one adverse event with 5% incidence rate. An exact 90% binomial 
confidence interval (CI) will be provided for overall response rate. With the 55 subjects 
and 40% overall response rate, the expected two-sided 90% CI would be 29% to 52%. 
10.3 
Adaptive Design 
Details of the adaptive BLRM design are described in Appendix J. 
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
In the dose escalation part, safety data will be reviewed on an ongoing basis.  Based on 
accumulating toxicity information, BLRM will be used to make dosing recommendations.  
In dose level review team meetings (DLRMs), Amgen, in consultation with the site 
investigators, will review the BLRM recommended dose level and will review all available 
cumulative data by cohort prior to making dose escalation decisions. As a sensitivity 
analysis, a one-parameter Continual Reassessment Method model may be used to 
estimate the dose-toxicity relationship to help making dose escalation decisions.  
Adverse events and DLTs observed in all subjects will be evaluated continually and fully 
integrated into all DLRMs and considered in all enrollment and dosing decisions.  
The clinical activity of AMG 562 in the dose expansion part will be examined using a 
Bayesian predictive probability design. If the posterior probability is more than 85% that 
the ORR is 40% or less, then this is considered insufficient anti-lymphoma activity. If the 
ORR is too low, enrollment may be terminated early due to insufficient anti-lymphoma 
activity. The guidelines for futility due to insufficient efficacy assuming a prior beta 
distribution (0.8, 1.2) are presented in Table 15. The operating characteristics in 
Table 16 provide the probability of stopping the trial early for given hypothetical true 
ORR rates whereas the stopping criteria in Table 15 are based on situations where the 
empirical evidence would result in a posterior probability of ≥85% that the true ORR rate 
is ≤ 40%. 
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 The DLRT will be convened in the dose expansion part of the study to review efficacy 
data (with recruitment ongoing) after the first 15 subjects are enrolled and have had the 
opportunity to receive at least five weeks of treatment (with recruitment ongoing). 
Table 15.  Guideline for Insufficient Efficacy  
Number of Treated Subjects 
Efficacy Futility Guideline 
15 
4 or fewer responders 
20 
5 or fewer responders 
25 
7 or fewer responders 
30 
9 or fewer responders 
35 
11 or fewer responders 
40 
12 or fewer responders 
45 
14 or fewer responders 
50 
16 or fewer responders 
55 
Trial will stop 
Table 16.  Operating Characteristics for futility With Batch Size of 5 Subjects 
True ORR Rate 
Probability of Stopping Early for 
Futility 
Average Sample Size 
0.25 
95% 
21 
0.30 
81% 
27 
0.35 
59% 
36 
0.40 
36% 
43 
0.45 
18% 
49 
0.50 
8% 
52 
0.55 
3% 
54 
Additionally, the DLRT will review safety data and conduct evaluations of the ongoing 
DLT rate to assess if the threshold for early trial termination has been reached.   
The stopping rules use a Bayesian approach to terminate the study if the posterior 
probability that the DLT rate is greater than 33% is > 90%.  The stopping boundaries 
assuming a prior beta distribution (0.66, 1.33) are presented in Table 17.  The operating 
characteristics in Table 18 provide the probability of stopping the trial early for given 
hypothetical true DLT rates whereas the stopping criteria in Table 17 are based on 
situations where the empirical evidence would result in a posterior probability of ≥ 90% 
that the true DLT rate is ≥ 33%. The evaluations could occur more frequently if 
necessary to address emerging safety concerns.   
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Table 17.  Stopping Boundaries 
Number of DLT Evaluable Subjects 
Stop Study If Observing These Many DLTs 
10 
≥ 6  
15 
≥ 8  
20 
≥ 10  
25 
≥ 12  
30 
≥ 14  
35 
≥ 16  
40 
≥18  
45 
≥ 20  
50 
≥ 21  
55 
Trial will stop 
Table 18.  Operating Characteristics for stopping early With Batch Size of 
5 Subjects 
True DLT Rate 
Probability of Stopping Early 
Average Sample Size 
0.20 
1% 
55 
0.25 
4% 
53 
0.3 
13% 
51 
0.33 
22% 
48 
0.35 
31% 
45 
0.40 
56% 
37 
0.45 
79% 
29 
10.4.2 
Dose Level Review Team (DLRT) 
Dose Level Review Meetings (DLRMs) will be held to review data, monitor safety, and 
make recommendations on dose escalation or / changes. The DLRT will be composed 
of the investigators or designees, and the following Amgen representatives: Medical 
Monitor/early development leader or designee, global safety officer or designee, clinical 
study manager, biostatistician and clinical pharmacologist. Additional members may be 
added as needed. The following members are responsible for DLRT recommendations: 
treating investigators, Amgen Medical Monitor, and global safety officer or designee 
before rendering final decision by Amgen.     
A quorum as defined below must be in attendance for the DLRM. The quorum is defined 
as > 50% of the participating investigators or their qualified designee (ie, sub-investigator 
or research nurse or study coordinator possessing written documentation [eg e-mail] of 
the investigator’s vote), as well as > 50% of Amgen representatives listed above. The 
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early development leader/medical monitor  must attend for the quorum to be reached. 
The DLRM will be rescheduled if a quorum is not reached. 
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, efficacy 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 recommendations.  
All DLRM requirements are outlined in the protocol.  A DLRM Charter will not be used. 
10.4.3 
Primary Analysis 
The primary analysis for the dose exploration part will occur when targeted enrollment is 
complete and each subject either completes 3 months on study or withdraws from the 
study. The primary analysis for the dose expansion part will occur when targeted 
enrollment is complete and each subject had the opportunity to receive at least 3 months 
of treatment. 
10.4.4 
Final Analysis 
The final analysis will occur after all subjects have ended the study.  
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic 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. 
10.5.2 
Primary Endpoint(s) 
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 562. 
Dose Limiting Toxicities 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose level. Adverse Events 
Subject incidence of all treatment-emergent adverse events (TEAEs) will be tabulated by 
system organ class and preferred term.  The number and percentage of subjects 
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reporting TEAEs will be evaluated overall and by dose level and will also be tabulated by 
relationship to study drug. 
Tables of TEAEs serious TEAEs, TEAEs leading to withdrawal from investigational 
product or other protocol-required therapies, TEAEs that happen to ≥ 10% subjects, 
treatment related adverse events and fatal adverse events will also be provided. 
Disease-related Events 
Subject incidence of all treatment emergent disease-related events and fatal 
disease-related events will be provided.   
Clinical Laboratory Tests 
Clinical chemistry, hematology, coagulation and urinalysis data will be reviewed for each 
subject.  Depending on the size and scope of changes in laboratory data, summaries of 
laboratory data over time and/or changes from baseline over time may be provided.  
Tables of maximum shifts from baseline for selected laboratory values may also be 
provided. 
Vital Signs 
Vital signs data will be 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.  
Physical Measurement 
Physical measurement data will be listed and reviewed for each subject. Depending on 
the size and scope of changes, summaries of changes from baseline over time may be 
provided. Unscheduled assessments will be included in this summary. 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. Subjects' maximum change from baseline in [QTcF, QTcB] 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 
electrocardiogram (ECG) data will be listed [and select parameters of interest plotted]. 
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10.5.3 
Secondary Endpoints 
10.5.3.1 
Pharmacokinetics Data Analysis 
For AMG 562, PK parameters including including Cmax, Tmax, and AUC will be determined 
from the time-concentration profile using standard non-compartmental approaches and 
considering the profile over the complete sampling interval.  Based on the review of the 
data, analyses to describe the relationship between AMG 562 exposure and either 
pharmacodynamic effects and/or clinical outcome may also be performed. 
10.5.3.2 
Efficacy Endpoint Analyses 
The following analyses will be done for all subjects in the dose exploration cohorts and 
the dose expansion groups.  The proportion of subjects by overall response and overall 
response category and corresponding exact 90% CI will be calculated and tabulated for 
subjects treated at the MTD. Response will be determined by Lugano Classification. The 
Lugano Classification response definitions for PET-CT evaluations of FDG-avid 
lymphomas uses the terminology CMR, PMR, NMR, or PMD. Corresponding 
designations from earlier response criteria include CR, PR, SD, or PD. Overall response 
includes CMR and PMR. 
Other efficacy endpoints includes duration of response (DOR), progression-free survival 
(PFS) and overall survival (OS). 
DOR: DOR is calculated only for subjects who achieve a response (CMR or PMR). The 
duration will be calculated from the date a response is first achieved until the earliest 
date of a disease assessment indicating a disease progression or death, whichever 
occurs first. Subjects who do not have a relapse event will be censored on their last 
disease assessment date. If the last disease assessment date is after the date that 
triggers the analysis, the subject will be censored at the analysis trigger date. 
PFS: PFS is calculated as the time from the date of first dose of AMG562 until the date 
of diagnosis of progression of lymphoma, or date of death, whichever is earliest. 
Subjects who are alive and did not have progression will be censored at the last date of 
radiographic assessment of PET-CT scans. 
OS: OS is calculated as the time from the first dose of AMG562 until death due to any 
cause. Subjects who are alive at the date that triggers the analysis will be censored at 
the date last known to be alive. If the date last known to be alive is after the date that 
triggers the analysis, the subject will be censored at the analysis trigger date. 
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Kaplan Meier curve will be presented for DOR, PFS, and OS with estimates for rates 
and 90% CI at selected weeks. 
10.5.4 
Exploratory Endpoints 
The incidence and percentage of subjects who develop anti-AMG 562 antibodies 
(binding and/or neutralizing) at any time will be tabulated.  
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the Investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
Investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential subject population. 
Before a subject’s participation in the clinical study, the Investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/ are 
administered.  
The Investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the Investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the Investigator will be acting in that capacity, the Investigator is to 
document such in the subject’s medical record.   
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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. Non-decisional 
Subjects Who Require Consenting via Legally Authorized Representative Will Not be 
Allowed to Enroll in This Study. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
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. 
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In compliance with governmental/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The Investigator is obligated to inform and obtain the consent of 
the subject to permit named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the Investigator or, in the case of 
multi-center studies, the coordinating Investigator. 
The coordinating Investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The Investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The Investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
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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.   
Elements to include: 
• 
Subject files containing completed eCRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, IB, copies of prestudy 
documentation, and all correspondence to and from the IRB/IEC and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable. 
• 
Non-investigational product(s), and/or medical device(s) or combination 
product(s) documentation, as applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
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The Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study related records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the electronic eCRFs must be 
maintained and readily available. 
• 
Updates to electronic 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. 
12.4 
Investigator Responsibilities for Data Collection 
The Investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 8 through Table 11), the Investigator can search 
publically available records [where permitted]) to ascertain survival status.  This ensures 
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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.  eCRFs must be 
completed in English. TRADENAMES (if used) for concomitant medications may be 
entered in the local language.   
12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors Recommendations for the 
Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical Journals, 
which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception 
and design, acquisition of data, or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final 
approval of the version to be published; and (4) agreement to be accountable for 
all aspects of the work in ensuring that questions related to the accuracy or 
integrity of any part of the work are appropriately investigated and resolved.  
Authors should meet conditions 1, 2, and 3 and 4. 
• 
When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
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. 
REFERENCES 
AMG 562 Investigator’s Brochure. Thousand Oaks, CA: Amgen Inc. 
Babb, J., Rogatko, A., Zacks, S. (1998). Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Statistics in Medicine 17:1103–1120 
Bradbury LE, Kansas GS, Levy S, et al. The CD19/CD21 signal transducing complex of 
human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 
molecules. J Immunol. 1992;149(9):2841-50. 
Blincyto® (blinatumomab) [US Prescribing Information]. Thousand Oaks, CA: Amgen Inc; 
May 2017. 
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of 
pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 
2008;26:2767–2778 
Conley ME, Dobbs AK, Farmer DM, et al. Primary B Cell Immunodeficiencies: 
Comparisons and Contrasts. Annual Review of Immunology. 2009;27(1):199-227 
Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, 
dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin 
chemotherapy before autologous stem-cell transplantation for relapsed and refractory 
aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32(31):3490-3496. 
DeVita VT Jr, Canellos GP, Chabner B, et al. Advanced diffuse histiocytic lymphoma, a 
potentially curable disease. Lancet. 1975;1(7901):248-50. 
Drug Facts and Comparison 2006. 60th ed. Philadelphia, PA: Lippincott Williams & 
Wilkins; 2005. 
Evens AM, Blum, KA (Eds). Non-Hodgkin Lymphoma: Pathology, Imaging, and Current 
Therapy. Springer International Publishing AG; 2015. 
FDA Approved Drug Products: YESCARTA prescribing information, 2017. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/
ApprovedProducts/UCM581226.pdf.  
FDA Approved Drug Products: KYMRIAH prescribing information, 
2018.https://www.fda.gov/downloads/UCM573941.pdf 
FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
Fisher SG, Fisher RI. The Epidemiology of Non-Hodgkin's Lymphoma. Oncogene. 
2004;23(38):6524-534. 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous 
transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 
2010;28(27):4184-4190.  
Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 1996. 
Haematological Malignancy Research Network Incidence Statistics. 
https://www.hmrn.org/statistics/incidence 
Katz BZ, Herishanu Y. Therapeutic targeting of CD19 in hematological malignancies: 
past, present, future and beyond. Leuk Lymphoma. 2014;55(5):999-1006. 
Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood. 2014;124(2):188-195. 
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Martelli M, Ferreri AJ, Agostinelli C, et al. Diffuse Large B-cell Lymphoma. Crit Rev 
Oncol Hematol. 2013;87:146-171. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008;27:2420–2439 
Offner S, Hofmeister R, Romaniuk A, et al. Induction of regular cytolytic T cell synapses 
by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol 
Immunol. 2006;43:763-771. 
Oken MM, Creech RH, Tormey DC et al.  Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655. 
Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow 
transplantation after failure of conventional chemotherapy in adults with 
intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 
1987;316(24):1493-1498. 
Physician’s Desk Reference, 2002. 
Robinson SP, Boumendil A, Finel H, et al. Autologous stem cell transplantation for 
relapsed/refractory diffuse large B-cell lymphoma: efficacy in the rituximab era and 
comparison to first allogeneic transplants. A report from the EBMT Lymphoma Working 
Party. Bone Marrow Transplant.  2016;51(3):365-371. 
Saber H, Gudi R, Manning M, et al. An FDA oncology analysis of CD3 bispecific 
constructs and first-in-human dose selection. Regul Toxicol Pharmacol. 
2017;5(90):144-152. 
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the 
context of clinical and biologic heterogeneity. Blood.  2015;125(1):22-32. 
van Imhoff GW, et al. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study 
(OMB110928). 56th Annual Meeting of the American Society of Hematology.  
2014;124:630. 
Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager 
(BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. 
Blood.  2016;127(11):1410-1416. 
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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 link: 
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 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.4.1 and Section 6.4.2 or who experience AST or ALT elevations > 3 x ULN or 
2-fold increase above baseline values for subjects with evaluated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
• 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
Complete blood count (CBC) with differential to assess for eosinophilia 
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− 
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 
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Appendix B.  Sample Serious Adverse Event Form or eSerious Event Contingency 
Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Response Assessment per the Lugano Classification  
5- point scale (Deauville) 
1. no uptake above background;  
2. uptake ≤ mediastinum;  
3. uptake > mediastinum but ≤ liver;  
4. uptake moderately > liver;  
5. uptake markedly higher than liver and/or new lesions;  
X. 
new areas of uptake unlikely to be related to lymphoma. 
Response 
Compete 
Response  
Partial Response 
Stable Disease 
Progressive 
Disease 
PET/CT 
Response 
Complete 
Metabolic 
Response 
Partial Metabolic 
Response 
No Metabolic 
Response 
Progressive 
Metabolic Disease 
Target 
Masses 
Score 1, 2, or 3 
with or without a 
residual mass 
Score 4 or 5  
reduced uptake 
compared with 
baseline  
residual mass(es) 
of any size 
Score 4 or 5  
no significant 
change in FDG 
uptake from 
baseline  
Score 4 or 5 with an 
increase in intensity 
of uptake from 
baseline and/or 
new FDG-avid foci 
consistent with 
lymphoma  
New 
Lesions 
None 
None 
None 
New FDG-avid foci 
consistent with 
lymphoma rather 
than another 
etiology  
Bone 
Marrow 
No FDG avid focal 
lesions 
Residual uptake 
higher than 
uptake in normal 
marrow but 
reduced 
compared with 
baseline  
No change from 
baseline 
New or recurrent 
FDG-avid foci 
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Appendix E.  Medications That May Cause QTc Prolongation 
A list of medications known to cause QTc interval prolongation is available at the 
following link:  https://crediblemeds.org/index.php/login/dlcheck 
If a 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. 
Table 19 presents a list of drugs that may prolong 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.  Use of these drugs should be 
discussed with the Amgen Medical Monitor.  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: 
Table 19.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
Alfuzosin 
~10 hours 
 
7 
Amantadine 
17 ± 4 hours (10-25) 
 
4 
Amiodarone 
(cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26-64) 
 
10 
Chloral hydrate 
Readily converted to trichloroethanol 
(active metabolite T½ = 7-10 hours) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 ± 7 hours 
 
 
Clarithromycin 
Non-linear PK 3-4 hr (250 mg 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 
 
Erythromycin 
*Each salt form has different Half-Life* 
 
 
Page 1 of 3 
Footnotes defined on last page of this table 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 148 of 158 
CONFIDENTIAL 
 
 
Table 19.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible 
Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
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 
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 
 
Page 2 of 3 
Footnotes defined on last page of this table 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 149 of 158 
CONFIDENTIAL 
 
 
Table 19.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible 
Washout 
Period – Hours 
Possible 
Washout 
Period - Days 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active metabolite) 
T½ = 21-30 hours (extensive to poor 
metabolizer) 
 
4 
Salmeterol 
5.5 hours (only 1 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). 
Sources:  Drug Facts and Comparison 2006, 2005; Physician’s Desk Reference, 2002; and Goodman & 
Gilman’s the Pharmacological Basis of Therapeutics, 1996. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 150 of 158 
CONFIDENTIAL 
 
 
Appendix F.  Performance Status According to Eastern Cooperative Oncology 
Group (ECOG) Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg light housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
Source:  Oken et al, 1982 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 151 of 158 
CONFIDENTIAL 
 
 
Appendix G.  Examples of CYP450 Substrates With Narrow Therapeutic Range 
Alfentanil 
Astemizole* 
Cisapride* 
Cyclosporine 
Diergotamine 
Ergotamine 
Fentanyl 
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus 
Terfenadine* 
*Not available in the US 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 152 of 158 
CONFIDENTIAL 
 
 
Appendix H.  Extended Neurological Examination 
Abnormalities of the following should be recorded: level of consciousness, orientation, 
vision, cranial nerves and brain stem functions, pyramidal and extra pyramidal motory 
system, reflexes, muscle tone and trophic findings, coordination, sensory system, 
neuropsychological findings (eg, speech, cognition and emotion). Neurological 
examiniations will include a wrting test to detect cerebral signs. For the writing tests, 
patients will be asked to write down the current date and time as well as an arbitrary 
sentence (this should be the same sentence throughout the study). 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 153 of 158 
CONFIDENTIAL 
 
 
Appendix I.  Protocol Sampling Scheme (Nominal Times) 
Study Day 
Infusion 
Length (hr) 
PK Draw Timepoint since 
Start of Infusion 
Suggested PK Draw 
Windows 
1 
Pre-Dose 
± 15 mins 
 (EOI) 
6 hours 
12 hours 
2 
24 hours 
± 1 hour 
3 
48 hours 
4 
72 hours 
8 
Pre-Dose 
± 15 mins 
 (EOI) 
15 
Pre-Dose 
± 15 mins 
 (EOI) 
22 
Pre-Dose 
± 15 mins 
 (EOI) 
6 hour 
12 hour 
23 
24 hours 
± 1 hour 
24 
48 hours 
25 
72 hours 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 154 of 158 
CONFIDENTIAL 
 
 
Appendix J.  Two-parameter BLRM Design 
A two-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
exploration.  The MTD target Toxicity Probability Interval (TPI) for DLT is (0.20, 0.33] 
and TPIs of (0.33, 0.60] and (0.60, 1.00] are defined as excessive and unacceptable, 
respectively.  The design seeks to identify a dose most likely to have a DLT rate in the 
target TPI, but with overdose control that limits the possibility the dose has an excessive 
or unacceptable DLT rate (Babb et al, 1998).  The probability of a DLT at dose level di is 
assumed to follow a Bernoulli distribution with probability pi where the logit of pi 
increases linearly with the log of the standardized dose in the following 2-parameter 
logistic model: 
 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is 1 of the planned dose selected as the 
reference dose.   
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for 
theta = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
planned dose is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference 
dose is 0.05.  These values were selected such that pi is 0.01 for the starting dose and 
0.40 for the reference dose (
 µg). Subsequent model runs may adjust the reference 
dose level lower or higher depending on the true DLT dose levels.   
The operating characteristics of the two-parameter BLRM design were evaluated via 
simulation using EAST version 6.4.1.  The cohort size was fixed to 3 or 4 subjects. All 
simulated studies start with the multiple subject cohorts. The initial multiple subject dose 
level is 
 µg and subsequent doses were selected based on the following rules: 
After each cohort, the next dose is the one with the highest probability of the target TPI, 
but with a less than 0.40 probability of an excessive or unacceptable TPI. 
Dose exploration will continue until any of the following events. 
• 
The highest planned dose level is determined to be safe and tolerable (minimum of 
6 treated subjects) 
• 
An MTD is identified where BLRM repeats the recommendation of a dose level 
(minimum of 6 treated subjects) 
• 
If fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability.  
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 155 of 158 
CONFIDENTIAL 
 
 
Operating characteristics are described below. 
Operating characteristics 
The 6 planned dose levels (unit:  µg) for the multiple subject cohorts were considered:  
 in these simulations.  This assumes that the single 
subject cohorts execute without any safety issue. 
The design was evaluated for 3 possible dose-response scenarios:  “Low”, “Mid”, and 
“High” MTD.  Table 20 shows the dose level and true probability of DLT for each 
scenario used in the simulated studies estimating the MTD.  Table 21 reports the 
operating characteristics from 10,000 simulated studies estimating the MTD when the 
target TPI is (0.20, 0.33].  Table 22 reports the operating characteristics from 
10,000 simulated studies estimating the MTD when using a 3+3 design.  
Table 20.  True Probability of DLT by Scenario for Simulated Studies Estimating 
MTD 
Dose Level (µg) 
MTD Scenario 
 
 
 
 
 
 
 High 
0.02 
0.08 
0.12 
0.15 
0.18 
0.33 
 Mid 
0.04 
0.12 
0.18 
0.3 
0.4 
0.5 
 Low 
0.06 
0.18 
0.3 
0.45 
0.5 
0.6 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 156 of 158 
CONFIDENTIAL 
 
 
Table 21.  Operating Characteristics by Scenario for Simulated Studies Estimating 
the MTD When the Target TPI is (0.20, 0.33) 
MTD Scenario 
High 
Mid 
Low 
 
4 subjects 
per cohort 
3 subjects 
per cohort 
4 subjects 
per cohort 
3 subjects 
per cohort 
4 subjects 
per cohort 
3 subjects 
per cohort 
Number of Subjects 
 Median (IQR) 
24 
(20 to 28) 
18 
(1 to 3) 
24 
(20 to 24) 
18 
(15 to 18) 
20 
(16 to 24) 
15 
(12 to 18) 
Number of DLTs 
 Median (IQR) 
3 
(2 to 4) 
2 
(1 to 3) 
4 
(3 to 5) 
3 
(2 to 4) 
5 
(4 to 6) 
3 
(3 to 4) 
Proportion of DLT (%) 
 Median (IQR) 
13 
(10 to 17) 
10 
(6 to 14) 
20 
(15 to 23) 
20 
(14 to 22) 
25 
(20 to 29) 
25 
(20 to 28) 
Percentage of studies recommending dose with DLT probability of: 
 ≤ 10%  
2.2 
2.3 
2.0 
2.0 
6.0 
7.9 
 > 10% and ≤ 20% 
83.2 
87.9 
37.7 
35.0 
25.7 
20.8 
 > 20% and ≤ 33% 
14.6 
9.5 
49.9 
50.7 
49.1 
44.7 
 > 33% 
0 
0 
10.4 
12.3 
22.2 
26.6 
Probability of 
identifying MTD with  
DLT probability of 
>15% and ≤ 33%  
54.6 
53.2 
81.8 
77.8 
74.8 
65.5 
DLT = dose-limiting toxicity; IQR = interquartile range; MTD = maximum tolerated dose; TPI = toxicity 
probability interval. 
Table 22.  Operating Characteristics by Scenario for Simulated Studies Estimating 
the MTD Using a 3+3 Design 
MTD Scenario 
High 
Mid 
Low 
Number of Subjects 
 Median (IQR) 
21 
(18 to 24) 
18 
(15 to 21) 
15 
(12 to 18) 
Number of DLTs 
 Median (IQR) 
3 
(2 to 3) 
3 
(2 to 4) 
3 
(2 to 4) 
Proportion of DLT (%) 
 Median (IQR) 
14 
(10 to 17) 
19 
(17 to 22) 
22 
(17 to 25) 
Percentage of studies recommending dose with DLT probability of: 
 ≤ 10%  
19.4 
16.0 
30.4 
 > 10% and ≤ 20% 
57.7 
55.8 
38.7 
 > 20% and ≤ 33% 
0 
20.53 
24.5 
 > 33% 
22.53 
7.4 
6.1 
Probability of 
identifying MTD with  
DLT probability of 
>15% and ≤ 33% 
25.0 
54.8 
63.2 
DLT = dose-limiting toxicity; IQR = interquartile range; MTD = maximum tolerated dose 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 157 of 158 
CONFIDENTIAL 
 
 
Appendix K.  Cairo-bishop Clinical Tumor Lysis Syndrome Definition and Grading 
CTCAE version 4.0 classifies TLS in grade 3 (present), grade 4 (life threatening 
consequences; urgent intervention indicated) and grade 5 (death).  Presence of TLS is 
not clearly defined by CTCAE version 4.0.  Cairo and Bishop developed a system for 
defining and grading TLS based on Hande-Garrow classification of laboratory or clinical 
TLS (Coiffier et al, 2008).  For this trial the Cairo-Bishop classification will be used to 
define presence of TLS, ie, presence of laboratory TLS (see Table 23) and clinical TLS 
(see Table 24) including grading as detailed below  
Based on the Cairo and Bishop system, laboratory TLS is present when levels of 2 or 
more serum values of uric acid, potassium, phosphorus, or calcium are more than or 
less than normal at presentation or if they change by 25% within 3 days before or 7 days 
after initiation of treatment (Table 23). 
Table 23.  Cairo-bishop Definition of Laboratory Tumor Lysis Syndrome 
Element 
Value 
Change from Baseline 
Uric acid 
≥ 476 µmol/L or 8 mg/dL 
25% increase 
Potassium 
≥ 6.0 mmol/L or 6 mg/L 
25% increase 
Phosphorus 
≥ 2.1 mmol/L for children or 
≥ 1.45 mmol/L for adults 
25% increase 
Calcium 
≤ 1.75 mmol/L 
25% decrease 
Note:  Two or more laboratory changes within 3 days before or 7 days after cytotoxic therapy will constitute 
laboratory TLS. 
Clinical TLS requires the presence of laboratory TLS in addition to 1 or more of the 
following significant complications:  renal insufficiency, cardiac arrhythmias/sudden 
death, and seizures (Table 24).  The grade of clinical TLS is defined by the maximal 
grade of the clinical manifestations as detailed in Table 24. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 158 of 158 
CONFIDENTIAL 
 
 
Table 24.  Cairo-bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Grade 
Creatininea, b 
Cardiac Arrhythmiaa 
Seizurea 
0 
≤ 1.5 x ULN 
None 
None 
1 
1.5 x ULN 
Intervention not 
indicated 
-- 
2 
> 1.5 – 3.0 x ULN 
Non urgent medical 
intervention indicated 
One brief, generalized seizure; 
seizure(s) well controlled by 
anticonvulsants or infrequent focal 
motor seizures not interfering with ADL 
3 
> 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (eg, 
defibrillator)  
Seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; with breakthrough 
generalized seizures despite medical 
intervention 
4 
> 6.0 x ULN 
Life-threatening (eg, 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Seizure of any kind which are 
prolonged, repetitive or difficult to 
control (eg, status epilepticus, 
intractable epilepsy) 
5 
Death 
Death 
Death 
Note.  Laboratory TLS and at least 1 clinical complication will constitute clinical TLS. 
ADL = activities of daily living, CHF = congestive heart failure, TLS = tumor lysis syndrome, ULN = upper 
limit of normal 
a Not directly or probably attributable to therapeutic agent 
b If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:  > 1 to < 12 years of 
age, both male and female, 61.6 µmol/L; ≥ 12 to < 16 years, both male and female, 88 µmol/L; ≥ 16 years, 
female 105.6 µmol/L, male 114.4 µmol/L. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 1 of 50 
CONFIDENTIAL 
 
 
Amendment 4 
Title:  A Phase 1, First-in-human, Open-Label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With 
Relapsed / Refractory Diffuse Large B Cell Lymphoma, Mantle Cell Lymphoma, or 
Follicular Lymphoma 
Amgen Protocol Number (AMG 562) 20170533 
Amendment Date: 
07 August 2019 
 
Rationale: 
This amendment contains changes to the inclusion and exclusion criteria, to the 
definition of a dose limited toxicity (DLT) evaluable subject, and clarifications to the 
Schedule of Assessments that were made based on investigator and external advisor 
feedback to align with clinical standards and to address the urgent treatment need of the 
eligible patient population. The premedication schedule was adjusted based on the dose 
level review meeting (DLRM) outcome of Cohort 1 review. Operational changes and 
changes for clarification were made. 
The following updates were made to the protocol amendment 3: 
• 
Updated language regarding dose level review meeting decisions to 
recommendations to align with Amgen standard processes 
• 
Adjustment of premedication schedule based on cohort 1 DLRM 
recommendation and allowing oral premedication with dexamethasone to add 
convenience 
• 
Adjustment of reference dose for Bayesian Model based on the observation of a 
DLT at an early cohort 
• 
Restructured inclusion criteria  
• 
Allowing prior CD19 targeting therapies except prior CD19-directed CAR-T cell 
therapies   
• 
Added biopsy to SOA for subjects with prior CD19 targeting treatment  
• 
DLT evaluable subject definition updated 
• 
Inclusion of treatment holiday  
• 
Revisions to Disease Related Adverse Events collection guidelines as per ASAE 
Adoption Committee (AAC) guidance 
• 
Adverse event (AE) management guideline changes to improve clarity and 
implementation at site level  
• 
Revisions to adverse event management section to include information on 
hospitalizations for AEs and restart of IP following adverse events  
• 
PK schedule adjustments to align with ECG timepoints to fulfill QT/QTc 
evaluation 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  07 August 2019 
Page 2 of 50 
CONFIDENTIAL 
 
 
• 
Biomarker language clarification for sample collection based on disease type and 
study part 
• 
Typographical and grammatical errors corrected and aligned between sections 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  10 March 2019 
Page 1 of 6 
CONFIDENTIAL 
 
 
Amendment 3 
Title:  A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With 
Relapsed / Refractory Diffuse Large B Cell Lymphoma, Mantle Cell Lymphoma, or 
Follicular Lymphoma 
Amgen Protocol Number (AMG 562) 20170533 
Amendment Date: 
10 March 2019 
Rationale: 
This amendment contains changes that were requested by health authorities. In 
addition, it contains changes to the inclusion and exclusion criteria that were made 
based on investigator and external advisor feedback to align with clinical standards and 
to address the urgent treatment need of the eligible patient population. 
The following updates were made to the protocol amendment 2: 
• 
Language clarification:  
o Table 7. Grading and Management of Cytokine Release Syndrome.  
o Permanent discontinuation criteria for the occurrence of multiple Grade 2 or 
higher CRS events 
o Concomitant therapies for infection treatment  
• 
Washout period for check-point inhibitors and monoclonal antibody-based 
therapy was reduced based on the aggressive disease condition. A longer 
washout period is not feasible as per the standard of care.   
• 
Excluded medication for infection treatment during DLT window unless discussed 
with Amgen medical monitor 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  30 November 2018 
Page 1 of 23 
CONFIDENTIAL 
 
 
Amendment 2 
Title:  A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With 
Relapsed / Refractory Diffuse Large B Cell Lymphoma, Mantle Cell Lymphoma, or 
Follicular Lymphoma 
Amgen Protocol Number (AMG 562) 20170533 
Amendment Date: 
30 November 2018 
Rationale: 
This amendment contains changes that were requested by health authorities and 
institutional review boards/ ethics committees. In addition, it contains changes to the 
inclusion and exclusion criteria that were made based on investigator and external 
advisor feedback. 
The following updates were made to the protocol amendment 1: 
• 
Typographical errors and inconsistencies between sections throughout the 
protocol were corrected 
• 
Clarifications were made regarding schematics for weekly dosing to differentiate 
from Blincyto IP administration 
• 
Background information was updated to reflect the recent approved therapy and 
benefit risk profile 
• 
The step dosing triggers, conductance of DLRM clarified 
• 
Premedication rules prior to IP administration updated based on HA feedback 
• 
DLRT data review timelines for the Dose expansion clarified  
• 
Table 8 to Table 11 (Schedule of Assessments) footnotes were updated to reflect 
the changes for VS and LTFU 
• 
Several changes were made to inclusion/exclusion criteria at the request of 
health authorities or for streamlining purposes. The following inclusion/exclusion 
criteria were amended based on investigator and external advisor feedback: 
o Legally Acceptable Representatives (LAR’s) removed based on EC feedback 
o Disease diagnosis clarified for DLBCL population 
o Washout period reduced for prior exposure to Rituxan based on in vitro data   
• 
Shortening of Hospitalization requirement only after substantial amendment 
clarified  
• 
Table 7. Restart guidance for Grade 3 CRS for Grading and Management of 
CRS events updated 
• 
LTFU visit requirements for onsite vs. remote visits clarified  
• 
Table 13. List of analytes updated based on lab or site performing the evaluation  
• 
Dose Level Review Team (DLRT) language clarified  
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  30 November 2018 
Page 2 of 23 
CONFIDENTIAL 
 
 
• 
SEC (Self Evident Corrections) removed based on recent updates within 
organization to remove from all protocols 
• 
Appendix I (PK samples timepoint collection clarified based on Start of Infusion) 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  20 February 2018 
Page 1 of 15 
CONFIDENTIAL 
 
 
Amendment 1.0 
Title:  A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / Refractory Diffuse 
Large B Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma 
Amgen Protocol Number (AMG 562) 20170533 
Amendment Date: 
20 February 2018 
 
Rationale: 
The following changes were made to the protocol dated 10 January 2018 to incorporate 
requested changes from FDA IND review, updates to PK, biomarker assessments and 
administrative clarifications: 
• 
Updated dose regimens in the step-up dose exploration  
• 
Modified to specify that the DLRT may prolong the dosing interval to every 2, 3 or 
4 days. 
• 
Updated to specify that enrollment in multiple subject cohorts will be staggered 
by 3 days. 
• 
Updated to remove PPS and minocycline in the dose escalation portion of the 
protocol Section 3.1 
• 
Revised to limit subsequent dose increases to no more than 2-fold after the 
occurrence of a DLT or ≥ 2 patients experiencing a Grade 2 AE. 
• 
Revised to discontinue AMG 562 if the subject experiences Grade 3 or higher 
seizure on AMG 562. 
• 
Revised to specify a Grade (eg, less than Grade 3 which resolves to Grade 2 or 
less) and a time to resolution for the DLT exceptions of headache and insomnia; 
and to include a time to resolution for the DLT exception of Grade 3 fever in 
Section 6.2.1.3. 
• 
Updated to extend the DLT evaluation period to 28 days for single patient 
cohorts. 
• 
Updated to remove the phrase “treatment related” from rules for transition from 
single subject to multiple subject cohorts. 
• 
Updated to specify the requirement to submit a protocol amendment before 
administering doses > 1000 micrograms. 
• 
Revised to clearly state that proposed changes to the DLT window will not 
include a shorter DLT evaluation period. 
• 
Revise Table 7 to include the approved dose of 8 mg/kg of tocilizumab for 
treatment of CRS for patients. 
• 
Revised Table 7 to state that subjects who experience Grade 3 CRS should 
receive steroids and tocilizumab. 
Approved 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  20 February 2018 
Page 2 of 15 
CONFIDENTIAL 
 
 
• 
Revised to allow flexibility for use of additional medications eg, antihistamines 
and H2 blockers which could be administered prior to administration of AMG 562. 
• 
Updated to remove dosing by bolus injection. 
• 
Modified eligibility criteria to include patients with FL or MCL who have received 
three or more prior therapies. 
• 
Updated Table 8 to Table 12 (Schedule of Assessments) to: 
o remove PB for MRD assessments by NGS  
o Removed some PK and biomarker assessment time points 
• 
Updated protocol body and footnotes to reflect Table 8 to Table 12 revisions 
• 
Corrected grammar errors throughout document. 
• 
Updated Page numbers in Table of Contents.   
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 562 
Protocol Number:  20170533 
Date:  06 January 2022 
Page 1 of 35 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
20170533 
Short Protocol Title: 
A Phase 1, First-in-Human, Open-Label Study 
Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of AMG 562 in Subjects With Relapsed / 
Refractory Diffuse Large B Cell Lymphoma, Mantle 
Cell Lymphoma, or Follicular Lymphoma 
Protocol Number: 
20170533 
Authors: 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Tel: 805-447-1000 
Fax: 805-499-9495 
SAP Date: 
Document Version 
Date 
Original (v 1.0) 
SAP Amendment 1 
(v2.0) 
23 April 2018 
30 September 2020 
Enter Date 
Amendment [2 (v3.0)] 
06 January 2022 
NCT Number: NCT03571828
This NCT number has been applied to the document 
for the purposes of posting on clinicaltrials.gov


Product:  AMG 562 
Protocol Number:  20170533 
Date:  06 January 2022 
 
Page 2 of 35 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
23 April 2018 
 
Amendment 1 (v2.0) 
6 July 2020 
The purpose of SAP amendment 1 is to 
align with the Protocol Amendment 4 
dated 07 August 2019 and also to limit 
the scope of analysis due to early 
discontinuation of the study. The scope of 
the analysis is restricted to key endpoints/ 
parameters, for selected parts of the 
study in agreement with study team to be 
used for the purpose of synopsis Clinical 
Study Report. 
Amendment 2 (v3.0) 
6 January 2022 
 
Baseline section updated for 
overall survival 
 
 
Efficacy section updated by 
adding tables for secondary 
efficacy endpoints 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  06 January 2022 
 
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CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size .............................................................................................. 12 
3.3 
Adaptive Design ........................................................................................ 12 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 13 
5. 
Definitions ............................................................................................................. 13 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
All Enrolled Subjects ................................................................................. 18 
6.1.1 
Primary Analysis Set ................................................................. 18 
6.2 
Safety Analysis Set ................................................................................... 18 
6.3 
Per Protocol Set(s)  ................................................................................... 18 
6.4 
DLT Analysis Set ....................................................................................... 18 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s)  ............................... 19 
6.6 
Interim Analyses Set(s)  ............................................................................ 19 
7. 
Planned Analyses ................................................................................................. 19 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 19 
7.2 
Primary Analysis ....................................................................................... 22 
7.3 
Final Analysis ............................................................................................ 22 
8. 
Data Screening and Acceptance ........................................................................... 23 
8.1 
General Principles ..................................................................................... 23 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 23 
8.3 
Handling of Missing and Incomplete Data ................................................. 23 
8.4 
Detection of Bias ....................................................................................... 23 
8.5 
Outliers ..................................................................................................... 23 
8.6 
Distributional Characteristics ..................................................................... 23 
8.7 
Validation of Statistical Analyses ............................................................... 23 
9. 
Statistical Methods of Analysis.............................................................................. 24 
9.1 
General Considerations ............................................................................. 24 
9.2 
Subject Accountability ............................................................................... 24 
9.3 
Important Protocol Deviations ................................................................... 24 


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9.4 
Demographic and Baseline Characteristics ............................................... 25 
9.5 
Efficacy Analyses ...................................................................................... 25 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)) ................................. 25 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) ............................. 25 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s)  ............................ 26 
9.6 
Safety Analyses ........................................................................................ 26 
9.6.1 
Dose Limiting Toxicities ............................................................. 26 
9.6.2 
Adverse Events and Disease-related Events ............................. 26 
9.6.3 
Laboratory Test Results ............................................................ 27 
9.6.4 
Vital Signs ................................................................................. 28 
9.6.5 
Physical Measurements ............................................................ 28 
9.6.6 
Electrocardiogram ..................................................................... 28 
9.6.7 
Antibody Formation ................................................................... 28 
9.6.8 
Exposure to Investigational Product .......................................... 28 
9.6.9 
Exposure to Concomitant Medication ........................................ 29 
9.7 
Other Analyses ......................................................................................... 29 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 29 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 30 
9.7.3 
Analyses of Health Economic Endpoints ................................... 30 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 30 
10. 
Changes From Protocol-specified Analyses.......................................................... 30 
11. 
Literature Citations / References ........................................................................... 32 
12. 
Prioritization of Analyses....................................................................................... 33 
13. 
Data Not Covered by This Plan............................................................................. 33 
14. 
Appendices ........................................................................................................... 34 
Appendix A.  Imputation Rules for Partial or Missing Stop Dates .......................... 35 
 


Product:  AMG 562 
Protocol Number:  20170533 
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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BLRM 
Bayesian logistic regression model 
B-NHL 
B-cell Non-Hodgkin’s Lymphoma 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CMR 
complete metabolic response 
COO 
cell-of-origin 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
DLRM 
dose level review team meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicities 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
End of Follow-up 
It is defined as when the last subject completes the last 
protocol-specified assessment in the study 
End of Study (Individual 
Subject) 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject (ie, the date the subject 
withdraws full consent from the study, completes the safety 
follow-up visit or long-term follow up [whichever is later] or 
death). 
End of Study (primary 
completion) 
The time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the 
primary analysis. 
End of Study (end of trial) 
It is defined as when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, LTFU). 


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Abbreviation or Term 
Definition/Explanation 
End of Treatment 
Defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FIH 
first-in-human 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IPD 
Important Protocol Deviation 
IV 
intravenous 
MRD 
minimal residual disease  
MTD 
maximum tolerated dose 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD 
pharmacodynamics 
PET-CT 
positron emission tomography-computed tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PMD 
progressive metabolic disease 
PMR 
partial metabolic response 
PR 
partial response 
PT 
thromboplastin time 
PTT 
partial thromboplastin time 
QTc interval  
QT interval corrected for heart rate using accepted methodology 
RP2D 
recommended phase 2 dose 
RR 
respiratory rate 
SD 
stable disease 
SFU 
safety follow-up 
LTFU 
long-term follow-up 
Tmax 
time of maximum concentration 
TPI 
toxicity probability interval 
ULN 
upper limit of normal 
 
 
 
 
 


Product:  AMG 562 
Protocol Number:  20170533 
Date:  06 January 2022 
 
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CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 4 for study 20170533, 
AMG 562 dated Enter Date. 07 August 2019. The original scope of this plan included the 
interim analyses, the primary analysis and the final analysis that were planned and would 
be executed by the Amgen Global Biostatistical Science department unless otherwise 
specified. The scope of the analysis has been restricted due to the discontinuation 
of the study earlier than planned. The key analyses to be performed have been 
identified by the study team and are outlined in this revised document. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability of 
AMG 562 in adult subjects with relapsed 
/ refractory DLBCL, MCL, or FL 
 
Estimate the maximum tolerated dose 
(MTD) and/or a biologically active dose 
(eg, recommended phase 2 dose 
[RP2D]) 
 
Incidence of dose limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, 
disease-related events and 
clinically-significant changes in vital signs, 
physical examinations, electrocardiograms 
(ECG) and clinical laboratory tests 
Secondary 
 
Characterize the pharmacokinetics (PK) 
of AMG 562 
 
AMG 562 PK parameters including, but not 
limited to, maximum concentration (Cmax), 
minimum concentration (Cmin), time of 
maximum concentration (Tmax), area under 
the concentration-time curve (AUC), and if 
feasible, half-life (t1/2) 
 
Evaluate anti-lymphoma activity of 
AMG 562 
 
ORR according to Lugano classification 
 
Best Overall response by category. 
[Response terminology reflects the 
response criteria used. The Lugano 
Classification response definitions for 
positron emission tomography-computed 
tomography (PET-CT) evaluations of 
fluorodeoxyglucose (FDG)-avid 
lymphomas uses the terminology complete 
metabolic response (CMR), partial 
metabolic response (PMR), no metabolic 
response  (NMR), or progressive metabolic 
disease (PMD). Corresponding 
designations from earlier response criteria 
include complete response (CR), partial 
response (PR), stable disease (SD), or 
progressive disease (PD)] 
 
Duration of response (DOR) 


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CONFIDENTIAL  
 
 
 
Progression free survival (PFS) 
 
Overall survival (OS) 
 
Exploratory 
 
 
Evaluate the formation of anti-AMG 562 
antibodies 
 
Incidence of anti-AMG 562 antibody 
formation 
 
 
 
2.2 
Hypotheses and/or Estimations 
The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 562 
will have an acceptable safety profile and evidence of anti-lymphoma activity in patients 
with relapsed and/or refractory B-NHL, specifically DLBCL, MCL, or FL as measured by 
the overall response rate (ORR) and rate of CR. No formal hypothesis testing will be 
performed, and all statistical analyses are descriptive. 
3. 
Study Overview 
3.1 
Study Design 
This is a multicenter, Phase 1, first-in-human (FIH), non-randomized, open-label study in 
adult subjects with relapsed / refractory DLBCL, MCL, or FL. AMG 562 will be administered 
weekly as short term IV infusions (1.5 hour). 
The study will consist of up to a 21-day screening period, a treatment period, a safety 
follow-up (SFU) visit conducted 30 (+7) days after the last dose of AMG 562, and a 
long-term follow-up (LTFU) period that will begin after the SFU visit is completed. Subjects 
will be followed for response evaluation at week 5, week 15, week 25 and at end of 
treatment if end of treatment is at week 35 or beyond (± 3 days) .  Subjects who 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 9 of 35 
CONFIDENTIAL  
 
 
stopped response evaluations will be followed every 3 months (± 2 weeks) for survival 
follow-up. The total duration of the LTFU will be up to 2 years from the first dose of AMG 
562.  
Treatment Holiday 
Starting with cycle 4, a longer treatment holiday between cycles may be 
implemented on a per subject basis for individual treatment cycles after approval 
by the Amgen Medical Monitor ( see Section 6.2.1.1. of protocol for details) 
For subjects identified as having confirmed CR/CMR, investigators may choose to 
implement treatment-free intervals of 2-4 weeks (“Consolidation Phase”). For 
subjects remaining in CR/CMR at 12 months, treatment-free intervals may be 
increased to 8 weeks between cycles (“Maintenance Phase”). Treatment for these 
subjects can be continued until progression or at the discretion of the investigator. 
Treatment can be discontinued for patients remaining in CR/CMR at the discretion 
of the investigator.  
This phase 1 study consists of two parts: 
 
Part 1 includes dose exploration to evaluate the safety and tolerability of AMG 562 
as monotherapy in subjects with relapsed/refractory DLBCL, MCL, or FL. 
 
Part 2 is an evaluation of AMG 562 in a dose expansion group to gain further 
efficacy and safety experience with AMG 562 as monotherapy in subjects with 
DLBCL. Part 2 will start with a dose that is identified by the DLRT following 
estimation of the MTD/RP2D in Part 1. 
Part 1: Dose Exploration 
Up to approximately 30 subjects will be enrolled to the dose exploration cohorts to 
estimate the MTD, safety, tolerability, PK, and pharmacodynamics of different doses of 
AMG 562 in subjects with relapsed / refractory DLBCL, MCL, or FL. Dose exploration will 
be conducted in 2 stages using a Bayesian logistic regression model (BLRM) design to 
guide dose escalation. In the initial cohorts, single subjects will be enrolled at dose levels 
anticipated to be lower than the dose levels at which adverse events related to AMG 562 
may be observed. Enrollment will proceed with multiple subject cohorts of 3 to 4 subjects 
per cohort when higher dose levels are open for enrollment by the Dose Level Review 
Team (DLRT) or if at least one subject experiences any of the three safety events below 
(whichever occurs earlier): 
1. Non hematologic adverse event grade ≥ 2   


Product:  AMG 562 
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Page 10 of 35 
CONFIDENTIAL  
 
 
2. Hematologic adverse event grade ≥ 3 including anemia, neutropenia, leukopenia, 
thrombocytopenia, and lymphopenia   
3. DLT 
Enrollment of subjects at each dose level in the multiple subject cohorts will be 
staggered by at least 3 days. 
AMG 562 will be administered as IV infusions at weekly intervals. If no DLTs are observed, 
the dose escalation will continue to the next planned dose cohort as planned. Once a 
subject experiences a DLT, the dose for the subsequent cohorts will be decided by the 
DLRT after evaluating all available safety, laboratory, and PK data as well as the 
recommendation from the BLRM. Subsequent dose escalation will be limited to 2-fold 
increases or lower after a subject experiences a DLT or ≥ 2 patients experience a grade ≥ 
2 adverse event. 
The DLRT may also alter the dosing schedule (dosing interval) for subsequent cohorts. 
The changes to the dosing schedule may also include the implementation of step-up 
dosing for future cohorts based on tolerability as observed in the clinical and 
pharmacological data.  
The DLT evaluation period will be at least 28 days for all cohorts. The DLT evaluation 
period may also be extended to assess events starting within the DLT window. Any 
adverse event occurring outside the DLT window that meets the DLT definition and is 
determined by the investigator to be possibly related to AMG 562, and 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 event and all available safety data. A DLRM will be conducted after the 
subjects in each dose cohort have had the opportunity to complete the DLT evaluation 
period. The DLRT may also convene at any time to review safety data if deemed 
necessary.   
Subjects who complete the DLT period may proceed to a higher dose level for the next 
dosing (intra-subject dose escalation) once this higher dose level has been deemed safe 
by the DLRT and after consultation with the Amgen medical monitor if: 
 No DLT has been reported for this subject during or after completion of the DLT 
period 
 The subject has not experienced any ≥ grade 2 adverse events (deemed treatment 
related by the investigator) during treatment 


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DLTs experienced by subjects after completing the DLT period will be considered in the 
BLRM design to account for any late onset toxicity. 
Dose exploration will continue until any of the following events: 
 The highest planned dose level is determined to be safe and tolerable (minimum 
of 6 treated subjects) 
 An MTD is identified where BLRM repeats the recommendation of a dose level 
(minimum of 6 treated subjects) 
 If fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability. 
Further details can be found in protocol section 3. 
Step-up Dosing (Estimation of initial dose and target dose) 
Step-up dosing will be explored to prevent first dose effects like CRS or neurologic events 
that have been observed with other BiTE antibodies. It will be introduced when two or 
more DLTs consistent with potential first-dose effects are observed in one cohort. Further 
details can be found in protocol section 3. 
 
 
 


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Part 2: Dose Expansion 
Upon completion of the dose exploration part of the study, up to approximately 
55 additional subjects will be enrolled in the dose expansion part to gain further clinical 
experience, safety and efficacy data for AMG 562 in subjects with relapsed / refractory 
DLBCL. The dose to be evaluated will be at or below the MTD estimated in the dose 
exploration cohorts. Additional expansion cohorts may be enrolled to evaluate alternative 
dose levels, or biologic subsets, or other disease entities included in the dose exploration. 
A final estimate of the MTD and RP2D will be evaluated and confirmed utilizing all DLT-
evaluable subjects from the dose exploration and the dose expansion cohorts. The DLRT 
will be convened in the dose expansion part of the study to review efficacy data (with 
recruitment ongoing). Additionally, the DLRT will review safety data in the expansion part, 
after the first 15 subjects were enrolled and had the opportunity to receive at least five 
weeks of treatment (with recruitment ongoing). The guidelines for futility due to insufficient 
efficacy are in Table 2 in the protocol. Ad hoc meetings may be convened at any time by 
the DLRT to review the safety data if deemed necessary. 
3.2 
Sample Size 
It is anticipated that approximately 85 subjects will be enrolled in this study. Approximately 
30 subjects will be enrolled in the dose escalation cohorts and up to 55 additional subjects 
will be enrolled in the dose expansion cohort. The sample size in the dose escalation is 
based on practical considerations and is consistent with conventional oncology studies 
with the objective to estimate the MTD. With 3 subjects per cohort, there is a 27-70% 
probability of observing at least one DLT if the true DLT rate is 10-33% and with 4 subjects 
per cohort, there is a 34-80% probability. In the dose expansion cohort, 55 subjects will 
provide a 43% probability of observing at least one adverse event with a true 1% incidence 
rate and 94% probability of observing at least one adverse event with a true 5% incidence 
rate. With 55 subjects and a 40% ORR, the expected 90% CI would be 29% to 52%. 
3.3 
Adaptive Design 
A two-parameter Bayesian Logistic Regression Model (BLRM) is used to guide dose 
exploration.  The MTD target Toxicity Probability Interval (TPI) for DLT is (0.20, 0.33] and 
TPIs of (0.33, 0.60] and (0.60, 1.00] are defined as excessive and unacceptable, 
respectively.  The design seeks to identify a dose most likely to have a DLT rate in the 
target TPI, but with overdose control that limits the possibility the dose has an excessive 
or unacceptable DLT rate (Babb et al, 1998).  The 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: 


Product:  AMG 562 
Protocol Number:  20170533 
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Page 13 of 35 
CONFIDENTIAL  
 
 
 
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref) 
where a and b are random variables and dref is 1 of the planned dose selected as the 
reference dose.  
A bi-variate normal prior distribution (Neuenschwander et al, 2008) was selected for theta 
= (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest planned 
dose is 
 and the probability the true DLT rate is ≤ 0.05 at the reference dose is 0.05.  
These values were selected such that pi is 0.01 for the starting dose and 0.40 for the 
reference dose (
 µg).   
The operating characteristics of the two-parameter BLRM design were evaluated via 
simulation using EAST version 6.4.1.  The cohort size was fixed to 3 or 4 subjects. All 
simulated studies start with the multiple subject cohorts. The initial multiple subject dose 
level is 
 µg and subsequent doses were selected based on the following rules: 
After each cohort, the next dose is the one with the highest probability of the target TPI, 
but with a less than 0.40 probability of an excessive or unacceptable TPI. 
Dose exploration will continue until any of the following events. 
 
The highest planned dose level is determined to be safe and tolerable (minimum of 
6 treated subjects) 
 
An MTD is identified where BLRM repeats the recommendation of a dose level 
(minimum of 6 treated subjects) 
 
If fewer than 6 subjects are treated at the MTD/RP2D, additional subjects may be 
enrolled to confirm safety and tolerability. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable.  
4.2 
Subgroups 
No Subgroup analysis planned due to early termination of the study. 
5. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the 
clinical database. 
Baseline 
Unless otherwise specified, the baseline value for parameters/assessments scheduled to 
be performed on the same day as the first administration of AMG 562, is the last value 


Product:  AMG 562 
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Page 14 of 35 
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measured before the first administration of AMG 562 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 562, the baseline value is the value 
from the screening period measured closest to the day of first administration of AMG 562.  
In the event that multiple assessments are done on the same day as the first administration 
of AMG 562 and there is no time associated with the assessments, the value associated 
with the last clinically planned event before the first administration of AMG 562 will be 
used as the baseline value 
The baseline ECG is defined as the mean of all pre-dose assessments from cycle 1 day 1. 
The mean of the values within a triplicate will be calculated and used in the analysis. 
Where an ECG is missing within a triplicate, all available data will be averaged for that 
time point. 
Body Mass Index (BMI) 
Body Mass Index should be calculated using the following formula:  
BMI (kg/m2) = weight (kg) / [height (cm)/100]2  
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  
QTcB=QT/(RR/1000)1/2 
Change From Baseline 
Change from Baseline is the arithmetic difference between post-Baseline and Baseline. 
Disease-related Event (DRE) 
Disease-Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease including Lymphadenopathy, Disease 
progression, Fatigue, Weight decreased and Night sweats. 
Duration of Response (DOR) 
DOR is calculated only for subjects who achieve a response (CMR or PMR). The 
duration will be calculated from the date a response is first achieved until the earliest 
date of a disease assessment indicating a disease progression or death, whichever 
occurs first. Subjects who do not have a relapse event will be censored on their last 
disease assessment date. If the last disease assessment date is after the date that 
triggers the analysis, the subject will be censored at the analysis trigger date.  


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Censoring rule for duration of response: Data for responders who are alive and 
without disease progression are censored at the time of last evaluable disease 
assessment by PET-CT scan. 
Dose Limiting Toxicity (DLT) 
A DLT is any of the events described in section 6.2.1.3 of the protocol, occurring in a 
subject during the DLT window unless clearly attributable to causes other than AMG 562 
treatment. 
DLT Evaluable Period 
DLT evaluable period will be at least 28 days for all cohorts and may be extended to 
assess events starting within the DLT window. 
 
 


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Enrollment Date 
Enrollment Date is defined as the date of enrollment collected on the CRF. 
End of Treatment 
Defined as the last assessment for the protocol-specified treatment phase of the study 
for an individual subject. 
End of Study (Individual Subject) 
The end of study date for an individual subject is the last day that protocol-specified 
procedures are conducted for that subject. The end of study date for an individual 
subject is recorded on the end of study CRF page. 
End of Study (primary completion) 
It is defined as when the last subject is assessed or receives an intervention for the 
purposes of final collection of data for the primary analysis. 
End of Study (End of Trial) 
It is defined as when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit), following any additional parts in the 
study (eg, LTFU). 
End of Follow-up 
It is defined as when the last subject completes the last protocol-specified assessment in 
the study. 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  
QTcF=QT/(RR/1000)1/3 
Long Term Follow Up (LTFU) 
Following the SFU visit, there will be a LTFU period for clinical evaluation of disease 
status and survival.  Subjects will be followed via on-site visit every 6 weeks (± 3 days) 
for assessments of disease status and documentation of anti-lymphoma treatment until 
progression of disease.  From this time point onwards subjects will be followed every 
3 months (± 2 weeks) for survival and anti- lymphoma treatment (on-site visits are not 
required, if needed also interrogation of public databases is acceptable).  Subjects will 
be followed for a maximum of 2 years from the first dose of AMG 562, or until subject 
death, whichever occurs first. 


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Maximum Tolerated Dose (MTD) 
An estimate of the MTD will be made based on a Bayesian Logistic Regression Model 
(BLRM) utilizing all DLT-evaluable subjects from the dose exploration and dose 
expansion cohorts. Based on the BLRM, the MTD is defined as the dose with the highest 
probability of a DLT rate between the targeted toxicity (0.2, 0.33) interval while 
controlling the probability of excessive and unacceptable toxicity below 40%. 
Investigational Product 
The term ‘investigational product’ is used in reference to AMG 562. 
Objective Response 
Objective response is defined as a tumor response assessment of either complete 
metabolic response or partial metabolic response determined by Lugano Classification. 
Objective Response Rate 
ORR is defined as the incidence rate of a confirmed CMR or PMR while on study as 
defined by Lugano Classification. 
Overall Survival 
OS is calculated as the time from the first dose of AMG 562 until death due to any 
cause. Subjects who are alive at the date that triggers the analysis will be censored at 
the date last known to be alive. If the date last known to be alive is after the date that 
triggers the analysis, the subject will be censored at the analysis trigger date. 
Last known alive date: For subjects who do not have death date available i.e. 
subject was alive throughout, last known alive date is defined as the latest of all 
the date variable in the study. 
Progression Free Survival (PFS) 
PFS is calculated as the time from the date of first dose of AMG 562 until the date of 
diagnosis of progression of lymphoma, or date of death, whichever is earliest. Subjects 
who are alive and did not have progression will be censored at the last date of 
radiographic assessment of PET-CT scans. 
Study Day 
Post study day 1: study day = (date - date of Study Day 1) + 1 
Pre study day 1: study day = (date – date of Study Day 1) 
Study Day 1 


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Defined as the first day that protocol specified investigational products are administered 
to the subject.  The day prior to Study Day 1 is considered Day -1. 
Safety Follow-up (SFU) 
The SFU visit should occur approximately 30 (+7) days after the last dose of AMG 562. 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is any adverse event including disease related 
events starting on or after the first dose of investigational product, as determined by the 
flag indicating if the adverse event started prior to the first dose on the Adverse Events 
Summary CRF, and up to and including 30 days after the end of investigational product.  
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. 
Toxicity Probability Interval (TPI) 
Toxicity probability intervals for dose-limiting toxicity (DLT) are defined as (0.20, 0.33], 
(0.33, 0.60] and (0.60, 1.00] for target, excessive and unacceptable toxicity, respectively. 
Half-Life (t1/2) 
The time required for the observed concentration of a drug to be reduced by one-half. 
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set. 
6.1 
All Enrolled Subjects 
All enrolled subjects analysis set consists of the subjects who are enrolled into the study. 
6.1.1 
Primary Analysis Set 
Not applicable to this study.  
6.2 
Safety Analysis Set 
Safety analysis set is defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 562. 
6.3 
Per Protocol Set(s)  
Not applicable to this study. 
6.4 
DLT Analysis Set 


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All subjects who are DLT-evaluable (see Section 6.2.1.3 of the protocol). DLT-evaluable 
subjects are those who 1) experienced DLTs or 2) completed DLT observational period 
and did not experience DLTs. 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s)  
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
AMG 562 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. 
6.6 
Interim Analyses Set(s)  
At interim analysis with cutoff determined, the DLT data will be analyzed based on DLT 
analysis set, and other data will be reported using safety analysis set, unless otherwise 
specified. 
7. 
Planned Analyses 
The following analyses are planned. 
7.1 
Interim Analysis and Early Stopping Guidelines 
In the dose escalation part, safety data will be reviewed on an ongoing basis. Based on 
accumulating toxicity information, BLRM will be used to make dosing recommendations. 
In dose level review team meetings (DLRMs), Amgen, in consultation with the site 
investigators, will review the BLRM recommended dose level and will review all available 
cumulative data by cohort prior to making dose escalation decisions. As a sensitivity 
analysis, a one-parameter Continual Reassessment Method model may be used to 
estimate the dose-toxicity relationship to help making dose escalation decisions. Adverse 
events and DLTs observed in all subjects will be evaluated continually and fully integrated 
into all DLRMs and considered in all enrollment and dosing decisions.  
The clinical activity of AMG 562 in the dose expansion part will be examined using a 
Bayesian predictive probability design. If the posterior probability is more than 85% that 
the ORR is 40% or less, then this is considered insufficient anti-lymphoma activity. If the 
ORR is too low, enrollment may be terminated early due to insufficient anti-lymphoma 
activity. The guidelines for futility due to insufficient efficacy assuming a prior beta 
distribution (0.8, 1.2) are presented in Table 7-1. The operating characteristics in 
Table 7-2 provide the probability of stopping the trial early for given hypothetical true ORR 
rates.  


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The DLRT will be convened in the dose expansion part of the study to review efficacy data 
(with recruitment ongoing) after the first 15 subjects are enrolled and have had the 
opportunity to receive at least four weeks of treatment (with recruitment ongoing).  


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Table 7-1.  Guideline for Insufficient Efficacy 
Number of Treated Subjects 
Efficacy Futility Guideline 
15 
4 or fewer responders 
20 
5 or fewer responders 
25 
7 or fewer responders 
30 
9 or fewer responders 
35 
11 or fewer responders 
40 
12 or fewer responders 
45 
14 or fewer responders 
50 
16 or fewer responders 
55 
Trial will stop 
Table 7-2.  Operating Characteristics With Batch Size of 5 Subjects 
True ORR Rate 
Probability of Stopping Early for Futility 
Average Sample Size 
0.25 
95% 
21 
0.30 
81% 
27 
0.35 
59% 
36 
0.40 
36% 
43 
0.45 
18% 
49 
0.50 
8% 
52 
0.55 
3% 
54 
Additionally, the DLRT will review safety data and conduct evaluations of the ongoing DLT 
rate to assess if the threshold for early trial termination has been reached. The stopping 
rules use a Bayesian approach to terminate the study if the posterior probability that the 
DLT rate is greater than 33% is > 90%. The stopping boundaries assuming a prior beta 
distribution (0.66, 1.33) are presented in Table 7-3. The operating characteristics in 
Table 7-4 provide the probability of stopping the trial early for given hypothetical true DLT 
rates. The evaluations could occur more frequently if necessary to address emerging 
safety concerns. 


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Table 7-3.  Stopping Boundaries 
Number of DLT Evaluable Subjects 
Stop Study If Observing These Many DLTs 
10 
≥ 6 
15 
≥ 8 
20 
≥ 10 
25 
≥ 12 
30 
≥ 14 
35 
≥ 16 
40 
≥18 
45 
≥ 20 
50 
≥ 21 
55 
Trial will stop 
Table 7-4.  Operating Characteristics With Batch Size of 5 Subjects 
True DLT Rate 
Probability of Stopping Early 
Average Sample Size 
0.20 
1% 
55 
0.25 
4% 
53 
0.3 
13% 
51 
0.33 
22% 
48 
0.35 
31% 
45 
0.40 
56% 
37 
0.45 
79% 
29 
 
7.2 
Primary Analysis 
Originally the primary analysis would occur when target enrollment is complete and each 
subject either completes 3 months on study or withdraws from the study. Due to the 
discontinuation of the study, the primary analysis will occur at the time of study 
termination decision and include all required available data up to the point of that 
snapshot which is going to be taken for the primary analysis. This snapshot will 
have all data up to the LFTU for all subjects except one ongoing subject. 
7.3 
Final Analysis 
Originally, the final analysis would occur after all subjects have ended the study. Due to 
the discontinuation of the study, the final analysis will occur when the last enrolled 
patient has ended the study. 


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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. The database will be subject to edit checks outlined in the Clinical Data 
Management Plan (DMP). See details of this section in the DMP. 
8.3 
Handling of Missing and Incomplete Data 
Incomplete adverse event and concomitant medication dates missing data will be imputed 
as described in Appendix A. For efficacy data of overall response, subjects without tumor 
response assessments will be considered as non-responders. Otherwise, only non-
missing data will be analyzed.  
Ineligible subjects and subjects enrolled in Part 1 who are not DLT evaluable may be 
replaced. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations. 
8.5 
Outliers 
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. Suspected outliers will be included in all 
analyses unless there is sufficient scientific justification to exclude them. 
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.   


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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 9.3 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, and PK data by 
dose, dose schedule, and time as appropriate. Unless otherwise stated, the data analysis 
will be conducted using subjects in the Safety analysis set by cohorts and overall.  
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. 
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), completed safety follow-up and long term follow-up will be 
summarized by cohort and dose. 
Key study dates for the first subject enrolled, last subject enrolled and last subject’s end 
of study will be summarized. 
A summary noting inclusion in each analysis subset will be provided for all subjects 
enrolled. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, subcategory codes, and descriptions 
will be used during the course of the study.  Eligibility deviations are defined in the protocol. 
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 
Demographic (ie, age, age groups [< 65, > = 65 and < 75, and > = 75], sex, race, ethnicity) 
and baseline characteristics will be summarized by cohort and dose using descriptive 
statistics. If multiple races have been reported for a subject, the subject will be categorized 
as multiple race. 
The baseline characteristics to be summarized included: 
 
Height 
 
Weight 
 
BMI 
 
ECOG status 
 
Number of previous lines of treatment 
 
Relapse vs. refractory status 
 
Type of lymphoma 
 
Transformed Disease (yes/no) 
 
Bulky disease (yes/no) 
9.5 
Efficacy Analyses 
Due to early discontinuation of the study, limited efficacy data will be provided as 
tables and listings.  
The proportion of subjects by best overall response and best overall response 
category will be presented. Response will be determined by Lugano Classification. 
The Lugano Classification response definitions for PET-CT evaluations of FDG-avid 
lymphomas uses the terminology CMR, PMR, NMR, or PMD. Corresponding 
designations from earlier response criteria include CR, PR, SD, or PD. Objective 
response includes CMR and PMR.  
Other efficacy endpoints includes duration of response (DOR), progression-free 
survival (PFS) and overall survival (OS).  
9.5.1 
Analyses of Primary Efficacy Endpoint(s)) 
Not applicable for this study. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)  
Subject listings will be provided based on the available efficacy data. 
Proportion of subjects with best overall response and by best overall response 
category will be presented. Response will be determined by Lugano classification 


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which includes complete metabolic response (CMR), partial metabolic response 
(PMR), no metabolic response (NMR) and progressive metabolic disease (PMD). 
Proportion of subjects with an objective response of CMR or PMR per Lugano 
classification along with corresponding 90% CI will be calculated using Clopper-
Pearson method. 
DOR will be calculated only for subjects who achieve a best overall response of 
PMR or better. Subjects will be censored following the censoring strategy 
described in the definition of DOR. The distribution of DOR, including the median 
and quartiles will be characterized using the Kaplan-Meier(KM) method based on 
the subjects who achieve a best response of PMR or better. The 90% CIs for the 
median and quartiles of DOR will be constructed using the Brookmeyer and 
Crowley method. 
The distribution of PFS, including median, will be estimated using the Kaplan-
Meier method. The 90% CIs for the median and other percentiles of PFS will be 
constructed using the Brookmeyer and Crowley method. 
OS will be analyzed using the same method as describe for the PFS endpoints. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s)  
Exploratory endpoints will not be analyzed with the limited scope of analysis for the 
discontinued study. 
9.6 
Safety Analyses 
9.6.1 
Dose Limiting Toxicities 
Subject incidence of DLTs will be used to fit the BLRM model to estimate the probability 
of having a DLT across dose levels. Subject incidence of DLTs by SOC and PTs will be 
presented. 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. 
9.6.2 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19 or later will be used 
to code all events categorized as adverse events to a system organ class and a preferred 
term. 
The  below adverse event tables will not be created if two or fewer subjects experience 
the adverse event. 


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The subject incidence of adverse events will be summarized by cohort and dose group  
for all treatment-emergent adverse events, treatment-emergent serious adverse events, 
treatment-emergent adverse events leading to interruption or withdrawal from 
investigational product or other protocol-required therapies, treatment-related treatment-
emergent adverse events and fatal adverse events. The severity of each adverse event 
will be graded using CTCAE version 4.03 criteria.   
Subject incidence of all treatment-emergent adverse events, treatment-emergent serious 
adverse events, treatment-emergent adverse events leading to interruption or withdrawal 
from investigational product, treatment-emergent adverse events leading to dose 
reduction, treatment-related treatment-emergent adverse events and fatal adverse 
events will be tabulated by system organ class and preferred term in descending order of 
frequency.   
Subject incidence of disease-related events will be summarized for all treatment-emergent 
disease-related events by system organ class and preferred term. 
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) when defined will also be summarized according to their categories 
and preferred term. 
Details of each adverse event will be listed. 
9.6.3 
Laboratory Test Results 
The selected laboratory parameters of interest include: platelets, white blood cell, 
hemoglobin, absolute neutrophil count, lymphocyte, AST, ALT, total bilirubin, alkaline 
phosphatase, PT or INR, PTT, amylase, lipase, LDH, uric acid, immunoglobulins .  
Summaries of the absolute value and/or changes and percentage changes from 
baseline at each scheduled assessment will be provided by cohort and dose. 
Additionally, summary of toxicity grades will be provided for laboratory analytes 
for which CTCAE grades are available by cohort and dose .  
Potential Hy’s law cases will be summarized. A Hy’s Law case is defined as:  AST or 
ALT values of ≥ 3x ULN AND with serum total bilirubin (TBIL) level of > 2x ULN or INR > 
1.5 without signs of cholestasis and with no other clear alternative reason to explain the 
observed liver-related laboratory abnormalities  


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9.6.4 
Vital Signs 
Summary statistics for each vital sign parameter (e.g., systolic / diastolic blood pressure, 
heart rate, respiratory rate, temperature and pulse oximetry )will be provided for baseline 
and each scheduled post-baseline assessment. summaries of changes and percentage 
changes from baseline over time will be provided at scheduled time points as per protocol.  
9.6.5 
Physical Measurements 
Subject’s weight, height and BMI will be presented as part of baseline 
characteristics. 
9.6.6 
Electrocardiogram 
Where multiple ECG measurements are taken at the same assessment the mean value 
will be calculated and used in the analysis. For baseline ECG, mean value of the three 
triplicates 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 and percentage changes from baseline over time 
will be provided for all ECG parameters at scheduled time points as per protocol.  
 
9.6.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 562 antibodies 
(binding and/or neutralizing) at any time may be summarized by cohort and dose. 
Positive anti-AMG 562 antibody data will be reviewed for each subject. Summaries of 
positive anti-AMG 562 antibody test results over time may be provided. 
9.6.8 
Exposure to Investigational Product 
Details for each AMG 562 administration will be reviewed 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.  
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be summarized 
by preferred term or category as coded by the World Health Organization Drug (WHO 
DRUG) dictionary.   


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9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
The PK analyses will be performed by CPMS group. 
Serum concentrations of AMG 562 will be determined using a validated assay.  
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). Pharmacokinetic parameters will be 
estimated using standard non-compartmental approaches based on the PK analysis set 
and summarized by dose level using means, standard deviations, medians, minimums, 
and maximums.  
Serum concentrations below the lower limit of quantification 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.  


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Individual concentration-time data will be summarized by dose level. Individual 
concentration-time data will also be tabulated and presented graphically. Summary 
statistics will be computed for each sampling time and parameter as appropriate.  
Additional PK analyses, including but not limited to analysis of the relationship between 
AMG 562 dose and exposure parameters (AUC and Cmax) and dose proportionality 
assessments, may also be conducted.  
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable for this study. 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable for this study. 
9.7.4 
Analyses of Biomarker Endpoints 
Not applicable due to restricted scope of analysis post the discontinuation of the 
study. 
10. 
Changes From Protocol-specified Analyses 
To restrict the scope of analysis post the discontinuation of the study, following changes 
were made in the reporting of results from protocol-specified analysis: 
 
Primary analysis to include the reduced set of analyses at time of decision to 
terminate the study. Final analysis will include the follow-up for the single patient 
still receiving treatment. 
 
Analysis of exploratory endpoints will not be performed. 
 
Probability of each TPI and DLT will not be summarized.  
 
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 will not be provided for selected laboratory parameters of 
interest.   
 
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 not be provided for selected laboratory parameters of 
interest. 


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 
The number and percentage of subjects experiencing treatment emergent 
laboratory toxicities with worst post dose CTCAE grades of 1, 2, 3 and 4 will not 
be presented. 
 
A listing of laboratory toxicity grade 3 or higher will not be provided. 
 
Vital signs listing will not be provided. 
 
Summary and shift table for ECOG will not be provided. 
 
ECG listing will not be provided. 
 
Analysis of biomarker endpoints will not be performed. 
 


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11. 
Literature Citations / References 
Babb J, Rogatko A, Zacks S. Cancer Phase I Clinical Trias: Efficient Dose Escalation 
with Overdose Control. Statistics in Medicine 1998; 17:1103-1120  
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008 Jun 15; 27(13):2420-39 
Clopper C.J. and Pearson E.S. The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika Vol. 26, No. 4 (Dec., 1934): 404-413 


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12. 
Prioritization of Analyses 
Not Applicable for the study. 
13. 
Data Not Covered by This Plan 
All data are covered by this plan and this section is no longer applicable post the 
discontinuation of the study.  


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14. 
Appendices 
 
 
 
 
 
 
 
 
 
 


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Appendix A.  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 
concomitant medication 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.