Clinical trial NCT03296696
Conditions: Glioblastoma or Malignant Glioma
Keywords: Phase 1/1b EGFRvIII-positive glioblastoma or malignant glioma safety and tolerability AMG 596
Sponsor: Amgen
Start date: 2018-04-18; Completion date: 2021-08-28
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 monotherapy or in combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII).

This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive glioblastoma or malignant glioma. This study will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and maintenance treatment after SoC in newly diagnosed disease (Group 2).

Detailed description:

Arms: arm 1: Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404 arm 2: Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404
Interventions: intervention 1: AMG 596 intervention 2: AMG 404
Intervention descriptions: intervention 1: Drug intervention 2: Drug

Protocol documents:
Prot_000.pdf: 
Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 1 of 169
CONFIDENTIAL
Title:  Phase 1
Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 596 as Monotherapy and in Combination With 
AMG 404 in Subjects With Glioblastoma or Malignant Glioma Expressing Mutant 
Epidermal Growth Factor Receptor Variant III (EGFRvIII)
AMG 596
Amgen Protocol Number 20160132 
IND Number 134352
EudraCT number 2017-001658-32
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320 
Phone: +1 805-447-1000
Key Sponsor Contact(s):
, PhD
Early Development Lead
Phone: 
Email: 
, PhD
Clinical Research Study Manager
Phone 
Email: 
Date:
28 April 2017
Amendment 1 Date:
05 July 2017
Amendment 2 Date:
30 January 2018
Amendment 3 Date:
17 May 2018
Amendment 4 Date:
Amendment 5 Date: 
11 March 2019
29 July 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; Australia 1800 803 
638; France + 33 (0)9 69 363 363; Germany, +49 800 264 36-44; Netherlands, +31 76 
5732500; Spain 900850153; Amgen’s general number in the US (1-805-447-1000).
Approved
NCT Number: NCT03296696
This NCT number has been applied to the document
for the purposes of posting on clinicaltrials.gov


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 2 of 169
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled, “Phase 1
Study to Evaluate Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 as Monotherapy 
and in Combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma 
Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) dated
29 July 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 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 3 of 169
CONFIDENTIAL
Protocol Synopsis
Title:  Phase 1
Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 596 as Monotherapy and in Combination with AMG 404 in Subjects 
with Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor 
Variant III (EGFRvIII)
Study Phase:  1
Indication:  EGFRvIII-positive glioblastoma (GBM) or malignant glioma after recurrence or as 
maintenance after Standard of Care (SoC) treatment in newly diagnosed subjects
Primary Objective:  
Evaluate the safety and tolerability of AMG 596 administered by continuous intravenous (cIV) 
infusion in monotherapy (Arm 1) and in combination with AMG 404 (anti-programmed cell death-1 
(PD-1) antibody ( Arm 2) in subjects with EGFRvIII-positive glioblastoma or malignant glioma in 
the recurrent setting (Group 1) and in the maintenance treatment phase of newly diagnosed 
glioblastoma (maintenance setting Group 2)
Secondary Objective(s):  

Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by cIV 
infusion either in monotherapy or in combination with AMG 404

Evaluate the pharmacokinetics (PK) of AMG 404 in serum when administered by short 
term infusion in combination with AMG 596

Evaluate the clinical benefit of AMG 596 and AMG 596 in combination with AMG 404 as 
determined by objective response rate (ORR) per modified Response Assessment in 
Neuro-Oncology Criteria (RANO) in subjects with EGFRvIII-positive glioblastoma or 
malignant glioma in the recurrent and in the maintenance setting

Evaluate progression free survival (PFS) at 6 and 12 months after initiation of treatment
for any Part, Arm and Group of the study
Exploratory Objective(s):
Hypotheses:  

AMG 596 monotherapy and in combination with AMG 404 are safe and well tolerated in 
at least one dose level when administered in subjects with EGFRvIII-positive 
glioblastoma, or malignant glioma in the recurrent (Group 1) and in the maintenance 
setting (Group 2)

AMG 596 monotherapy and/or AMG 596 in combination with AMG 404 can induce 
objective tumor shrinkage and/or overcome lack of response to SoC in subjects with 
EGFRvIII-positive glioblastoma or malignant glioma in either recurrent or in the 
maintenance setting at a tolerable dose.
Primary Endpoint:

Dose limiting toxicities (DLT), treatment-emergent adverse events, treatment-related 
adverse events and changes in vital signs, physical examinations, and clinical laboratory 
tests
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 4 of 169
CONFIDENTIAL

Secondary Endpoint(s): PK parameters for AMG 596 including, but not limited to, 
average steady-state concentration (Css), area under the concentration-time curve (AUC), 
clearance, volume of distribution and half-life (t1/2) for serum AMG 596 

PK parameters of AMG 404 including, but not limited to, maximum observed serum 
concentration (Cmax), time to achieve Cmax (tmax) and AUC. 

PK parameters for AMG 596 dosed in combination with AMG 404 including, but not 
limited to, average steady-state concentration (Css), area under the concentration-time 
curve (AUC), clearance, volume of distribution and half-life (t1/2) for serum AMG 596 

Objective response (OR) as per modified RANO, time to response, response duration 
and time to progression (TTP); progression free survival (PFS) at 6 and 12 months after 
treatment initiation with AMG 596 monotherapy or AMG 596 in combination with
AMG 404

Exploratory Endpoint(s): 
Study Design:  
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with 
EGFRvIII-positive glioblastoma or malignant glioma exploring of AMG 596 monotherapy (Arm 1) 
and the combination of AMG 596 with AMG 404 (Arm 2). Both Arm 1 and Arm 2 consist of 2 
parts, dose escalation (Part 1) and dose expansion (Part 2).  Both Arm 1 and Arm 2 will enroll 
2 groups of subjects according to disease stage, recurrent disease (Group 1) and maintenance 
treatment after SoC in newly diagnosed disease (Group 2). Part 1, Dose Escalation: The 
purpose of dose escalation is to make a preliminary estimate of the Recommended Phase 2 
Dose (RP2D)/ Maximum Tolerated Dose (MTD) of AMG 596 monotherapy and in combination 
with AMG 404. Treatment is divided into 2 periods: (1) DLT period 1 for 
 of 
AMG 596 infusion and (2) DLT period 2 for 
 of infusion (applies for both Arms). 
This distinction between DLT period 1 and DLT period 2 is maintained throughout dose escalation 
until the end of the dose escalation phase.  Observations from other bispecific T-cell engager 
(BiTE®) studies have shown that the occurrence of initial non-cumulative toxicities associated with 
cytokine release within the first 48 hours after start of infusion may limit dose escalation resulting 
in the utilization of below doses assumed to be associated with anti-tumor activity. However, 
should the initial dose (DLT period 1) be limited by severe adverse events related to first dose 
effects (eg, cytokine release associated adverse events), an MTD for the first dose step may be 
defined.  Further dose escalation in DLT period 2 is possible resulting in a step-dosing and a 
second (and higher) MTD. This approach supports the ongoing evaluation of initial toxicity, as 
well as after an MTD for the start dose has been defined. 
The start dose based on preclinical evaluations for the estimation of the Minimum Anticipated 
Biological Effective Level (MABEL) is 
 µg/day. 
Further pre-specified nominal AMG 596 doses for potential use in any dose escalation Arms are 
 µg/day. The dose level review team (DLRT) 
may consider treating at intermediate doses if required. If the MTD or a biological active dose 
considered the RP2D is not reached within the pre-planned nominal dose range, the DLRT may 
decide to expand the nominal dose range to dose levels 
 µg/day after careful 
consideration of all available safety, laboratory, and PK information. The preliminary estimate of 
the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent disease (Group 1) and 
separately in subjects with maintenance treatment after SoC in newly diagnosed disease 
(Group 2) and separately for AMG 596 monotherapy and in combination with AMG 404. 
If the same AMG 596 doses are to be explored in monotherapy and in combination, the 
monotherapy cohort must be completed before enrollment in the combination cohort. In the 
multiple subject cohorts, a safety observation window of at least 72 hours must apply between 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 5 of 169
CONFIDENTIAL
start of subjects 1, 2 and 3 of each dose escalation cohort. Intra-subject dose escalation will be 
allowed to higher AMG 596 dose levels in subsequent treatment cycles once a higher dose has 
been deemed safe by the DLRT. Subjects who do not proceed to a higher dose may continue at 
the original dose. 
Group 1, Recurrent Disease

Dose Escalation in single subject cohorts:

In first cohorts AMG 596 will be administered as a cIV infusion for 
 
 at escalating doses with N=1 per cohort.  In the single subject cohorts, only a 
limited number of subjects will be enrolled at dose levels anticipated to be lower 
than those at which visible pharmacodynamics activity including adverse events 
related to AMG 596 therapy will be expected.  In addition, the investigator 
together with the subject will decide on subsequent treatment duration carefully.  
Subjects are allowed to stay on study in 
 cycles until 
discontinuation criteria apply.

Combination of AMG 596 and AMG 404: The starting dose of AMG 596 is 
ug/day administered in
cycles and the defined 
AMG 404 dose is
mg every 4 weeks. 

The cohort size will be increased to N=2-4 subjects (ie, Start of multiple subject 
cohorts) after observation of 

Treatment-related adverse events of common terminology criteria for 
adverse events (CTCAE 4.0) grade 2 or higher and/or

Quantifiable cytokine levels in blood or CSF above baseline

Dose Escalation in multiple subject cohorts: 

Subjects in the first multiple subject cohort receive the same dose as the last 
single subject cohort

All subjects receive AMG 596 in
infusion cycles until 
treatment discontinuation criteria apply. 
It is anticipated that dose-escalation will proceed according to the pre-planned nominal 
doses though intermediate dose levels may be used if required after reviewing all 
available safety data.  When a first DLT is observed, the Bayesian logistic regression 
model (BLRM) will be used to guide dose level selection (Neuenschwander et al., 2008). 
The cohort size will be N=2-4 subjects. On a limited basis, after agreement between the 
investigator and medical monitor, one additional subject may be allowed to be enrolled if 
the subject has been determined to be eligible and the cohort has been filled. In this 
case, all five subjects will be reviewed and assessed in the Dose Level Review Meeting 
(DLRM). After each cohort, the model’s recommended MTD dose level for evaluation is 
the dose level with the highest probability of the target toxicity probability interval (TPI), 
but with a less than 0.25 probability of an excessive or unacceptable TPI. The target TPI 
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 actual dose selected at each dose decision may be at or 
below the model’s recommended dose as determined by the DLRT after considering all 
information.  Dose escalation will be completed when any of the following occurs:

The maximum total sample size of N=45 DLT evaluable subjects (including single 
subject cohorts) is reached for AMG 596 monotherapy and N=30 DLT evaluable 
subjects for AMG 596 in combination with AMG 404

The BLRM model recommends the same dose level at least 2 times and that at least 
6 subjects have been treated at the recommended RP2D/MTD dose level. If 
step -dosing is required, this stopping criterion applies separately to each period.

The highest planned dose level is reached without any DLTs being observed
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 6 of 169
CONFIDENTIAL
Group 2, Maintenance Treatment after SoC in Newly Diagnosed Disease

A first cohort will start after observation of a first objective anti-tumor response in Group 1
subjects with recurrent EGFRvIII-positive glioblastoma or malignant glioma. The starting
dose of AMG 596 monotherapy in Group 2 will be decided by DLRT and will be the
current highest dose deemed safe of Group 1. Treatment may consist either of 
dose AMG 596 cIV infusion or step-dosing as established for recurrent disease.  Further
treatment cycles with 
 between cIV infusions will be provided until any of
the treatment discontinuation criteria applies.

The starting dose of AMG 596 in combination with AMG 404 for Group 2 will be one dose
level below the selected start dose for AMG 596 monotherapy and an AMG 404 dose of
 mg.

The BLRM will be used to guide dose level selection. The cohort size will be N=2-4 
subjects. The actual dose selected at each dose decision may be at or below the model’s 
recommended dose as determined by the DLRT after considering all information.

Dose escalation in Group 2 will be completed when any of the following occurs.

The maximum sample size of N=15 DLT evaluable subjects is reached for AMG 596
monotherapy or N=20 DLT evaluable subjects for the AMG 596 in combination with
AMG 404.

At least 6 subjects have been treated at the recommended RP2D/MTD dose level

The highest pre-specified nominal dose level is reached without any DLTs being
observed
Part 2: Dose Expansion
The purpose of dose expansion will be to further explore safety and to evaluate preliminary 
antitumor activity in subjects with recurrent disease (Group 1) and in subjects in the maintenance 
setting (Group 2). It is anticipated that 15 subjects will be enrolled to Group 1 and up to 
25 subjects will be enrolled to Group 2. 
In Group 2 (maintenance setting), the objective response rate (ORR) of interest is 20% or higher 
while an ORR of 5% or less is considered insufficient antitumor-activity. The ORR in Group 2 will 
be evaluated after 10 subjects are treated and have been evaluated at the first on study imaging 
scan or have discontinued the study before that. If ORR is lower than 5%, enrollment may be 
terminated due to futility. Otherwise, the ORR will be evaluated for additional new subjects and 
the futility stopping rules are calculated using a Bayesian predictive probability design 
(see Section 10.2. for details). 
A BLRM design may be used to update the estimate of the RP2D/MTD using data from subjects 
enrolled to dose escalation and dose expansion. Based on this revised RP2D/MTD estimate and 
reviewing all available safety data, the dose level for dose expansion may be revised.
The subjects enrolled in Part 2 dose expansion will be followed for imaging evaluation until the 
earliest of: clinically significant disease progression, death, consent withdrawal, start of new 
anti-tumor therapies or 12 months after treatment initiation. Subjects who stopped treatment will 
be contacted for long term follow up for up to 12 months after treatment initiation.
Sample Size:  It is anticipated that around 190 subjects will be enrolled in the study, up to 
100 subjects will be enrolled to Arm 1 and up to 90 subjects will be enrolled to Arm 2. Enrollment 
for Arm 1 and Arm 2 will occur at 12 or more sites across US, Australia and Europe.
For Group 1 (recurrent disease), the following are the planned sample sizes.

In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to monotherapy Arm 1
and up to 30 DLT-evaluable subjects to combination Arm 2

In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and up to
15 subjects to combination Arm 2.
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 7 of 169
CONFIDENTIAL
For Group 2 (maintenance setting), the following are the planned sample sizes.

In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 
and up to 20 DLT-evaluable subjects to combination Arm 2 

In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and up to 
25 subjects to combination Arm 2
The sample size in dose escalation is based on practical considerations and it is consistent with 
conventional oncology studies with the objective to identify the RP2D/MTD. With 2 subjects per 
cohort, there is a 19-56% probability of observing at least one DLT for a cohort if the true DLT 
rate is 10-33% and with 6 subjects per cohort, the probability is 47-91%.
For both Arm 1 and Arm 2, the sample size for Group 1 dose expansion is based on practical 
considerations. With 21 subjects treated at the respective Group 1 RP2D/MTD (6 from dose 
escalation and 15 from dose expansion), there is a 66% probability of observing an adverse event 
with 5% incidence rate. For an objective response rate (ORR) of 20%, the probability of
observing the OR in at least 4 subjects would be 63%. The estimated ORR for 4 responses is 
19% (exact 80% confidence interval (CI): 9%-35%).
For both Arm 1 and Arm 2, the sample size for Group 2 dose expansion is based on a Bayesian 
predictive probability design (Lee, 2008). In Group 2, the ORR of interest is 20% or higher while 
an ORR of 5% or less is considered insufficient antitumor-activity. The maximum sample size is 
31 subjects (6 from dose escalation and 25 from dose expansion).  Futility will be assessed 
initially after treating 10 subjects have been evaluated at the first imaging scan or have dropped 
out before that and continuously for each additional subject afterwards. If ORR is lower than 5%, 
enrollment may be terminated due to futility.  See Section 10.2 for early termination guideline 
details. 
With this design, the probability of accepting the treatment is 0.05 (type I error) when ORR=5% 
and 0.8 (power) when ORR=20%.  If the ORR is 5%, the probability of stopping the trial early at 
the interim with 10 evaluable subjects for futility is 60% and the expected additional subjects to be 
assessed in dose expansion is 9.6. 
Investigational Product (IP)
Amgen Investigational Product Dosage and Administration: AMG 596, AMG 404 and the 
intravenous solution stabilizer (IVSS) will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  
AMG 596 is supplied as a sterile, single-use, preservative-free concentrate for solution for 
infusion in a vial containing  mg/mL AMG 596.  The drug product is formulated with 10 mM 
sodium acetate, 9% sucrose, 0.01% (w/v) polysorbate 80, pH 5.5.  The final container is a 5cc 
glass vial and contains 1 mL deliverable volume of AMG 596.  
AMG 404 is supplied in a 3 mL Type 1 glass tubing vial containing 1 mL deliverable volume of 
mg/mL. The drug product is formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) 
sucrose, 0.01% (w/v) polysorbate 80, pH 5.2 and will be prepared for IV administration by dilution.
IVSS is supplied in 10 mL single-use glass vials as a sterile, preservative-free, clear, 
colorless-to---slightly-yellow liquid concentrate.  It consists of 25 mM citric acid monohydrate, 
1.25 M L-lysine hydrochloride, and 0.1% (w/v) polysorbate 80, pH 7.  The IVSS is intended to 
prevent adsorption of AMG 596 to surfaces of the infusion components.
AMG 596 solution for intravenous infusion will be prepared in bags for IV infusion and delivered 
through infusion lines using preprogrammed infusion pumps approved for use in the country in 
which the subject is undergoing treatment. The drug will be administered as a cIV infusion at a 
constant flow rate for 
 cycles or over
 cycles, followed by a 
 
infusion-free interval prior to the following treatment cycle, until confirmed disease progression. 
The start dose based on preclinical evaluations for the estimation of the MABEL is 
 µg per 
day.  Further pre-planned dose levels are 
 
 µg per day; step-dosing can be introduced. 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 8 of 169
CONFIDENTIAL
AMG 404 will be delivered using infusion pumps approved for use by the appropriate regulatory 
authority for the country in which the subject is undergoing treatment. AMG 404 solution for 
infusion will be prepared in bags for IV infusion and delivered through infusion lines.  The drug will 
be administered as an IV infusion at a constant flow rate over 30 minutes every 
  
The RP2D/ MTD or highest tested dose per group will be administered in the dose-expansion 
cohorts.
Procedures: The pre-screening evaluation is optional and serves to pre-determine 
EGFRvIII -positivity. Pre-screening can start once written informed consent for pre-screening has 
been obtained.  Up to 500 subjects with diagnosed glioblastoma or malignant glioma may 
undergo the pre-screening evaluation, which can be performed any time prior to signing consent 
for study participation.  During pre-screening, a tissue and/or plasma or CSF sample obtained 
any time after initial diagnosis of glioblastoma or malignant glioma will be collected and tested by 
an appropriate In Vitro Diagnostic (IVD) assay(s) for EGFRvIII-positivity (further details on the 
screening assays are provided in Section 7.2.1). After EGFRvIII-positivity has been confirmed 
and prior to signing consent for study participation, the subject may still receive one or more 
antitumor-treatments. Subjects may also enter directly into the screening period without 
pre-screening.
All subjects will be hospitalized for the following periods: 
Cycle 1: 

For the first 
 of AMG 596 monotherapy (Arm 1) 

For the first 
 of AMG 596 in combination with AMG 404 (Arm 2), hence AMG 404 
will be administered on 

For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 and Arm 2 

For additional 72 hours after AMG 596 step dose if necessary
Cycle 2 and all subsequent cycles: 

For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2

For additional 72 hours after AMG 596 step dose if necessary. 
Hospitalization may be shortened to 48 hours from the 6th cycle onwards at the discretion of the 
investigator.
AMG 404 can be administered in an outpatient setting starting from cycle 1 
onwards. 
Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after 
start of each AMG 404 infusion from cycle 1 
onwards.
Restart of infusion should be performed in the clinic/hospital under the supervision of the 
investigator or designee and the subject should be hospitalized for a minimum of 24 hours when 
the infusion interruption meets the following criteria:

associated to an AE, or

interruption > 24 hours due to a pump related issue.
Dosing with AMG 596 or the combination of AMG 596 and AMG 404 can continue unless the 
subject becomes intolerant to investigational product, the signs and symptoms of clinical 
progression are evident as determined by the investigator, or the subject withdraws consent. 
Tumor evaluations by MRI will occur every 10 to 12 weeks from treatment initiation.  Earlier 
assessments can be made if clinically indicated at the discretion of the investigator. Modified 
RANO criteria will be used allowing subjects to stay on study until discontinuation criteria are met. 
Upon discussion with the Sponsor, subjects may continue to receive treatment beyond 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 9 of 169
CONFIDENTIAL
radiographic confirmation of progressive disease as long as they continue to derive clinical 
benefit and until further increase in tumor burden. For analyses purpose, date of progressive 
disease (PD) is the date of initial observed clinical or radiographic PD.
Assessments during the course of the study include: Clinical evaluation (physical examination, 
Eastern Cooperative Oncology Group [ECOG] status, height, and weight), vital signs, pulse 
oximetry, neurological evaluation, electrocardiogram (ECG) triplicate measurement, laboratory 
assessments (including serum pregnancy test, if applicable, coagulation, hematology, chemistry, 
urinalysis, hepatitis serology, human immunodeficiency virus (HIV) test, 
 
 
  For a full list of study procedures, including the timing of each procedure, please 
refer to Section 7 and the Section 7.1 Schedule of Assessment.
Statistical Considerations:
A primary analysis will be performed for each group separately when target enrollment in Part 1 
and Part 2 is complete and each subject either completes 6 months on study or withdraws from 
the study.  
For both Arm 1 and Arm 2, in dose escalation, the DLRT will review the safety data after each 
cohort and make a decision on the next dose level to be explored for the estimate of RP2D/MTD 
based on a BLRM design. For both Arm 1 and Arm 2, in dose expansion for Group 2, futility will 
be assessed initially for N=10 and continuously afterwards using a Bayesian predictive probability 
design.  
Descriptive statistics will be provided for selected demographics, safety, PK, PD, efficacy and 
biomarker data by dose, dose schedule, and time as appropriate.  Descriptive statistics on 
continuous data will include means, medians, standard deviations and ranges, while categorical 
data will be summarized using frequency counts and percentages.  ORR will be presented with 
80% Clopper-Pearson exact CI.  PFS will be summarized using Kaplan-Meier (KM) method. 
Graphical summaries of the data may also be presented.
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc.
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 10 of 169
CONFIDENTIAL
Figure 1. Study Design and Treatment Schema
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 11 of 169
CONFIDENTIAL
Study Glossary
Abbreviation or Term
Definition/Explanation
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AMG 596
Anti EGFRvIII Bispecific T-cell Engager
ANA
Anti-nuclear antibody
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BiTE®
Bispecific T-cell engager
BLRM
Bayesian logistic regression model
CAR
Chimeric antigen receptor
CBC
Complete blood count
CEA
Carcinoembryonic antigen
CI
Confidence interval
cIV
Continuous intravenous
CNS
Central nervous system
CPK
Creatine phosphokinase
CR
Complete response
CRP
CRS
C-reactive protein
Cytokine-release syndrome
CSF
Cerebrospinal fluid
Cmax
Maximum serum concentration
Css
Steady-state drug concentration in plasma during constant-rate infusion
CTCAE
Common terminology criteria for adverse events
d
Day
DILI
Drug induced liver injury
DLRM
Dose level review meeting
DLRT
Dose level review team
DLT
Dose-limiting toxicity 
DNA
Deoxyribonucleic acid
DW
Diffusion-weighted
DWI
Diffusion-weighted imaging
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 12 of 169
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
EC50
50% of the maximal effective concentration level
EC90
90% of the maximal effective concentration level
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ECOG
Eastern cooperative oncology group
EGF
Epidermal growth factor
EGFRvIII
Epidermal growth factor receptor variant III
EOT
End of treatment, defined as the last assessment for the protocol 
specified treatment phase of the study for an individual subject
EOI
End of infusion
EudraCT
European clinical trials database
eSAE
Electronic serious adverse event (form)
FDA
Food and drug administration
FFPE
Formalin-fixed, paraffin-embedded
FIH
First in human
GBM
Glioblastoma 
GCP
Good clinical practice
GGT
Gamma glutamyltransferase
GLP
Good laboratory practice
Heart rate
Number of cardiac cycles per unit of time
HepBsAg
Hepatitis B surface antigen
HepCAb
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HNSTD
Highest non-severely toxic dose
hr
Hour
ICF
Informed consent form
ICH
International conference on harmonisation
ICMJE
International committee of medical journal editors
IDH
Isocitrate dehydrogenase
IEC
Independent ethics committee
IHC
Immunohistochemistry
IND
Investigational new drug
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Abbreviation or Term
Definition/Explanation
INR
International normalized ratio
IP
Investigational product
IPIM
Investigational product instruction manual
IRB
Institutional review board
IUD
Intrauterine device
IVD
In vitro diagnostic
IVSS
Intravenous solution stabilizer
kg
Kilogram
KM
Kaplan-Meier method
L
Liter
LDH
Lactate dehydrogenase
LKM 1
Liver kidney microsomal antibody 1
1st LGBM
Glioblastoma in first line maintenance
LTFU
Long term follow-up
MABEL
mAB
Minimum anticipated biological effective level
Monoclonal antibody
MDRD
Modification of Diet in Renal Disease
mg
Milligram
MHC
Major histocompatibility complex
min
Minute
mL
Milliliter
mM
Millimolar
MPV
MRI
Mean platelet volume
Magnetic resonance imaging
MTD
Maximum tolerated dose
MW
Molecular Weight
NASH
Nonalcoholic fatty liver disease, including steatohepatitis
ng
Nanogram
nM
Nanomolar
OR
Objective response
ORR
Objective response rate
PBMCs
Peripheral blood mononuclear cells
PK
Pharmacokinetic
PCR
Polymerase chain reaction
PD
Progressive disease
PD
Pharmacodynamic
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Abbreviation or Term
Definition/Explanation
POR
Proof of receipts
pg
Picogram
Primary Completion
Defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), for 
the purposes of conducting the primary analysis, whether the study 
concluded as planned in the protocol or was terminated early 
PR
Partial response
RANO
Response assessment in neuro-oncology
RBC
Red blood cell count
rGBM
Recurrent Glioblastoma
RDW
Red cell distribution width
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SCR
Screening
SD
Stable disease
SEC
Self-evident corrections
SFUP
Safety follow up visit: defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, 
long-term follow-up), as applicable 
SoC
Source Data
Standard of care
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 
product(s)/protocol-required therapies is/are administered to the subject
t1/2
Terminal-phase elimination half-life
TBL
Total bilirubin
TMZ
Temozolomide
TNF
Tumor necrosis factor
TPI
Toxicity probability interval
TTP
Time to progression
T2/FLAIR
T2-weighted fluid-attenuated inversion recovery
ULN
Upper limit of normal
Approved 
 
 


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Abbreviation or Term
Definition/Explanation
Vss
Apparent volume of distribution at steady state
WBC
White blood cell
WHO
World health organization
w/v
Weight/volume
µg
Microgram
Approved 
 
 


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Table of Contents 
Protocol Synopsis ............................................................................................................. 3 
Study Glossary ................................................................................................................ 11 
1. 
OBJECTIVES ......................................................................................................... 22 
1.1 
Primary ....................................................................................................... 22 
1.2 
Secondary .................................................................................................. 22 
1.3 
Exploratory ................................................................................................. 22 
2. 
BACKGROUND AND RATIONALE ........................................................................ 22 
2.1 
Disease ....................................................................................................... 22 
2.2 
Amgen Investigational Product Background AMG 596 .............................. 26 
2.2.1 
Nonclinical Pharmacology .......................................................... 26 
2.2.2 
Nonclinical Pharmacokinetics ..................................................... 27 
2.2.3 
Toxicology .................................................................................. 27 
2.3 
Amgen Investigational Product Background AMG 404 .............................. 28 
2.3.1 
Nonclinical Pharmacology .......................................................... 28 
2.3.2 
Nonclinical Pharmacokinetics ..................................................... 28 
2.3.3 
Toxicology .................................................................................. 29 
2.4 
Risk Assessment ........................................................................................ 29 
2.4.1 
AMG 596 Monotherapy .............................................................. 29 
2.5 
Study Rationale .......................................................................................... 32 
2.5.1 
Rationale for AMG 596 Monotherapy ......................................... 32 
2.5.2 
Rationale for the Combination of AMG 596 With 
AMG 404 .................................................................................... 33 
2.5.3 
Dose Rationale ........................................................................... 34 
2.5.3.1 
AMG 596 Monotherapy ............................................ 34 
2.5.3.2 
AMG 596 in Combination With AMG 404 ................ 36 
2.6 
Clinical Hypotheses .................................................................................... 37 
3. 
EXPERIMENTAL PLAN ......................................................................................... 37 
3.1 
Study Design .............................................................................................. 37 
3.2 
Number of Sites .......................................................................................... 43 
3.3 
Number of Subjects .................................................................................... 43 
3.4 
Estimated Study Duration ........................................................................... 44 
3.4.1 
Study Duration for Subjects ........................................................ 44 
3.4.2 
End of Study ............................................................................... 44 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 44 
4.1 
Inclusion Criteria ......................................................................................... 44 
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4.2 
Exclusion Criteria ........................................................................................ 46
5.
SUBJECT ENROLLMENT ..................................................................................... 48
5.1 
Treatment Assignment ............................................................................... 50
6.
TREATMENT PROCEDURES ............................................................................... 51
6.1 
Classification of Product(s), Medical Device(s), and/or 
Combination Product(s) .............................................................................. 51
6.2 
Investigational Products ............................................................................. 51
6.2.1
Amgen Investigational Product AMG 596 and IVSS .................. 51
6.2.1.1
Dosage, Administration, and Schedule for 
AMG 596 .................................................................. 52
6.2.1.2
Overdose ................................................................. 54
6.2.1.3
AMG 596 Outpatient Dosing .................................... 54
6.2.2
Amgen Investigational Product AMG 404 ................................... 55
6.2.2.1
Dosage, Administration, and Schedule for 
AMG 404 .................................................................. 55
6.2.2.2
Overdose ................................................................. 56
6.2.3
Dose Escalation, Stopping Rules and Dose-limiting 
Toxicities (DLTs) ........................................................................ 56
6.2.4
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 57
6.2.4.1
AMG 596 .................................................................. 57
6.2.4.2
AMG 404 .................................................................. 61
6.2.5
Permanent Discontinuation ........................................................ 62
6.3 
Specific Recommendations for Cytokine Release Syndrome, 
Neurologic Events and Hepatotoxicity ........................................................ 63
6.3.1
Cytokine Release Syndrome (CRS) ........................................... 63
6.3.2
Infusion Interruption/Dose Modification due to 
Neurologic Events ...................................................................... 65
6.3.3
Hepatotoxicity Stopping and Rechallenge Rules ........................ 66
6.3.4
Criteria for Permanent Withholding of Amgen 
Investigational Product due to Potential Hepatotoxicity ............. 67
6.3.5
Criteria for Conditional Withholding of Amgen 
Investigational Products due to Potential 
Hepatotoxicity ............................................................................. 68
6.3.6
Criteria for Rechallenge of Amgen Investigational 
Product After Potential Hepatotoxicity ........................................ 68
6.4 
Other Protocol-required Therapies ............................................................. 69
6.5 
Concomitant Therapy ................................................................................. 69
6.6 
Medical Devices ......................................................................................... 70
6.7 
Product Complaints .................................................................................... 70
6.8 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period ................................................................................... 70
7.
STUDY PROCEDURES ......................................................................................... 71
Approved 
 
 


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7.1 
Schedule of Assessments .......................................................................... 71 
7.2 
General Study Procedures ......................................................................... 99 
7.2.1 
Pre-Screening and Screening .................................................. 102 
7.2.2 
Treatment ................................................................................. 104 
7.2.3 
End of Treatment (EOT) ........................................................... 106 
7.2.4 
Safety Follow Up Visit ............................................................... 107 
7.2.5 
Long Term Follow Up ............................................................... 108 
7.3 
Description of Study Procedures .............................................................. 108 
7.3.1 
Informed Consent ..................................................................... 108 
7.3.2 
Demographic Data .................................................................... 109 
7.3.3 
Medical History, Current Malignancy and Prior 
Therapy .................................................................................... 109 
7.3.4 
Concomitant Medications ......................................................... 109 
7.3.5 
Weight Measurements .............................................................. 109 
7.3.6 
Height Measurements .............................................................. 109 
7.3.7 
Vital Signs ................................................................................. 109 
7.3.8 
Pulse Oximetry ......................................................................... 110 
7.3.9 
Electrocardiogram Performed in Triplicate ............................... 110 
7.3.10 
Physical Examination ............................................................... 110 
7.3.11 
Eastern Cooperative Oncology Group (ECOG) ........................ 111 
7.3.12 
Clinical Laboratory Tests .......................................................... 111 
7.3.13 
Serum Pregnancy Test ............................................................. 111 
7.3.14 
Adverse Events ........................................................................ 112 
7.4 
Pharmacokinetic Blood Sampling ............................................................. 112 
7.8 
Sample Storage and Destruction .............................................................. 114 
7.9 
Imaging Assessment of Disease Burden .................................................. 115 
7.9.1 
Magnetic Resonance Imaging (MRI) ........................................ 115 
7.9.2 
Tumor Assessment by MRI ...................................................... 116 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 116 
8.1 
Subjects’ Decision to Withdraw ................................................................ 116 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 117 
8.3 
Reasons for Removal From Treatment or Study ...................................... 117 
8.3.1 
Reasons for Removal From Treatment .................................... 117 
8.3.2 
Reasons for Removal From Study ........................................... 117 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 118 
9.1 
Definition of Safety Events ....................................................................... 118 
9.1.1 
Disease-Related Events ........................................................... 118 
9.1.2 
Adverse Events ........................................................................ 119 
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9.1.3 
Serious Adverse Events ........................................................... 120 
9.2 
Safety Event Reporting Procedures ......................................................... 120 
9.2.1 
Reporting Procedures for Disease-Related Events .................. 120 
9.2.2 
Adverse Events ........................................................................ 121 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .......................... 121 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events .................................................................... 122 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................. 123 
9.3 
Pregnancy and Lactation Reporting ......................................................... 123 
10. 
STATISTICAL CONSIDERATIONS ..................................................................... 124 
10.1 
Study Endpoints, Analysis Sets, and Covariates ...................................... 124 
10.1.1 
Study Endpoints ....................................................................... 124 
10.1.2 
Analysis Sets ............................................................................ 125 
10.1.3 
Covariates and Subgroups ....................................................... 125 
10.2 
Sample Size Considerations .................................................................... 126 
10.3 
Adaptive Design ....................................................................................... 128 
10.4 
Planned Analyses ..................................................................................... 129 
10.4.1 
Interim Analyses ....................................................................... 129 
10.4.2 
Dose Level Review Team (DLRT) ............................................ 130 
10.4.3 
Primary Analysis ....................................................................... 131 
10.4.4 
Final Analysis ........................................................................... 131 
10.5 
Planned Methods of Analysis ................................................................... 131 
10.5.1 
General Considerations ............................................................ 131 
10.5.2 
Primary Endpoint(s) .................................................................. 131 
10.5.3 
Secondary Endpoint(s) ............................................................. 132 
10.5.4 
Exploratory Endpoints .............................................................. 133 
11. 
REGULATORY OBLIGATIONS ........................................................................... 133 
11.1 
Informed Consent ..................................................................................... 133 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 134 
11.3 
Subject Confidentiality .............................................................................. 135 
11.4 
Investigator Signatory Obligations ............................................................ 135 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 136 
12.1 
Protocol Amendments and Study Termination ......................................... 136 
12.2 
Study Documentation and Archive ........................................................... 136 
12.3 
Study Monitoring and Data Collection ...................................................... 137 
12.4 
Investigator Responsibilities for Data Collection ...................................... 138 
12.5 
Language.................................................................................................. 138 
12.6 
Publication Policy ..................................................................................... 139 
12.7 
Compensation .......................................................................................... 139 
Approved 
 
 


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13. 
REFERENCES ................................................................................................... 140 
14. 
APPENDICES .................................................................................................... 144 
List of Tables 
Table 1.  Potential Risks of AMG 596 ............................................................................ 30 
Table 3.  Hematological Criteria for Dose Reduction ..................................................... 59 
Table 4.  Non-hematological Criteria for Dose Reduction .............................................. 60 
Table 5.  Management of Neurologic Events (by Severity) ............................................ 65 
Table 6.  Schedule of Assessments-dose-escalation Cohort 
 Infusion 
Cycle 1 ................................................................................................... 72 
Table 7.  Schedule of Assessments-dose-escalation Cohort 
 Infusion 
Cycle 2 and all Subsequent Cycles ......................................................... 74 
Table 8.  Schedule of Assessments-dose Escalation Cohort 
 Infusion 
Cycle 1 (Arm 1, AMG 596 Monotherapy) ................................................ 76 
Table 9.  Schedule of Assessments Dose Escalation Cohort 
 Infusion 
Cycle 2, and all Subsequent Cycles (Arm 1, AMG 596 
Monotherapy) ......................................................................................... 78 
Table 10.  Schedule of Assessments Dose Escalation Cohort 
 Infusion 
Cycle 1 (Arm 2, Combination Therapy) ................................................... 80 
Table 11.  Schedule of Assessments Dose Escalation Cohort 
 
AMG 596 Cycle 2 (AMG 404 3rd Infusion), Cycle 4 and all 
Subsequent Even Number Cycles (Arm 2, Combination 
Therapy) ................................................................................................. 83 
Table 12.  Schedule of Assessments Dose Escalation Cohort 
 Infusion 
Cycle 3, and all Subsequent Odd Number Cycles (Arm 2, 
Combination Therapy) ............................................................................ 86 
Table 13.  Schedule of Assessments Dose Expansion Cohort 
 Infusion 
Cycle 1 (Arm 1, AMG 596 Monotherapy) ................................................ 89 
Table 14.  Schedule of Assessments Dose Expansion Cohort 
 Infusion 
Cycle 2 and all Subsequent Cycles (Arm 1, AMG 596 
Monotherapy) ......................................................................................... 91 
Table 15.  Schedule of Assessment Dose Expansion Cohort 
 Cycle 1 
and all Subsequent Odd Number Cycles (Arm 2, Combination 
Therapy) ................................................................................................. 93 
Table 16.  Schedule of Assessment Dose Expansion cohort 
 Cycle 2 
and all Subsequent Even Number Cycles (Arm 2, Combination 
Therapy) ................................................................................................. 96 
Table 17.  List of Analytes ........................................................................................... 101 
Table 18.  Disease-Related Adverse Events by System Organ Class.......................... 118 
Table 19.  Stopping Boundary for Dose Expansion ..................................................... 128 
Table 20.  Operating Characteristics With Batch Size of 10 Subjects .......................... 128 
Approved 
 
 


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Table 21.  Measurement Summary ............................................................................... 155 
Table 22.  Response Assessment ................................................................................ 155 
List of Figures 
Figure 1.  Study Design and Treatment Schema ............................................................ 10 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 145 
Appendix B.  Electronic Serious Adverse Event Contingency Form ............................. 147 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 152 
Appendix D.  Modified Response Assessment In Neuro-Oncology (RANO) ................ 154 
Appendix E.  Grading and Management of Cytokine Release Syndrome 
(CRS) ..................................................................................................... 157 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ............................................................. 159 
Appendix G.  Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Reactions Associated With 
AMG 404* .............................................................................................. 160 
Appendix H.  Management of Infusion Related Reactions With AMG 404 ................... 168 
Appendix I.  Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ..................................................... 169 
Approved 
 
 


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1.
OBJECTIVES
1.1
Primary
The primary objective of this study is to:

Evaluate the safety and tolerability of AMG 596 administered by continuous 
intravenous (cIV) infusion in monotherapy (Arm 1) and in combination with 
AMG 404 (Arm 2) in subjects with EGFRvIII-positive glioblastoma or malignant 
glioma in the recurrent setting (Group 1) and in the maintenance treatment phase 
of newly diagnosed glioblastoma or malignant glioma (maintenance setting, 
Group 2)
1.2
Secondary
The secondary objectives of this study are to:

Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by 
cIV infusion either in monotherapy or in combination with AMG 404

Evaluate the pharmacokinetics (PK) of AMG 404 in serum when administered by 
short term infusion in combination with AMG 596

Evaluate the clinical benefit of AMG 596 monotherapy or AMG 596 in 
combination with AMG 404 as determined by objective response rate (ORR) per 
modified Response Assessment in Neuro-Oncology Criteria (RANO) 
(Okada et al., 2015) in subjects with EGFRvIII-positive glioblastoma or malignant 
glioma in the recurrent and in the maintenance setting

Evaluate progression free survival rate at 6 and 12 months after initiation of 
treatment for any Part, Arm and Group of the study
1.3
Exploratory
2.
BACKGROUND AND RATIONALE
2.1
Disease
Glioblastomas belong to the group of highly malignant brain tumors representing one of 
the most lethal human cancers.  The age-adjusted incidence of glioblastoma ranges 
from 0.59 to 3.69 per 100,000 persons worldwide (Ostrom et al., 2014).  Despite 
aggressive surgical, radiologic and chemotherapeutic intervention, tumors progress 
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within months or even weeks leading to an overall survival of 12 to 15 months with 
almost no change in prognosis since the FDA's approval of temozolomide (TMZ) in 2005 
(Omuro & DeAngelis, 2013).
The urgent medical need has driven the development of new immunotherapy concepts 
despite the classic dogma that the central nervous system is immune-privileged and 
hence inaccessible to potent antitumor immunity. The intriguing success of novel 
immunotherapeutic concepts in advanced melanoma, in non-small cell lung cancer and 
renal cell cancer in particular, together with new insights in relevant tumor antigens and 
expression of markers of immune regulation such as PD-L1 have provided grounds for 
clinical development of immuno-oncology agents targeting the central nervous system 
(Platten et al., 2016). Moreover, trafficking of functionally-active T-cells to the central 
nervous system (CNS) has been demonstrated (Gedeon et al., 2013). The regression of 
all intracranial and spinal glioblastoma lesions after multiple intracranial infusions of 
interleukin 13 receptor alpha 2 targeting CAR T-cell therapy was reported recently 
(Brown et al., 2016). Although this is only a single subject case report, the intriguing 
response provides preliminary evidence for safety and antitumor activity of 
T -cell--mediated immunotherapy in subjects with glioblastoma.
Epidermal growth factor receptor variant EGFRvIII
Epidermal growth factor receptor (EGFR) expression and enhanced EGF pathway 
signaling activity accompanied by amplification of the gene encoding EGFR have been 
documented in glioblastoma (GBM) (Mendelsohn & Baselga, 2006); (Mellinghoff et al., 
2005), almost exclusively in isocitrate dehydrogenase (IDH) wildtype glioblastoma 
(Louis et al., 2016). About 50% of glioblastomas are positive for EGFR amplification, 
half of which express the accompanying EGFR mutation, encoding a truncated and 
constitutively active receptor termed EGFRvIII.  Like native EGFR, mutant EGFRvIII is a 
membrane-bound receptor; however, the deletion results in a protein lacking 267 amino 
acid residues encompassing the extracellular ligand binding domain and characterized 
by a novel glycine residue occurring at the splice junction (Wong et al., 1992). While 
lacking an extracellular ligand binding domain, EGFRvIII has shown ligand-independent 
constitutive tyrosine kinase activity that stimulates downstream signaling pathways, 
which promote malignant growth (Mellinghoff et al., 2005). According to one
meta-analysis (Chen, Xu, Yao, & Qin, 2015), there is currently insufficient evidence that 
either EGFR amplification or the EGFRvIII mutation has prognostic value in patients with 
glioblastoma. EGFRvIII is nevertheless considered a bona-fide tumor-specific antigen 
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found exclusively on tumor cells thereby making it an attractive antitumor treatment 
strategy. Targeting by a bispecific T-cell engager (BiTE®) has revealed promising 
antitumor activity in preclinical settings (Choi et al., 2013; Kischel et al., 2016). 
AMG 596 is a BiTE® targeting EGFRvIII receptor as a tumor-specific antigen and T-cell 
receptor-associated complex cluster of differentiation 3 (CD3) on T-cells. AMG 596 
demonstrates bispecific binding to EGFRvIII on tumor cells and CD3 on T cells, leading 
to formation of an immunological synapse and potent T-cell-induced cytotoxicity. 
AMG 596 showed high cytotoxicity activity against EGFRvIII expressing GBM cell lines 
in vitro and significantly prolonged survival of systemically treated mice versus control 
animals (Kischel et al., 2016). Furthermore, no direct AMG 596-related adverse 
changes were observed in a preclinical safety study in cynomolgus monkeys at doses of 
up to 
 mg/kg/day with a large exposure at serum concentrations of up to 
approximately 21 µg/mL.
Checkpoint inhibitors for treatment of Glioblastoma (GBM)
Immunotherapies with checkpoint inhibitors have been explored in GBM with limited 
success (Omuro et al., 2018) and response rates have been rarely above 10 percent 
(Wang et al., 2019). Reasons for failure are associated with (1) genetic patterns 
supporting immunosuppressive tumor microenvironment, eg PTEN mutations leading to 
cell clustering and lack to increase T cell infiltration, (2) evolutionary patterns promoting 
negative selection of immunogenic neoepitopes, and (3) greater increase in T cell 
diversity leading to failure of selective recruitment of lymphocytes to tumor
(Zhao et al., 2019). 
Nivolumab, a fully human IgG4 subtype programmed death-1 (PD-1) immune checkpoint 
inhibitor was evaluated in a large randomized clinical trial (Reardon et al., 2017) in 
monotherapy or combination with ipilimumab and monotherapy was compared versus 
bevacizumab in 369 patients with first recurrence of GBM in the phase 3 part 
(NCT02017717). At baseline, most patients in the nivolumab (nivo, 83%) and 
bevacizumab (bev, 84%) arms had measurable disease, and 40% (nivo) and 43% (bev) 
of patients required corticosteroids, receiving up to ≥ 4 mg/day. The 12-month OS was 
42% in both monotherapy arms and median OS for nivolumab was 9.8 months 
compared to 10 months for bevacizumab. ORRs were 8% (nivo) and 23% (bev); median 
duration of response was 11.1 months (nivo) and 5.3 months (bev). Most common 
treatment-related AEs (≥ 10% of patients in either arm; nivo vs bev) were fatigue (21% 
vs 14%) and hypertension (1% vs 22%). Serious AEs (all causalities) were reported in 
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46% (nivo) and 35% (bev) of patients. Seizure (8% vs 6%) and malignant neoplasm 
progression (11% vs 7%) were the only serious AEs reported in ≥ 5% of patients in 
either arm. 
Pembrolizumab, a humanized IgG4 anti PD-1 monoclonal antibody (mAb), was explored 
in GBM in a basket trial (Keynote-028) with the GBM basket of patients with any 
recurrence including two-thirds being treated after their first recurrence
(Reardon et al., 2016). One partial response (ORR 4%) was observed within 25 patients 
and 12 patients (48%) presented with SD. Treatment-related AEs occurred in 19 (73.1%) 
patients, most commonly fatigue and rash (n=6 each, 23.1%). Four (15.4%) patients 
experienced grade 3–4 treatment-related AEs (lymphopenia, type 2 diabetes mellitus, 
arthritis, and syncope). Pembrolizumab in combination with bevacizumab was compared 
with pembrolizumab in 80 patients with recurrent GBM for the primary endpoint of 
6-month PFS per RANO (NCT02337491). At a median follow-up of 25 months the 
6-month PFS was 6.7% for pembrolizumab monotherapy and 25.3% for the combination
(Reardon et al., 2018). Most commonly observed treatment-related AEs were headache 
(30%) and fatigue (17%) for pembrolizumab monotherapy.
Although PD-L1 expression has been reported in GBM specimen, the observed clinical 
results were discouraging (Berghoff et al., 2015). Emerging evidence of relevant immune 
cell activation through blockade of PD-1/PD-L1 axis comes from most recently published 
studies with neoadjuvant checkpoint blockade. Patients with recurrent GBM receiving 
neoadjuvant pembrolizumab prior to surgical debulking experienced significantly longer 
overall survival versus those receiving adjuvant, postsurgical pembrolizumab. In the 
neoadjuvant group, focal induction of PD-L1 in the tumor microenvironment and
activation of tumor infiltrating lymphocytes, linked with upregulation of interferon gamma 
related genes suggesting relevant immune cell activation, were observed. Moreover, 
expanded T cell receptor clones correlating between tumor and blood with high overlap, 
and a decreasing monocytic population in the peripheral blood were associated with 
neoadjuvant pembrolizumab but not seen with adjuvant treatment only. Interestingly, 
dexamethasone was not found to impact upregulation of interferon gamma and T cell 
activation genes. Hence, only patients with baseline 4 mg/day or less dexamethasone 
were allowed to enroll. The authors concluded that an immune response leading to 
prolonged survival was induced by repeated PD-1 blockade whereby maintaining
functionality of tumor-specific T cell clones, and by down-regulation of cell cycle related 
gene expression within tumor cells through T cell-mediated interferon gamma 
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response(Cloughesy et al., 2019). A similar approach with neoadjuvant administration of 
nivolumab to patients undergoing surgery for GBM indicates the onset of 
antitumor-directed immune pharmacodynamic effects after treatment with neoadjuvant 
nivolumab (Schalper et al., 2019).
Ultimately, to overcome hurdles for success of immunotherapies in GBM such as a 
limited number of infiltrated T cells and an upregulated immunosuppressive signature, 
the combination of checkpoint blockade with BiTE® treatment may be an alternative 
approach to achieve clinically meaningful tumor regression. The combination of 
checkpoint inhibitors with various BiTE® molecules in preclinical studies showed that 
cytotoxic potential, T cell activation and proliferation are strongly enhanced upon 
blockade of the PD-1/PD-L1 axis (Kufer et al., 2016, Osada et al., 2015). The addition of 
AMG 404, an anti-PD-1 mAb that is being developed by Amgen, to AMG 596 may 
support maintaining T cell activation by blocking PD-1 upregulation on T cells and avoid 
T cell exhaustion facilitated by the immunosuppressive microenvironment. The current 
study with AMG 404 will enable a deeper understanding of synergistic efficacy, toxicity, 
and pharmacodynamic profiles of the combination of AMG 404 and AMG 596.  
2.2
Amgen Investigational Product Background AMG 596
2.2.1
Nonclinical Pharmacology
Nonclinical studies were performed in vitro and in vivo to investigate the mechanism of 
action of AMG 596 in redirecting human and cynomolgus monkey T-cells to lyse 
EGFRvIII-positive cells. No binding was observed in cell lines expressing other EGFR 
family members ((EGFR (HER1), HER2, HER3, and HER4)).  In vitro cytotoxicity 
experiments demonstrated that AMG 596 selectively mediated redirected lysis of 
EGFRvIII-positive cells in the presence of human effector cells in a time- and 
dose-dependent manner, with mean half-maximal tumor cell lysis concentrations (EC50) 
ranging from 0.137– 0.615 ng/mL. In addition, AMG 596-mediated cell lysis was also 
observed at varying ratios of effector-to-target (E:T) cell ratios.
In the presence of EGFRvIII-positive cells, AMG 596 induced a polyclonal activation of 
T-cells, resulting in the up-regulation of the T-cell activation markers CD25 and CD69, as 
well as the release of inflammatory cytokines ((interferon-γ, interleukin (IL)-2, IL-4, IL-10, 
and tumor necrosis factor (TNF)).
Mouse xenograft models of the human glioblastoma tumor cell line U-87 MG engineered 
to express human EGFRvIII were used in the nonclinical evaluation of the in vivo 
efficacy of AMG 596. NOD/SCID mice bearing subcutaneous or orthotopically injected 
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U-87 MG/EGFRvIII tumors were treated with AMG 596 or vehicle by daily intravenous 
bolus injections. AMG 596 monotherapy significantly inhibited subcutaneous tumor
growth as well as prolonged survival in the orthotopic U-87 MG/EGFRvIII glioblastoma 
xenograft model. In addition, no macroscopic brain tumors were found in surviving 
animals at necropsy after treatment with AMG 596.
2.2.2
Nonclinical Pharmacokinetics
The toxicokinetics of AMG 596 have been previously analyzed in two studies in 
cynomolgus monkeys, after cIV infusions of 
days.  After a
day cIV infusion, 
AMG 596 Cmax and AUClast values were dose proportional between doses of 
mg/kg/day, with mean Cmax and AUClast values ranging from 17–417 ng/mL 
and 2217-58245 ng*hr/mL, respectively. The highest AMG 596 exposures were 
observed after the 
mg/kg/day dose.  In the second study, AMG 596 was 
administered as a
day cIV 
 at doses of 
 mg/kg/day.  The average 
steady-state concentrations (CSS) at the 
 mg/kg/day dose levels were 
µg/mL and 
 µg/mL, respectively.  Serum concentrations of AMG 596 at the 
mg/kg/day dose group were approximately 10-fold higher than the 
 mg/kg/day 
group, describing an approximately dose linear behavior after the first two weeks of 
treatment; 
 after the second week was attributed 
to the impact of AMG 596 exposures during the third and fourth week of treatment.
2.2.3
Toxicology
The potential toxicity of AMG 596 was evaluated in a Good Laboratory Practice (GLP) 
compliant 
 cynomolgus monkey toxicology study. AMG 596 was administered 
daily by cIV infusion at 
 mg/kg/day. Two 
 mg/kg/day males were 
euthanized on days 18 and 27 due to: a deterioration in clinical condition likely due to: 
complications at the catheter site and subsequent infection; skin ulcerations secondary 
to irritation from the dose administration jacket. 
.  Findings considered directly related to AMG 596 were mostly 
confined to clinical and anatomical pathology assessments and tended to be of low 
severity and/or showed no clear dose relationship. Changes in hematology parameters 
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were noted at either dose level tested including: decreased red blood cell (RBC) mass 
with increased reticulocytes and red cell distribution width (RDW), mildly to moderately 
decreased lymphocytes and basophils with associated decreased white blood cells, and 
mildly to moderately increased mean platelet volume (MPV). Among coagulation and 
clinical chemistry parameters, AMG 596-related changes at either dose level included: 
increased C-reactive protein (CRP), globulins and fibrinogen correlating with decreased 
albumin; increased cholesterol and triglycerides; decreased gamma glutamyltransferase
(GGT); increased alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST). A transient and minimal increase in MCP-1 was observed at the 
 mg/kg/day 
dose following start of infusion, while a minimal increase in IL-6 and MCP-1 was 
observed on day 18 for the male from this group euthanized on this day. Flow cytometry 
revealed transient decreases in T and NK cells on day 1. Females treated with 
µg/kg/day also showed mildly increased bone marrow cellularity. 
 
 None of the other 
AMG 596-related changes were deemed adverse due to the magnitude of change 
and/or severity grading.  The Highest Non-Severely Toxic Dose (HNSTD) was 
considered to be 
 mg/kg/day.
2.3
Amgen Investigational Product Background AMG 404
2.3.1
Nonclinical Pharmacology
AMG 404 is an IgG1 antibody; however, the Fc region has been modified to eliminate 
undesired interactions with Fc gamma receptors.  The ligand blocking activity of 
AMG 404 was evaluated in three different assays using three different readouts and both 
cell-expressed, as well as recombinant, soluble ligands.  In each assay, AMG 404 
demonstrated the expected dose-dependent activity, indicating it is a potent inhibitor of 
human and cynomolgus monkey PD-1 binding.  
2.3.2
Nonclinical Pharmacokinetics
The toxicokinetics (TK) of AMG 404 were characterized in a Good Laboratory Practice 
(GLP) study after weekly IV administration of 
 mg/kg or SC administration of 
 mg/kg for four consecutive weeks.  Following repeat dose administration, AMG 404 
exposure increased approximately dose-proportionally from 
 mg/kg as 
measured by Cmax and AUC over 6 days.  AMG 404 exposures were similar between 
male and female animals.  
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2.3.3
Toxicology
The potential for AMG 404 to cause acute release of cytokines from human peripheral 
blood leukocytes (PBL) in the presence of human endothelial cells (HUVECs) was 
evaluated in vitro.  Under the conditions tested, AMG 404 did not induce cytokine 
release above background levels.
AMG 404 was evaluated in a 
 GLP toxicology study in cynomolgus monkeys.  
Doses of 
 mg/kg were administered by slow IV bolus, and doses of 
 
mg/kg were administered SC (3 animals/sex/group).  Animals were dosed once 
weekly (4 total doses).  There were no AMG 404-related clinical signs or effects on body 
weight, food consumption, respiratory rate, body temperature, organ weights, or 
urinalysis parameters and no AMG 404-related ocular, electrocardiographic, neurologic, 
or macroscopic findings.  AMG 404-related clinical pathology changes were limited to 
mild decreases in lymphocytes for females at all dose levels on Day 2 that were 
generally similar to control and/or baseline values on Day 9 and throughout the 
remainder of the study, and mildly increased C-reactive protein in some animals. 
In conclusion, administration of AMG 404 by once weekly IV bolus or SC injection was 
well tolerated in cynomolgus monkeys at levels of 
 mg/kg IV and 
 mg/KG IV and 
SC.
Refer to AMG 404 Investigators Brochure for more information.
2.4
Risk Assessment
2.4.1
AMG 596 Monotherapy
At this time, there is limited clinical experience with AMG 596 in humans derived from 
first 15 subjects treated in this study and data are summarized in the AMG 596 
Investigator’s Brochure.  Based on the AMG 596 BiTE® mode of action targeting 
EGFRvIII (expressed solely on cancer cells in glioblastoma), nonclinical data, and the 
clinical experience with other BiTE® molecules, the potential risks of AMG 596 include 
cytokine release syndrome (with associated signs and symptoms including fever, 
nausea, hypotension, tachycardia, asthenia, headache, rash, and dyspnea) and 
neurologic events. 
The drug product for AMG 596 contains sucrose, and the estimated sucrose exposure 
following administration of AMG 596 in the two highest pre-planned dose escalation 
cohorts may exceed an estimated toxicology-based limit for parenteral administration of 
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sucrose.  Cases of renal dysfunction have been reported with intravenous administration 
of some marketed products containing sucrose. 
An antibody-drug-conjugate (AMG 595) targeting EGFRvIII was explored in a first in 
human (FIH) study (NCT01475006).  Of the 31 subjects in the dose escalation analysis 
set of this study (all DLT-evaluable subjects), 10 subjects had DLTs (thrombocytopenia, 
grade 4 severity, and considered by the investigator as related to investigational 
product).  The most common treatment-related adverse events occurring in 
10% subjects overall were thrombocytopenia, fatigue, ALT increased, nausea, AST 
increased, and hypophosphatemia.  However, toxicity in this study is obviously mainly 
caused by the toxic payload and therefore, the information may only be of limited 
importance for the risk evaluation of AMG 596. 
For a listing of potential risks, see Table 1 below.  Please also refer to the AMG 596 
Investigator’s Brochure for further description of potential risks. 
Table 1.  Potential Risks of AMG 596 
Potential Risk 
Description 
Cytokine release 
syndrome (CRS) 
Non-antigen-specific toxicity occurring as a result of high-level immune 
activation (Please see 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 
Infusion reactions may be clinically indistinguishable from 
manifestations of CRS 
Neurologic events 
Patients with glioblastoma may present with generalized and focal 
neurologic signs and symptoms. 
A wide range of commonly observed neurological symptoms have 
been associated with the use of another BiTE® molecule, 
blinatumomab (anti-CD19 BiTE® antibody construct indicated for 
treatment of relapsed/refractory acute lymphoblastic leukemia). 
However, the spectrum of neurologic events has not been observed in 
clinical trials for other BiTE® molecules, and the neurotoxicity may in 
part be associated with targeting CD19. 
Sucrose toxicity (with 
high dose exposure) 
Estimated sucrose exposure following administration of AMG 596 in 
the two highest pre-planned dose escalation cohorts may exceed an 
estimated toxicology-based limit for parenteral administration of 
sucrose.  Cases of renal dysfunction have been reported with 
intravenous administration of some marketed products containing 
sucrose. 
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Approved 
 
 


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2.5
Study Rationale
2.5.1
Rationale for AMG 596 Monotherapy
Glioblastomas are still known to represent a therapeutic challenge characterized by 
inevitable disease recurrence. The high medical need in this indication has driven the 
development of new immunotherapeutic approaches over the last several years. T-cell
redirection to EGFRvIII-expressing tumor cells deserves attention as EGFRvIII is a 
unique surface receptor not expressed in normal brain tissue or outside the brain and is 
the most common EGFR mutation subtype in the brain. Preclinical studies have 
demonstrated that AMG 596, an EGFRvIII targeting BiTE®, facilitates interaction 
between T-cells and EGFRvIII-positive GBM cells independent of peptide-MHC 
expression or a functional T-cell receptor (Kischel et al., 2016). Furthermore, 
Approved 
 
 


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inflammatory responses are able to occur in the brain, indicating leucocyte infiltration 
into the brain; additionally, penetration of the blood brain barrier by activated T-cells has 
been demonstrated. These observations together with the most recently published case 
report on response of glioblastoma to CAR T-cell therapy (Brown et al., 2016) support 
the opportunity for antitumor immune responses to AMG 596. 
Upon recurrence after primary surgery, management of glioblastoma depends on age, 
performance status, histology, initial therapy response, time from original diagnosis and 
whether the occurrence is local or diffuse.  In the case of diffuse or multiple tumor 
recurrences, palliative care is the preferred choice. In patients with localized disease, 
combination of surgery, nitrosourea-based therapies and radiation (standard 
re-irradiation or highly conformal) is used with poor results. A response to 
chemotherapy is unlikely after 2 consecutive agents have failed to produce a response 
(Stewart, 2002).  
Moreover, no survival benefit has since been demonstrated for any new agent in a 
randomized trial (Mehta et al., 2017). With the current study, a new immunotherapeutic 
option will be explored.  After the observation of a first objective response (partial or 
complete) in the recurrent setting, the safety and tolerability of AMG 596 will be further 
explored as a maintenance therapy following SoC for newly diagnosed disease 
according to local guidelines assuming that subjects with lower disease burden may 
better tolerate treatment at higher doses.
2.5.2
Rationale for the Combination of AMG 596 With AMG 404
BiTE treatment helps T cells to infiltrate tumor and become activated independent of the 
immunosuppressive microenvironment. However, preclinical evaluations showed that 
BiTE induced T cell activation is associated with upregulation of PD-1 on T cells, a 
known immune-regulatory mechanism that may lead to diminished T cell cytolytic activity 
resulting in impaired ability of T cells to eradicate the tumor. Anti-PD-1 therapy is intend to 
reverse this T cell exhaustion. Indeed, in vitro combination of AMG 596 with AMG 404 
demonstrated more cytotoxic activity than AMG 596 alone.
We hypothesize that the addition of an anti-PD-1 antibody, such as AMG 404, may help
maintain AMG 596-induced tumor cell killing by T cells resulting in improved antitumor 
activity in the clinical setting. 
Initial signs of clinically meaningful antitumor effect with AMG 596 monotherapy in 
subjects with recurrent glioblastoma have been observed. In addition, monotherapy 
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administration of both novel products, AMG 596 and AMG 404, has been well tolerated, 
to date. Moreover, tolerability of anti-PD-1 antibodies has been demonstrated in subjects 
with glioblastoma in various clinical trials (Reardon et al., 2017, Schalper et al., 2019, 
Kufer et al., 2016, Osada et al., 2015). Considering the devastating nature of 
glioblastoma, the addition of AMG 404 to AMG 596, even in this early stage of the 
development of both investigational products, can be justified and can contribute to 
enrichment of treatment opportunities.
2.5.3
Dose Rationale
2.5.3.1
AMG 596 Monotherapy
The predicted human PK parameters of AMG 596 were derived from previous clinical 
experiences with AMG 211, a BiTE® molecule for solid tumor indications that targets 
CD3 located on T-cells and carcinoembryonic antigen (CEA) located on cancer cells of 
solid tumors (de Vries et al., 2015).  Given the similarities in protein structure, molecular 
weight, and solid tumor targets, the PK of AMG 596 was expected to be similar to 
AMG 211 (AMG 211 Investigator’s Brochure). In addition, previous clinical experience 
with other BiTE® antibody molecules, including blinatumomab and AMG 110, have 
exemplified the consistency of pharmacokinetics across the BiTE® platform, with renal 
excretion expected to be the primary route of elimination (based on MW) and observed 
terminal half-lives ranging between 2.1-4.4 hours. For these reasons, the PK of 
AMG 596 is expected to be consistent with previous BiTE® antibody molecules clinically, 
with a predicted half-life of 2.9 hours. Clinical PK data for AMG 596 can be found in the 
AMG 596 Investigator’s Brochure.  
The starting dose of AMG 596 was guided by the MABEL, an approach which has been 
safely used for previous BiTE® antibody molecules entering clinical testing. 
AMG 596-mediated redirected lysis of EGFRvIII-transduced U-251 MG glioblastoma 
cells (U-251 MG/EGFRvIII) was identified as a sensitive parameter for AMG 596 MABEL 
determination.  AMG 596-mediated redirected lysis by T cells from 20 different donors 
was analyzed and based on individual dose-response curves a mean (± SEM) 
EC20 value of 0.07 ng/mL (± 0.004 ng/mL) was calculated and defined as in vitro MABEL 
of AMG 596.  Using the assumptions of predicted human pharmacokinetics (PK) of 
AMG 596, a starting dose of 
µg/day is predicted to achieve a serum CSS of 
0.088 ng/mL, which approximates EC20 concentrations of AMG 596-mediated cell lysis.  
Additionally, the predicted CSF steady state concentrations of AMG 596 at this dose are 
0.66 pg/mL and 3.2 pg/mL assuming 0.75% and 3.6% CSF penetration, respectively, 
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relative to serum exposures. These estimates were based on literature reported CSF 
exposures with other protein therapeutics, including monoclonal antibodies and 
blinatumomab, a CD19-targeting BiTE® (Burstein et al., 2013; Klinger et al., 2016).
Furthermore, the lower molecular weight of AMG 596 (relative to monoclonal antibodies) 
and the impairment of the blood brain barrier in glioblastoma patients (eg, due to 
resection of tumors in the brain) may result in increased CSF and/or brain penetration 
(Tabrizi et al., 2010).  The selected start dose and dose escalation will aid in reducing 
number of dose escalation steps necessary to reach CSF concentrations associated 
with BiTE® activity, along with the use of single-subject cohorts and approx. 3-fold 
escalations in dose in the earlier cohorts. 
The starting dose is supported by the nonclinical toxicology studies in cynomolgus 
monkeys.  AMG 596 cross-reacts with cynomolgus CD3 and has been well-tolerated at 
doses up to 
 mg/kg/day, with no AMG 596-related adverse findings detected at this 
dose level. At the starting dose of 
 µg/day, the safety margins based on the observed 
Css were 13 400-fold before potency adjustment and 1910-fold after correction for a 
7-fold difference in AMG 596 potency between human and cynomolgus monkey effector 
cells. Although cynomolgus monkeys do not express EGFRvIII, any EGFRvIII- or 
CD3-mediated events that may require dose management, including the elevation of 
cytokines, can be resolved quickly due to the predicted short half-life of AMG 596 and 
the interruption of the cIV regimen, which will allow timely washout of AMG 596. 
Dose escalation decisions will be guided primarily by safety and tolerability to AMG 596 
and intermediate dose levels may be proposed if necessary.  These high doses may be 
necessary to achieve adequate tumor exposure of AMG 596 due to the specificity of 
EGFRvIII expression in glioblastomas and the natural barriers associated with brain 
penetration of various therapeutics.  It is also for this reason however, that systemic 
adverse events related to the BiTE® mechanism of action (eg, cytokine release 
syndrome) are expected to be limited.  Prophylactic treatment with corticosteroids and/or 
the implementation of step-dosing regimens can be used to mitigate further risk of 
adverse events from BiTE® activity. A pharmacodynamic drug interaction study showed 
that AMG 596-induced cytokine release could be reduced by dexamethasone, but 
dexamethasone might result in a reduced cytotoxic potency of AMG 596 when 
co-administered to patients.
At higher doses of AMG 596, there is a risk of potential acute renal dysfunction due to 
the inclusion of 9% sucrose in the IV formulation, an excipient common to many 
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IV formulations.  Although this risk is mainly associated with the 
 µg/day 
doses (which results in > 1.8 g/week of sucrose), sucrose-induced acute renal 
dysfunction is typically temporary and resolves within 7-15 days, and markers of renal 
function will be monitored throughout the study.  In addition, sucrose exposures at the 
highest dose in the study are expected to be lower than those achieved with several 
marketed IV-administered therapies (eg, infliximab, immune globulin intravenous), in 
which sucrose exposures of up to 26 g/week were observed.
Dose escalation in Group 2 subjects can start at the highest AMG 596 monotherapy 
dose deemed to be tolerated by DLRT for Group 1 subjects.
2.5.3.2
AMG 596 in Combination With AMG 404
No clinical safety information is available for the combination of AMG 596 with AMG 404.  
Based on biological mechanism of action and initial clinical safety information for 
monotherapies with AMG 596 and AMG 404, adverse events caused by synergistic 
activation of T cells are expected. 
The first-in-human dose exploration and expansion study evaluating AMG 404 in 
subjects with advanced solid tumors is currently ongoing. Preliminary PK results of 
AMG 404 in 11 subjects with advanced solid tumors after AMG 404 administration as 
short-term IV infusions (approximately 0.5 hours) 
 were available for dose levels of 
 mg (3 subjects, first and second dosing intervals) and 
 mg (8 subjects, 
first dosing interval).  The nonclinical pharmacology findings and preliminary human PK 
results from the FIH study provide increased confidence towards achieving an 
efficacious dose with doses planned in the study and results were consistent with those 
for other therapeutic anti-PD-1 mAbs. Moreover, no dose-limiting toxicities (DLTs) were 
observed in any of the 12 subjects who have received AMG 404 doses up to 
 mg 
 Treatment-emergent adverse events were reported in 9 subjects (75.0%); the 
most frequently reported adverse events (≥ 3 subjects) were fatigue (4 subjects, 33.3%) 
and nausea (3 subjects, 25.0%). Three subjects (25.0%) had 5 adverse events that were 
grade 3 in severity (dehydration, edema, fatigue, urinary tract infection, and vomiting); no 
grade 3 adverse event preferred term was reported in > 1 subject.
Since AMG 404 doses up to
 mg administered every 4 weeks have been shown to 
be tolerable, with the only treatment-related adverse event occurring in > 1 subject of 
nausea in 2 subjects (16.7%), the highest dose explored (
 mg) will be used for 
combination therapy with AMG 596. If a higher AMG 404 dose will be declared as 
recommended phase 2 dose in the ongoing Phase 1 study (Study 20180143), such a 
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dose can be explored in additional cohort(s) in combination with AMG 596 whereby 
using the highest AMG 596 dose shown to be tolerated in the combination cohorts with 
AMG 404. 
For AMG 596, the start dose in combination with AMG 404 treatment is based on the 
observation of pharmacodynamic effects observed at 
 µg/day in Group 1 subjects with 
recurrent malignant glioma. For Group 1 subjects, a dose of 
 µg/day administered in 
 infusion cycles will therefore be selected as first dose. The next AMG 596 
pre-defined doses will be used for further dose escalation.
For Group 2 subjects, the starting dose of AMG 596 in combination with AMG 404 will be 
one dose level below the selected start dose for AMG 596 monotherapy (eg a start dose 
of 
 µg/day for AMG 596 monotherapy in Group 2 subjects leads to the selection of 
 µg/day as start dose for AMG 596 in combination with AMG 404 in Group 2 
subjects). The next AMG 596 pre-defined doses will be used for further dose escalation.
To avoid cumulative toxicity associated with initial T cell activation after treatment start, a
first dose of AMG 404 will not be given until
 after start of the AMG 596 infusion. 
Prophylactic dexamethasone treatment as described in Section 6.5, should be given 
before starting any AMG 596 infusion. Dose escalation will start with single subject 
cohorts as a pharmacodynamic effect is expected resulting in a reduced cytotoxic 
potency of AMG 596 when co-administered with dexamethasone.
2.6
Clinical Hypotheses

AMG 596 monotherapy and in combination with AMG 404 are safe and well 
tolerated in at least one dose level when administered in subjects with 
EGFRvIII-positive glioblastoma or malignant glioma in the recurrent (Group 1) 
and in the maintenance setting (Group 2)

AMG 596 monotherapy and/or in combination with AMG 404 can induce 
objective tumor shrinkage and/or overcome lack of response to standard of care 
(SoC) in subjects with EGFRvIII-positive glioblastoma or malignant glioma in 
either recurrent or in the maintenance setting at a tolerable dose
3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects 
with EGFRvIII-positive glioblastoma or malignant glioma exploring AMG 596 
monotherapy (Arm 1) and combination of AMG 596 with AMG 404 (Arm 2). Each arm of 
the study consists of 2 parts, dose escalation (Part 1) and dose expansion (Part 2). This 
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study will enroll 2 groups of subjects according to disease stage, recurrent disease 
(Group 1) and maintenance treatment after SoC in newly diagnosed disease (Group 2). 
Part 1: Dose Escalation 
The purpose of dose escalation is to make a preliminary estimate of the RP2D /MTD of 
AMG 596 monotherapy and in combination with AMG 404. Treatment is divided into 
2 periods: (1) DLT period 1 for 
 of AMG 596 infusion and (2) DLT period 2 
for 
 of AMG 596 infusion (applies for both Arms). This distinction between 
DLT period 1 and DLT period 2 is maintained throughout dose escalation until the end of 
the dose escalation phase. Observations from other BiTE® studies have shown that the 
occurrence of initial non-cumulative toxicities associated with cytokine release within first 
48 hours after start of infusion may limit dose escalation below doses assumed to be 
associated with anti-tumor activity. However, should the initial dose (DLT period 1) be 
limited by severe adverse events related to first dose effects (eg, cytokine release 
associated adverse events) an MTD for the first dose step may be defined.  Further dose 
escalation in DLT period 2 is possible resulting in a step-dosing and a second (and 
higher) MTD. This approach supports the ongoing evaluation of initial toxicity, as well as 
toxicity after an MTD for the start dose has been defined.
The AMG 596 start dose based on preclinical evaluations for the estimation of the 
MABEL is 
µg/day. Further pre-specified nominal AMG 596 doses for potential use in 
any dose escalation Arm are 
 µg/day. 
The dose level review team (DLRT) may consider treating at intermediate doses if 
required. If the MTD or a biological active dose considered the RP2D is not reached 
within the pre-planned nominal dose range, the DLRT may decide to expand the nominal 
dose range to dose levels 
 µg/day after careful consideration of all available 
safety, laboratory, and PK information. The preliminary estimate of the RP2D/MTD of 
AMG 596 will be done initially in subjects with recurrent disease (Group 1) and 
separately in subjects with maintenance treatment after SoC in newly diagnosed disease 
(Group 2) and separately for AMG 596 monotherapy and in combination with AMG 404. 
If the same AMG 596 doses are to be explored in monotherapy and in combination, the 
monotherapy cohort must be completed before enrollment in the combination cohort. In 
the multiple subject cohorts, a safety observation window of at least 72 hours must apply 
between start of subjects 1, 2 and 3 of each dose escalation cohort. Intra-subject dose 
escalation will be allowed to higher AMG 596 dose levels in subsequent treatment cycles 
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once a higher dose has been deemed safe by the DLRT. Subjects who do not proceed 
to a higher dose may continue at the original dose. 
Group 1, Recurrent Disease 
 
Dose Escalation in single subject cohorts 
 
AMG 596 monotherapy: In first cohorts AMG 596 will be administered as 
a cIV infusion for 
 at escalating doses with N=1 per 
cohort.  In the single subject cohorts, only a limited number of subjects 
will be enrolled at dose levels anticipated to be lower than those at which 
visible pharmacodynamics activity including adverse events related to 
AMG 596 therapy will be expected.  In addition, the investigator together 
with the subject will decide on subsequent treatment duration carefully.  
Subjects are allowed to stay on study in 
 cycles until 
discontinuation criteria apply. 
 
Combination of AMG 596 with AMG 404: The starting dose of AMG 596 is 
ug/day administered in
cycles and the defined 
AMG 404 dose is 
 mg every 4 weeks.  
 
The cohort size will be increased to N=2-4 subjects (= Start of multiple 
subject cohorts) after observation of  
 Treatment-related adverse events of common terminology criteria 
for adverse events (CTCAE 4.0) grade 2 or higher and/or 
 
Quantifiable cytokine levels in blood or CSF above baseline 
 
Dose Escalation in multiple subject cohorts:  
 
Subjects in the first multiple subject cohort receive the same dose as the 
last single subject cohort. 
 
All subjects receive AMG 596 in 
 infusion 
cycles until treatment discontinuation criteria apply.  
It is anticipated that dose-escalation will proceed according to the pre-planned 
nominal doses though intermediate dose levels may be used if required after 
reviewing all available safety data.  When a first DLT is observed, the 
Bayesian logistic regression model (BLRM) will be used to guide dose level 
selection (Neuenschwander, Branson, & Gsponer, 2008).  The cohort size will 
be N=2-4 subjects.  On a limited basis, after agreement between the 
investigator and medical monitor, one additional subject may be allowed to be 
enrolled if the subject has been determined to be eligible and the cohort has 
been filled. In this case, all five subjects will be reviewed and assessed in the 
Dose Level Review Meeting (DLRM). After each cohort, the model’s 
recommended MTD dose level for evaluation is the dose level with the highest 
probability of the target toxicity probability interval (TPI), but with a less than 
0.25 probability of an excessive or unacceptable TPI.  The target TPI is (0.20, 
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0.33], and TPIs of (0.33, 0.60] and (0.60, 1.00] are defined as excessive and 
unacceptable, respectively. The actual dose selected at each dose decision 
may be at or below the model’s recommended dose as determined by the 
DLRT after considering all information. Dose escalation will be completed 
when any of the following occurs:

The maximum total sample size of N=45 DLT evaluable subjects (including 
single subject cohorts) is reached for AMG 596 monotherapy or N=30 DLT 
evaluable subjects for AMG 596 in combination with AMG 404.

The BLRM model recommends the same dose level at least 2 times and 
that at least 6 subjects have been treated at the recommended RP2D/MTD 
dose level.  If step-dosing required, this stopping criterion applies 
separately to each period.

The highest planned dose level is reached without any DLTs being 
observed
Group 2, Maintenance Treatment after SoC in Newly Diagnosed Disease

A first cohort will start after observation of a first objective antitumor response in 
Group 1 subjects with recurrent EGFRvIII-positive glioblastomas or malignant 
glioma. The starting dose of AMG 596 monotherapy in Group 2 will be decided 
by DLRT and will be the current highest dose deemed safe of Group 1.
Treatment may consist either of 
 dose AMG 596 cIV 
 or 
step-dosing as established for recurrent disease. Further treatment cycles with 
 between cIV infusions will be provided until any of the treatment 
discontinuation criteria apply. 

The starting dose of AMG 596 in combination with AMG 404 for Group 2 will be
one dose level below the selected start dose for AMG 596 monotherapy and an
AMG 404 dose of 
 mg. 

The BLRM will be used to guide dose level selection. The cohort size will be 
N=2-4 subjects.  The actual dose selected at each dose decision may be at or 
below the model’s recommended dose as determined by the DLRT after 
considering all information. 

Dose escalation in Group 2 will be completed when any of the following occurs:

The maximum sample size of N=15 DLT evaluable subjects is reached for 
AMG 596 monotherapy or N=20 DLT evaluable subjects for the AMG 596 in 
combination with AMG 404.

At least 6 subjects have been treated at the recommended RP2D/MTD dose 
level 

The highest pre-specified nominal dose level is reached without any DLTs 
being observed
Part 2: Dose Expansion
The purpose of dose expansion will be to further explore safety and to evaluate 
preliminary antitumor-activity in subjects with recurrent disease (Group 1) and in 
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subjects with maintenance setting (Group 2).  It is anticipated that 15 subjects will be 
enrolled to Group 1 in Arm 1 and Arm 2, respectively. Up to 25 subjects will be enrolled 
to Group 2 in Arm 1 and Arm 2, respectively. 
In Group 2 both for Arm 1 and Arm 2, the objective response rate (ORR) of interest is 
20% or higher while an ORR of 5% or less is considered insufficient antitumor-activity.  
For each arm, the ORR in Group 2 will be initially evaluated after 10 subjects are treated 
and have been evaluated at the first imaging scan or have dropped out before that.  If 
ORR is lower than 5%, enrollment may be terminated due to futility.  Otherwise, the 
ORR will be evaluated for additional new subjects and the futility stopping rules are 
calculated using a Bayesian predictive probability design (see Section 10.2 for details). 
During dose expansion and separately for the monotherapy arm (combining data from 
Groups 1 and 2) and for the combination arm (combining data from Groups 1 and 2),
Amgen will conduct evaluations of the ongoing grade 4 or higher treatment-related 
adverse event rate to assess if the threshold for possible early trial termination has been 
reached. The threshold for holding enrollment is as follows.
Number of subjects
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events
10
≥4
20
≥6
30
≥9
40
Study Complete
If this threshold is met, enrollment to dose expansion will be halted pending review of 
safety data by the DLRT. After receiving the DLRT recommendation, Amgen will choose 
to take one of the following actions: 1) Terminate the trial 2) Amend the protocol to 
potentially improve the benefit/risk for subjects (eg, increase safety monitoring, modify 
dose/schedule, mandate premedication) 3) Continue dose expansion without any 
changes. See Section 10.2 for further details regarding the derivation of these 
thresholds.
A BLRM design may be used to update the estimate of the RP2D/MTD using data from 
subjects enrolled to dose escalation and dose expansion. Based on this revised 
RP2D/MTD estimate and reviewing all available safety data, the dose level for dose 
expansion may be revised.
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The subjects enrolled in Part 2 dose expansion will be followed by imaging evaluation 
until the earliest of: clinically significant disease progression, death, consent withdrawal, 
start of new anti-tumor therapies or 12 months after treatment initiation. Subjects who 
stopped treatment will be contacted for long term follow up for up to 12 months after 
treatment initiation.
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3.2
Number of Sites
This study will be conducted at approximately 12 or more sites in the United States, 
Australia and Europe.  Additional countries or sites may be added if deemed necessary.  
Sites that do not enroll subjects into an open cohort within 6 months of site initiation may 
be closed or replaced.  
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.
It is anticipated that around 190 subjects will be enrolled in the study.  
It is anticipated that up to 100 subjects will be enrolled to Arm 1 in this study and up to 
90 subjects will be enrolled to Arm 2 in this study. 
For Group 1 (recurrent disease), the following are the planned sample sizes.

In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to
monotherapy Arm 1 and up to 30 DLT-evaluable subjects to combination Arm 2 

In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and 
up to 15 subjects to combination Arm 2.
For Group 2 (maintenance setting), the following are the planned sample sizes.

In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to
monotherapy Arm 1 and up to 20 DLT-evaluable subjects to combination Arm 2 

In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and 
up to 25 subjects to combination Arm 2.
The rationale for the number of subjects is provided in Section 10.2.
Replacement of Subjects
Ineligible subjects (ie, subjects who were exposed to investigational product (IP) but 
after starting AMG 596 treatment were found to be ineligible) may be replaced. During 
dose escalation, a subject that is not DLT-evaluable will be replaced with another subject 
to the same dose level.  A DLT-evaluable subject is defined as:

Subject in the 
 cycle receiving a complete first cycle with 100% 
of the planned doses of investigational product, or

Subject in the 
 cycle receiving at least 90% of the planned 
doses of investigational products, or

Subject that has experienced a DLT. 
Subjects will not be replaced after end of the DLT period.
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3.4
Estimated Study Duration
The duration of this study will be approximately 4.5 years, with about 42 months for 
enrollment (a maximum of 30 months for the dose escalation cohorts, and 12 months for 
the dose expansion cohort) and 12 months protocol treatment period.
3.4.1
Study Duration for Subjects
It is anticipated that an individual subject will participate in the study for approximately 
8 months including an effective screening period lasting 14 days, a treatment period 
lasting approximately 4 to 6 months, and a safety follow up period lasting 30 days 
(+/- 7 days). Additionally, there is a long term follow up for up to 12 months from 
treatment initiation.  The actual duration for individual subjects will vary depending upon 
tolerability of AMG 596, evidence of clinical progression, and willingness to participate in 
the study.
In the event that a subject demonstrates clinical benefit from therapy, he or she may 
continue treatment with AMG 596 until he or she experiences an unacceptable adverse 
event, clinically significant disease progression, or he or she wishes to withdraw 
consent.
The safety follow-up study visit (SFUP) should occur 30 days (+/- 7 days) after the last
dose of AMG 596 or prior to the initiation of other therapy, whichever occurs first. End of 
study for an individual subject is defined as the date of the final long-term follow up study 
visit (LTFU) when assessments and procedures are performed. 
3.4.2
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; a primary 
analysis will be performed for each group separately when target enrollment in Part 1 
and Part 2 is complete and each subject either completes 6 months on study or 
withdraws from the study.
End of Study: the time when the last subject is assessed or receives an intervention for 
evaluation in the study. The final analysis will occur at this time.
4.
SUBJECT ELIGIBILITY
4.1
Inclusion Criteria
101.
Subject has provided written informed consent prior to initiation of any 
study-specific activities/procedures
102.
Male or female, of at least 18 years of age 
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103.
Eastern Cooperative Oncology Group (ECOG, Appendix F) Performance Status 
of ≤ 1
104.
Life expectancy of at least 3 months, in the opinion of the investigator.
105.
Must have pathologically documented, and definitively diagnosed World Health 
Organization (WHO) grade 4, glioblastoma or lower grade malignant gliomas with 
EGFRvIII positive tumor
106.
Must have recurrent disease confirmed by MRI (Group 1) or completed SoC
therapy such as surgery with adjuvant radiochemotherapy with or without
maintenance temozolomide according to local standards for newly diagnosed 
disease (Group 2)
107.
Group 1 subjects must have ≥1 index lesion by modified RANO criteria 
(Appendix D), exemption: non-measurable disease is allowed for subjects with 
re-surgery (surgery for recurrent disease) before start of screening; Group 2 
subjects must have radiographically measurable disease or non-measurable 
disease by modified RANO criteria or both at the time of enrollment are allowed:

Bidimensionally measurable, contrast-enhancing lesions with clearly defined 
margins by MRI with perpendicular diameters of at least 10 mm x 10 mm and 
noted in more than one imaging slice

Imaging must be performed within 14 days of enrollment.  Subject can be on 
stable dose steroid medication (systemic corticosteroid doses of ≤2 mg of 
dexamethasone (or equivalent) per day after consultation with Sponsor) for at 
least 5 days immediately before and during imaging study
108.
Confirmed EGFRvIII positivity from pre-screening or confirmation at time of study 
enrollment required if prior treatment included EGFRvIII – or amplified
EGFR- targeted therapy (one test sufficient, please refer to Section 7.2.1)
109.
Archived tumor tissue from initial diagnosis or subsequent relapse for submission 
to central review
110.
Hematological function as follows:

Absolute neutrophil count (ANC) > 1500/mm3 (1.5 × 109/L)

Platelet count > 100,000 mm3 (100 × 109/L)

White blood cell (WBC) count > 3 × 109/L

Hemoglobin > 9.0 g/dL
111.
Renal function as follows: serum creatinine < 2.0 mg/dL and estimated 
glomerular filtration rate ≥60 mL/min/1.73 m2 by MDRD and urine protein 
quantitative value of < 30 mg/dL in urinalysis or ≤ 1+ on dipstick
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112.
Hepatic function as follows:

Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) 
≤3.0 x upper limit of normal (ULN)

Bilirubin ≤ 1.5 x ULN (unless considered due to Gilbert's syndrome or 
hemolysis)
4.2
Exclusion Criteria
201.
History or evidence of central nervous system bleeding as defined by stroke or 
intraocular bleed (including embolic stroke) not associated with any antitumor 
surgery within 6 months before enrollment
202.
Evidence of acute intracranial / intratumoral hemorrhage, except for subjects with 
stable grade 1 hemorrhage or fresh biopsy
203.
Known hypersensitivity to immunoglobulins or to any other component of the IP 
formulation
204.
Prior malignancy (other than in situ cancer) unless treated with curative intent 
and without evidence of disease for > 2 years before screening
205.
Active infection requiring intravenous antibiotics that was completed < 1 week of 
study enrollment (day 1) with the exemption of prophylactic antibiotics for long 
line insertion or biopsy
206.
Known positive test for human immunodeficiency virus (HIV)
207.
Active hepatitis B and C based on the following results:

Positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B)

Negative HepBsAg and positive for hepatitis B core antibody: hepatitis B virus 
DNA by polymerase chain reaction (PCR) is necessary.  Detectable 
hepatitis B virus DNA suggests occult hepatitis B

Positive hepatitis C virus antibody (HepCAb): hepatitis C virus RNA by PCR 
is necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C
208.
Unresolved toxicities from prior antitumor therapy, defined as not having resolved 
to CTCAE, version 4.0 grade 1 (with the exception of myelosuppression, eg, 
neutropenia, anemia, thrombocytopenia), or to levels dictated in the eligibility 
criteria with the exception of alopecia or toxicities from prior antitumor therapy 
that are considered irreversible (defined as having been present and stable for 
> 2 months) 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 
sponsor
209.
Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, 
or investigational agent) within 14 days (Group 2 subjects) or 5 half-lives 
(whichever is longer: for Group 1 subjects) of day 1. Avastin, Pembrolizumab
must be stopped 14 days prior to day 1
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210.
Treatment with non-topical systemic corticosteroids within 14 days before 
enrollment (day 1) (exemption:prophylactic treatment with dexamethasone as
defined in section 6.5, and systemic corticosteroid doses of ≤2 mg of 
dexamethasone (or equivalent) per day after consultation with Sponsor,)
211.
Prior participation in an investigational study (drug, procedure or device) within 
21 days of study day 1
212.
Major surgery within 7 days of study day 1 with the exception of biopsy and long 
line insertion  
213.
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the investigator or Amgen physician, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures or completion
214.
Male and female of reproductive potential who are unwilling to practice highly 
effective method(s) of birth control while on study and through 30 days after 
receiving the last dose of AMG 596 and through 4 months (120 days) after 
receiving the last dose of AMG 404.  

Criteria for women of non-reproductive potential is as follows:

Postmenopausal as defined as:

Age of 55 years with cessation of menses for 12 months or more, OR

Age < 55 years and no spontaneous menses for at least 2 years, OR

Age < 55 years and spontaneous menses within the past year, but 
currently amenorrheic (eg, spontaneous or secondary to 
chemotherapy) AND with postmenopausal gonadotropin levels 
(luteinizing hormone and follicle-stimulating hormone level > 40 IU/L) 
or postmenopausal estradiol levels (< 5 ng/dL) according to the 
definition of “postmenopausal range” for the laboratory involved; OR 

History of hysterectomy; OR 

History of bilateral oopherectomy 
Highly effective methods of birth control include sexual abstinence (male, 
female); vasectomy; bilateral tubal ligation/occlusion; hormonal birth control or 
intrauterine device (IUD) (female).
215.
Female who is lactating/breastfeeding or who plans to breastfeed while on study 
through 30 days after receiving the last dose of AMG 596 and through 4 months 
(120 days) after receiving the last dose of AMG 404.
216.
Female with a positive pregnancy test.
217.
Female planning to become pregnant while on study through 30 days after 
receiving the last dose of AMG 596 and through 4 months (120 days) after 
receiving the last dose of AMG 404 infusion.
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218.
Male who is unwilling to abstain from sperm donation while on study through
30 days after receiving the last dose of AMG 596 and through 4 months
(120 days) after receiving the last dose of AMG 404. 
219.
Subjects likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge.
The following Exclusion Criteria apply in addition for enrollment in combination cohorts 
with AMG 404 
220.    History of solid organ transplantation. 
221.    Prior treatment with anti-PD-1, anti-PD-L1, CTLA-4 or other checkpoint inhibitor 
drugs
222. Prior treatment with AMG 596 monotherapy arm is not eligible to enroll in the 
combination therapy arm. 
223.    Live vaccine therapies within 4 weeks prior to study drug administration
224.    Evidence of interstitial lung disease or active, non-infectious pneumonitis
225.    History of any immune-related colitis. Infectious colitis is allowed if evidence of 
adequate treatment and clinical recovery exists and at least 3 months interval 
observed since diagnosis of colitis. 
226.    Active or history of any autoimmune disease or immunodeficiencies. Subjects 
with Type I diabetes, vitiligo, psoriasis, hypo-or hyper-thyroid disease not 
requiring immune-suppressive treatment are permitted. 
227.    Myocardial infarction within 6 months of study day 1, symptomatic congestive 
heart failure (New York Heart Association > class II), unstable angina, or cardiac 
arrhythmia requiring medication. 
5.
SUBJECT ENROLLMENT
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form (ICF) for 
pre-screening (for subjects undergoing optional pre-screening) and for study 
participation before commencement of study-specific activities/procedures. The 
Investigator is to document the enrollment decision and date, in the subject’s medical 
record and in/on the enrollment electronic case report form (eCRF). A subject is 
considered enrolled after meeting all eligibility criteria and treatment and cohort have 
been assigned for the study. Adverse events are to be collected for an eligible subject 
once they are enrolled in the study.  Adverse events occurring during the screening 
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period will be documented as medical history unless the subject has been enrolled in the 
study. 
Subjects diagnosed with malignant glioblastoma or malignant glioma are allowed to 
undergo pre-screening evaluations upon signing the pre-screening informed consent. 
Subjects may alternatively enter directly into the screening period (defined as the point 
at which the subject signs the informed consent for study participation) without 
pre-screening. 
Subjects will receive a unique subject identification number at the time of giving informed 
consent for either pre-screening or study participation (in case of not undergoing 
pre-screening). 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, 132).  The next 5 digits will 
represent the country code and site number (eg, 26001) and will be identical for all 
subjects at a particular 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 26001 will receive the number 13226001001, and the second subject at 
the same site will receive the number 13226001002.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  
All screening tests and procedures should be performed within 14 days before 
enrollment, unless otherwise indicated. Screening may pause between shipment of 
tissue samples for EGFRvIII analysis and availability of test result and this time will be 
deducted from screening time if no other evaluations were done in this screening pause.
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation (up to a total of 2 times during the 14-day screening period) if necessary 
before the subject is considered a screen failure.  If any assessments are repeated 
during the screening period, the value that is closest to the enrollment date will apply for 
the determination of eligibility and should be recorded in the screening eCRF.  
Subjects who do not meet the eligibility criteria within the 14-day effective screening 
period will not be eligible for enrollment.  Subjects may be re-screened up to 3 times at 
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the discretion of the investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside the 14-day screening period.  Hepatitis serology and HIV test do 
not need to be repeated in case of re-screening if they were performed within 6 weeks 
prior to start of treatment with AMG 596.  Test results confirming EGFRvIII-positivity 
expire with start of any antitumor therapy between re-screenings and need to be 
repeated in this case.
Subjects who are deemed ineligible will be documented as screen failures.
Subjects may be eligible to enroll once all screening tests and procedures are completed 
and results indicate that all eligibility criteria are met.  A site representative will complete 
and send the enrollment eligibility worksheet to the sponsor or designee.  The Amgen 
representative will acknowledge receipt and send confirmation of cohort and dose level 
assignment for the subject.
Screening assessments of new subjects can start upon DLT period completion and 
before the dose level review meeting (DLRM) of the preceding dose. Sites are allowed 
to start pre-screening subjects after the study site activation.
5.1
Treatment Assignment
An Amgen representative will notify the site(s) in writing when a cohort is open to screen 
new subjects. This study will enroll 2 groups of subjects according to disease stage, 
recurrent disease (Group 1) and maintenance treatment after SoC in newly diagnosed 
disease (Group 2). Subjects will be treated either with AMG 596 monotherapy or with 
AMG 596 in combination with AMG 404 in the respective treatment arm according their 
individual eligibility and availability of treatment slots. If AMG 596 doses are different, 
mono- and combination therapy cohorts can run in parallel. If same AMG 596 doses will 
be explored in monotherapy and in combination, the monotherapy cohort must be 
completed before enrollment in the combination cohort.  
Enrollment of Group 2 subjects can start after observation of a first objective response
during Group 1 dose escalation. 
At completion of the dose escalation cohorts, additional subjects (up to 15 Group 1 and 
up to 25 Group 2 subjects) will be enrolled in dose expansion cohorts to gain further 
clinical experience, safety and efficacy data in subjects with AMG 596 or AMG 596 in 
combination with AMG 404. The dose to be evaluated will be at or below the MTD
estimated in the dose escalation cohorts.
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The Sponsor will provide the exact treatment assignment (cohort) to sites including 
AMG 596 or AMG 596 and AMG 404 doses and schedule. The treatment assignment 
date is to be documented in the subject’s medical record and on the enrollment eCRF. 
6.
TREATMENT PROCEDURES
6.1
Classification of Product(s), Medical Device(s), and/or Combination 
Product(s)
The Amgen IPs used in this study include AMG 596, AMG 404 and intravenous solution 
stabilizer (IVSS).
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 596 and AMG 404.
The medical devices used in this study include: infusion pump, IV bag, and infusion line 
including a 0.2 μm in-line filter.
6.2
Investigational Products
All investigational products will be dispensed at the research facility by a qualified staff 
member.
A physician or nurse trained in emergency medicine must be available when the infusion 
of investigational product is started for immediate intervention in case of complications.  
6.2.1
Amgen Investigational Product AMG 596 and IVSS
AMG 596 and the IVSS will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  
AMG 596 is supplied as a sterile, single-use, preservative-free concentrate for solution 
for infusion in a vial containing 2 mg/mL AMG 596.  The drug product is formulated with 
10 mM sodium acetate, 9% sucrose, 0.01% (w/v) polysorbate 80, pH 5.5.  The final 
container is a 5cc glass vial and contains 1 mL deliverable volume of AMG 596. 
IVSS is supplied in 10 mL single-use glass vials as a sterile, preservative-free, clear, 
colorless-to-slightly-yellow liquid concentrate. It consists of 25 mM citric acid 
monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% (w/v) polysorbate 80, pH 7. 
The IVSS is intended to prevent adsorption of AMG 596 to surfaces of the infusion 
components.
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6.2.1.1 
Dosage, Administration, and Schedule for AMG 596 
AMG 596 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines using preprogrammed infusion pumps approved for use in the 
country in which the subject is undergoing treatment.  The drug will be administered as a 
cIV infusion at a constant flow rate for 
 cycles or over 
 cycles, until confirmed disease progression.  
Subjects should be encouraged to remain well hydrated throughout the treatment period. 
AMG 596 administration can cause dose dependent increase of peritumoral edema 
leading to development or worsening of depressed level of consciousness, a 
disease related event, which can be prevented by prophylactic administration of 
dexamethasone. Prophylactic use of corticosteroids is mandated for any subject 
receiving a new cycle of AMG 596 (
), with dexamethasone 
8 mg IV (or equivalent dose of other corticosteroids) given within 1 hour prior to 
administration of AMG 596 and a second dose of dexamethasone given 8 mg IV 
12 hours after start of the infusion. Subsequently, corticosteroids can be tapered at 
the discretion of the investigator based on clinical judgement. Same prophylactic 
use of dexamethasone is mandated for AMG 596 in combination with AMG 404 prior 
to the start of the AMG 596 infusion. 
Prophylactic treatment with steroid (eg, dexamethasone) is also mandated before 
restarting of AMG 596 or otherwise clinically indicated (see Section 6.2.4.1 and 
Section 6.3.2).  
Subjects will be hospitalized for the following periods:  
Cycle 1:  
 
For the first 
 of AMG 596 monotherapy (Arm 1)  
 
For the first 
 of AMG 596 in combination with AMG 404 (Arm 2), hence 
AMG 404 will be administered on 
 
 
For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 
and Arm 2  
 
For additional 72 hours after AMG 596 step dose if necessary  
Cycle 2 and all subsequent cycles:  
 
For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2 
 
For additional 72 hours after AMG 596 step dose if necessary.  
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Hospitalization may be shortened to 48 hours from the 6th cycle onwards at the 
discretion of the investigator. Subjects can be hospitalized for a longer time period at the 
discretion of the investigator.  If required for logistical reasons (eg, long travel times), 
subjects may be hospitalized the day before dosing (day -1) of any cycle.  
The start dose for AMG 596 based on preclinical evaluations for the estimation of the 
MABEL is 
µg per day. Further AMG 596 pre-planned dose levels are 
 
 µg per day; step-dosing can be introduced. 
Intra-subject dose escalation for AMG 596 will be allowed to higher dose levels in 
subsequent treatment cycles once a higher dose has been deemed safe by the DLRT. 
Subjects who do not proceed to a higher dose may continue at the original dose. The 
MTD/RP2D or highest tested dose per group will be administered in the dose-expansion 
cohorts.
The infusion start time should be chosen carefully to avoid any interference or 
inconvenience with time points of safety assessments, PK/PD measurements, and 
infusion bag changes. The site should record any unscheduled interruption of an 
infusion on the eCRF and provide the start and stop date/time of the infusion and the 
bag change. A new cycle for AMG 596 may begin +/- 2 days from the scheduled day 1 of 
the new cycle for logistical reasons.
AMG 596 should be administered through a central venous access. In the event that 
administration through a central venous access is not possible, AMG 596 may be 
administered temporarily through a peripheral venous line if the subject is hospitalized.  
The final solution for infusion should be administered through a 0.2 μm in-line filter. 
Infusion bags should be changed in accordance with country regulations and local 
pharmacy standards for infusion of compounded sterile products up to 48 hours in the 
US and up to 96 hours in Australia and Europe.  Specific details are provided in the 
IPIM. 
Treatment breaks exceeding 21 days can be decided by the Investigator after 
consultation with the Sponsor; and may be done to allow sufficient recovery from 
adverse events, due to the subject’s schedule (eg, going on vacation) or for other 
reasons requiring a longer break.  If there is indication through the course of the study 
that subjects may derive additional or more rapid benefit by shortening the breaks 
between treatment cycles, the DLRM may decide to shorten the break periods between 
the first 4 treatment cycles.
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The quantity administered, start date/time, stop date/time, and lot number of IP are to be
recorded on each subject’s eCRF.
6.2.1.2
Overdose
The effects of overdose of this product are not known. The daily AMG 596 dose may be 
up to 10% lower or higher in order to account for possible pump inaccuracies.  A dose of 
up to 10% higher than the intended dose may not require specific intervention.  
In case of overdose or medication error, the infusion should be immediately stopped.
Consultation with the Amgen medical monitor is strongly recommended for prompt 
reporting of clinically apparent or laboratory adverse events possibly related to overdose. 
Consultation with the Amgen medical monitor is also strongly recommended even if 
there are no adverse events, in order to discuss the minimal duration of dose 
interruption. If the overdose results in clinically apparent or symptomatic adverse 
events, the subject should be followed carefully until all signs of toxicity are resolved and 
the adverse event(s) should be recorded / reported as per Section 9.2. Resumption of 
AMG 596 is possible after consultation with the Amgen medical monitor and should 
adhere to the guidelines in Section 6.2.4. 
A dose of > 10% higher than the intended AMG 596 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 9.2.2.2.  The infusion must be restarted in 
the hospital.
6.2.1.3
AMG 596 Outpatient Dosing
If deemed stable by the investigator, a subject may continue AMG 596 cIV infusion as an 
outpatient. Vital signs should be within normal range or at baseline levels prior to the 
start of the infusion, per institutional guidelines, or deemed stable by the investigator.  
Subjects will receive a patient card indicating that the subject is participating in a clinical 
study. The patient card will also provide site contact details to be used in case of 
questions on the study or an emergency. 
For infusion bag changes in the outpatient setting, the subject will either return to the 
study site or, in individual cases in alignment with site specific study contracts, be visited 
by a well-trained home health care service (HHCS) provider at the required frequency. If
such contractually-agreed home visits for IV bag changes are required, the HHCS 
provider will change the infusion bag, measure vital signs, monitor and document 
adverse events and/or serious adverse events, and document any issues with the 
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cIV infusion or infusion pump. The subject and HHCS provider will be trained and will 
receive written instructions for storage of the IV bags. The home health care service 
provider will complete the study delegation log and will be authorized by the investigator 
before any study-related tasks are started. Refer to the home health care manual for 
detailed information on the storage, handling, and administration of AMG 596, 
mandatory procedures, and data collection requirements.
During cycle 1 and while the subject receives treatment in the outpatient setting, the 
study site personnel or HHCS provider will contact the subject on a daily basis to follow 
up on the status of the subject. The study site personnel or HHCS provider may also 
contact the subject via telephone to solve any issues related to the cIV infusion or 
infusion pump. All contacts will be monitored and documented, and the notes will be 
forwarded to the investigator and handled as source documents.
Any unexpected or unusual events identified during the home visits as well as any 
protocol deviations will be communicated promptly to the investigator.  If any adverse 
event occurs in the outpatient setting, the subject will contact the site directly for further 
management. 
The HHCS professionals provide 24-hour emergency on-call service for any pump 
related issues.  In the event of an interruption of > 24 hours of the AMG 596 cIV infusion 
due to a pump related issue, restart of the infusion should be performed in the 
clinic/hospital under the supervision of the investigator or designee and the subject 
should be hospitalized for a minimum of 24 hours (see Section 6.2.4.1.).  Infusion 
interruptions and restart times are to be recorded in the subject’s medical records and in 
the eCRF.
6.2.2
Amgen Investigational Product AMG 404
AMG 404 is supplied in a 3 mL Type 1 glass tubing vial containing 1 mL deliverable 
volume of 70 mg/mL. The drug product is formulated with 10 mM acetate (sodium 
counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2 and will be
prepared for IV administration by dilution.
6.2.2.1
Dosage, Administration, and Schedule for AMG 404
The investigational product will be dispensed at the research facility by a qualified staff 
member.
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At the beginning of a treatment cycle a physician or nurse trained in emergency medical 
care must be available when the infusion of investigational product is started for 
immediate intervention in case of complications.
AMG 404 will be delivered using infusion pumps approved for use by the appropriate 
regulatory authority for the country in which the subject is undergoing treatment. 
AMG 404 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines.   
The drug will be administered as an IV infusion at a constant flow rate over 30 minutes 
every 
 Subjects will be hospitalized for 24 hours after first 
administration of AMG 404 in Cycle 1 
 of the AMG 596 infusion and should be 
monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each 
following AMG 404 infusion. Assessments should be performed as indicated in the 
Schedule of Activities. 
The planned dose, start date, start time, stop date, stop time, dose administered, reason 
for dose change, and package lot number of AMG 404 are to be recorded on each 
subject's eCRF(s) and/or the site’s study files.  
6.2.2.2
Overdose
The effect of overdose of this product are not known. 
6.2.3
Dose Escalation, Stopping Rules and Dose-limiting Toxicities (DLTs)
The preliminary estimate of MTD will use BLRM design.  Refer to Section 10.2 for further 
details of stopping rules.
A DLT will be defined as any of the following occurring in a subject during the DLT 
period (first 
treatment days for both AMG 596 monotherapy and in combination with
AMG 404) and regarded to be related to AMG 596 and/or AMG 404.  For adverse event 
severity grading see Section 9.2 (Adverse Events). The Common Terminology Criteria
for Adverse Events (CTCAE version 4.0) will be used to assess toxicities/adverse 
events with the exception of cytokine-release syndrome (CRS) with grading performed 
according to the recommendations provided in Appendix E.
Hematological DLTs

ANC < 0.5 × 109/L for 7 days

Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection) with ANC < 0.5 × 109/L and fever 38.5°C
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• 
Platelets < 50 × 109/L > 7 days or clinically significant bleeding 
• 
Lymphopenia of any grade is not considered a DLT 
Non-hematological DLTs 
• 
Any grade 4 non-hematological toxicity  
- 
Laboratory parameters of grade ≥ 3, not considered clinically relevant, and 
improved to grade ≤ 2 within 72 hours will not be considered DLT (for ALT 
and GGT elevations grade ≥ 3, not considered clinically relevant, and 
improved to grade ≤ 2 within 7 days due to the long half-life of these 
parameters) 
• 
Any grade 3 or higher non-hematological toxicity if: 
- 
Nausea and vomiting, which is refractory to anti-emetics 
- 
Flare-up of pain because of potential increase in tumor volume is not 
regarded as a DLT 
- 
Grade 3 non-hematologic toxicity lasting > 3 days despite appropriate 
treatment 
- 
Grade 3 fatigue will not be classified as DLT, irrespective of duration 
- 
Grade 3 acute kidney injury 
- 
Any grade 3 seizure, ataxia or encephalopathy 
- 
Other grade 3 neurologic-related adverse events lasting > 3 days despite 
appropriate treatment 
- 
Neurologic-related adverse event leading to treatment interruption that 
needed more than 1 week to resolve to CTCAE grade ≤ 1 
- 
Any grade 3 endocrinopathy that cannot be adequately controlled by 
hormonal replacement 
Any adverse event occurring outside the DLT window that is determined by the 
investigator to be possibly related to the investigational product, which is seen more 
frequently or more severe than expected or is persistent despite appropriate 
management, can be determined to be a DLT upon unanimous decision by the DLRT 
after review of the adverse event and all available safety data.   
The dosing schedule is described by a schema in the protocol synopsis. 
6.2.4 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
6.2.4.1 
AMG 596 
Dose Delay or Dose Reduction 
Any clinically relevant (as determined by the investigator) grade 4 adverse event related 
to IP that does not meet the DLT criteria should lead to a dose delay and/or a dose 
reduction.  The decision if a dose delay or reduction will be performed is up to the 
investigator`s discretion.  The sponsor may be consulted.  
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In addition, cytokine release syndrome of ≥ grade 3 (Appendix E) should lead to dosing 
interruption and treatment with immunosuppressive therapies should be performed 
(see Section 6.3 for details). 
In case of re-appearance of the same grade 4 adverse event, IP should be permanently 
discontinued. 
For persistent or re-occurring clinically relevant grade 3 adverse event related to IP, a 
dose delay or a dose reduction should be considered. 
Infusion Interruption 
Significant events requiring a change in treatment will be managed by immediate 
infusion interruption and should be documented in source documents and in the eCRF:  
• 
The subject experiences a DLT as defined in Section 6.2.3. 
• 
The subject experiences a clinically relevant grade 4 adverse event related to IP 
(see above)  
• 
The subject meets criteria for discontinuation of IP as described in Section 8.3  
• 
Technical problem with the infusion pump 
• 
The investigational product is incorrectly prepared or administered (eg, overdose) 
Restarting the Infusion 
Treatment may resume if the interruption is ≤ 21 days:  
• 
If the interruption occurred due to other reasons than toxicity (technical or logistic 
reasons; eg, diagnostic measurements).  The infusion can be restarted at the 
same dose and without additional measures or delays. 
• 
The toxicity has resolved to ≤ grade 1.  The infusion can be restarted according 
to guidelines presented in Table 3 and Table 4.  Non-hematological Criteria for 
Dose Reduction.   
• 
The toxicity occurred during the DLT period and has resolved to grade 2.  The 
infusion can only be restarted in an individual subject with a clear clinical benefit 
from treatment after consultation with the sponsor on a case-by-case basis. 
Restarting the infusion after a treatment interruption requires care and should be 
performed in the clinic/hospital under the supervision of the investigator or designee and 
the subject should be hospitalized for a minimum of 24 hours when the infusion 
interruption meets the following criteria: 
• 
associated to an AE, or 
• 
interruption > 24 hours due to a pump related issue. 
The restart should be performed in the hospital with all infusion day 1 specific measures 
if the reason for the interruption was other than a technical issue (eg, pump related 
Approved 
 
 


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issue) or the interruption was > 24 hours independent of reason.  Prophylactic treatment 
with steroid (eg, dexamethasone) is mandated before restarting of AMG 596.  If 
step-dosing was already performed at the start of a cycle, the infusion should be 
restarted with step-dosing again if the infusion interruption was 
.  
Subjects in 
 that have a treatment interruption during cycle 1 should 
be allowed to complete a total of 
 infusion, and subjects in 
 
cycles that have a treatment interruption during cycle 1 should be given the opportunity 
to complete a total of 
 of infusion even though these may not be DLT evaluable 
subjects.  Replacement of subjects in 
 off schedule cohorts that have a 
treatment interruption during cycle 1 will require discussion on a case by case basis 
between sponsor and investigator.  
Restart after an interruption lasting 
 may be allowed after careful risk-benefit 
evaluation and requires discussion between investigator and sponsor.  Hematological 
criteria for dose reduction are presented in Table 3 and non-hematological criteria are 
presented in Table 4.  Dose reduction is possible with re-treatment at 1 dose level lower 
(Section 6.2.4.1) 
Table 3.  Hematological Criteria for Dose Reduction 
CTCAE Grade 
ANC (109/L) 
Platelets (109/L) 
Dose Delaya 
Dose Reduction 
Hematological 
0-2 
> 1.0 
> 50 
Continue infusion 
No change 
3 
< 1.0 – 0.5 
< 50 – 25 
Continue infusion 
until Investigator 
assesses toxicity 
to require 
interruption 
No change 
4 
< 0.5 
< 25 
Delay until 
≤ grade 2 
Restart at 1 dose 
level lower, consider 
re-escalation if 
completely recovered 
to baseline and no 
new toxicity occurred 
within 7 days of 
infusion. 
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Table 4.  Non-hematological Criteria for Dose Reduction 
CTCAE Grade* 
Dose Delay 
Dose Reduction 
Comment 
Non-hematological 
Cytokine release syndrome, tumor lysis syndrome, acute kidney injury 
2 
Delay until 
≤ grade 1 
No change 
Restart in hospital 
3 
Delay until 
≤ grade 1 
Restart at 1 dose level 
lower 
Consider re-escalation if 
completely recovered and no 
new toxicity occurred within 
7 days of infusion. 
Permanent discontinuation of 
study treatment if no recovery 
within 21 days. 
Start at the same dose if 
resolved cytokine release 
syndrome, infection, tumor lysis 
syndrome, or hypoxia. 
4 
Discontinue 
infusion 
Permanent 
discontinuation of study 
treatment 
- 
All other non-hematological toxicities and clinically significant laboratory parameters 
0-2 
Continue 
infusion 
No change 
Interruption can be considered 
if deemed necessary by the 
investigator 
3 
Delay until 
≤ grade 2 
Resolution to grade 1 or 
2: Restart at 1 dose level 
lower 
Resolution to normal 
within 1 week or a 
relationship to study drug 
can be ruled out: No 
change 
Per the Investigator medical 
discretion to decide whether to 
continue the infusion for up to 
72 hours if the toxicity or 
abnormal labs are responding 
to treatment or represents an 
asymptomatic laboratory 
change. 
Permanent discontinuation of 
study treatment if no recovery 
within 21 days 
4 
Discontinue 
infusion 
Permanent 
discontinuation of study 
treatment 
- 
ANC = Absolute neutrophil count; CTCAE = Common terminology criteria for adverse events; 
DLT = Dose-limiting toxicity 
a Applies to all hematologic toxicity that persists for > 24 hours despite appropriate treatment 
* For CRS criteria defined in Appendix E apply 
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6.2.4.2 
AMG 404 
Dose Delay or Dose Reduction 
Each subject will stay on the dose level assigned until treatment needs to be stopped. 
The reason for dose withholds and dose delays is to be recorded on each subject’s 
CRF. Specific guidance for management of adverse events associated with AMG 404 
are provided in Appendix G 
Immune-related Adverse Reactions 
Adverse events following the administration of AMG 404 may represent an immunologic 
etiology. Based on clinical experience with other anti-PD-L1 therapies, these 
immune-related toxicities may occur shortly after the first dose to several months after 
the last dose of treatment and may affect more than one body system simultaneously. 
Early recognition and management are critical to reduce complications.  
Most immune-related adverse events require adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests, such as bronchoscopy, 
endoscopy, or skin biopsy, may be included as part of the evaluation.  
Based on the type and severity of the immune-related adverse event, withholding or 
permanent discontinuation of AMG 404 may be required, in addition to treatment with 
corticosteroids and/or other therapies. Dose modification and toxicity management 
guidelines for immune-related adverse reactions are provided in Appendix G.  
Infusion-related Reactions 
Infusion-related reactions may occur with the administration of AMG 404. Monitor 
patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, 
rigors, flushing, urticaria, hypotension, dyspnea, wheezing, headache, back pain, and 
abdominal pain. If an infusion-related reaction is suspected, perform a physical 
examination, monitor vital signs, monitor pulse oximetry, and perform and ECG if the 
patient is experiencing chest pain or sustained tachycardia.  
For mild or moderate infusion-related reactions, interrupt or slow the rate of infusion.  For 
severe or life-threatening infusion-related reactions, permanently discontinue AMG 404. 
Treatment guidelines for infusion reactions associated with the administration of 
AMG 404 are provided in Appendix H.  
Approved 
 
 


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6.2.5 
Permanent Discontinuation 
A subject will permanently discontinue treatment with investigational products in the 
event of:  
• 
Dose-limiting or other unmanageable toxicity. For exemption, please see 
Section 6.2.3). 
• 
Clinically significant disease progression or deterioration. 
• 
Occurrence of neurologic-related adverse event considered related to AMG 596 
and/or AMG 404 by the investigator and meeting one or more of the following 
criteria: 
- 
Grade 3 seizure, ataxia or encephalopathy 
- 
A neurologic-related adverse event CTCAE grade 4 
- 
A neurologic-related adverse event leading to treatment interruption that 
needed more than 1 week to resolve to CTCAE grade ≤ 1 
• 
Occurrence of acute kidney injury considered related to AMG 596 and/or 
AMG 404 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 
• 
Subject’s request  
• 
Subject or investigator not compliant with the study protocol 
• 
Occurrence or progression of a medical condition which, in the opinion of the 
investigator after medical consideration, is not associated with the disease under 
study and should preclude further participation of the subject in the study  
• 
Pregnancy 
• 
A DLT leads to permanent discontinuation unless the following criteria apply, in 
which case a restart of treatment at the same or a lower dose may be allowed: 
− 
The AE (including relevant lab values) is reversible and improves to grade ≤ 1 
or baseline within 14 days 
− 
The patient is experiencing clinical benefit as assessed by the investigator 
− 
There is agreement between the investigator and the Amgen Medical Monitor 
that treatment may be restarted 
− 
The subject is willing to continue treatment after the investigator has led an 
appropriate discussion of potential risks and benefits with the subject 
All reasons for treatment discontinuation should be clearly and concisely 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 end of treatment (EOT) and safety 
Approved 
 
 


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follow up (SFUP) visits.  These data should be recorded, as they comprise an essential 
evaluation that should be performed prior to discharging any subject from the study and 
to allow for the evaluation of the study endpoints. 
6.3 
Specific Recommendations for Cytokine Release Syndrome, 
Neurologic Events and Hepatotoxicity 
6.3.1 
Cytokine Release Syndrome (CRS) 
Cytokine release syndrome is clinically defined and may have various manifestations.  
Most cancer immunotherapies bear the risk of cytokine-associated toxicity, also known 
as cytokine release syndrome caused by non-antigen specific high level immune 
activation (Lee et al, 2014 and Appendix E).  Signs and symptoms of CRS may include:   
• 
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 
Subjects may be at an increased risk for cytokine release syndrome during the first few 
days following the initial infusion of AMG 596 and/or AMG 404.  Cytokine release 
syndrome may be life-threatening or fatal.  Infusion reactions may be clinically 
indistinguishable from manifestations of cytokine release syndrome.  Throughout the 
infusion with AMG 596 and/or AMG 404, monitor subjects for clinical signs (eg, fever, 
tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) 
which may be related to cytokine release syndrome.  In the event of CRS, an 
unscheduled blood sample should be collected to measure cytokine levels. 
Grading of cytokine release syndrome should be performed according to the 
recommendations provided by Lee et al, 2014.  (see Section 13 and Appendix E). 
Interventions for cytokine release syndrome will be determined by its particular 
manifestations and magnitude in each subject.  Pyrexia may be managed with 
paracetamol/acetaminophen.  Management of hypotension should be managed by 
volume resuscitation and, in the event that it is not sufficient or if there is evidence of 
volume overload, pressor support may be added, with the type of vasopressive agent 
determined by the investigator depending on the totality of observed hemodynamic 
parameters (heart rate, cardiac output, central venous pressure). 
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For grade 2 CRS, the study drug should be interrupted and monitoring and management 
of CRS symptoms should be performed as described above and according to published 
recommendations by Lee et al, 2014 (Appendix E).  The study drug should be 
permanently discontinued for grade 2 CRS not improving to grade ≤ 1 within 7 days 
(Appendix E). 
For grade 3 or greater cytokine release syndrome, the study drug should be interrupted 
and immunosuppressive therapies should be provided.  Corticosteroids such as 
dexamethasone or methylprednisolone are the preferred choice for immunosuppression.  
Typical doses for dexamethasone are 8 mg IV q8 hours with subsequent tapering 
following symptom resolution.  Tocilizumab has been reported to be efficacious in this 
setting at a dose of 4-8 mg/kg as a single dose.  However, due to the reported potential 
aggravation of IL-6 levels in CNS in association with tocilizumab treatment decision 
should include careful risk-benefit evaluation.  The study drug should be discontinued for 
grade 3 CRS not improving to grade ≤ 2 within 5 days or grade ≤ 1 within 7 days 
(Appendix E). 
For grade 4 cytokine release syndrome, the study drug should be interrupted 
immediately and permanently discontinued.  The subject should be transferred to an 
intensive care unit (Appendix E).  After observation of first DLT (in DLT period 1) 
associated to cytokine release-associated adverse events, step dosing and/or 
prophylactic treatment with steroids (dexamethasone) is recommended to mitigate the 
cytokine release syndrome risk in further subjects.   
Prophylactic dexamethasone treatment according to the following schema will be 
recommended to all subject after the observation of a first cytokine release syndrome of 
grade 2 (see Appendix E) or higher.  
• 
Dexamethasone at a dose of 4 to 8 mg or equivalent corticosteroid will be 
administered orally or IV  
- 
8 to 12 hours prior to the start of the infusion on day -1 
- 
1 hour prior to the start of the infusion on day 1 
- 
Every 8 to 12 hours after start of infusion for first 24 hours of the infusion  
• 
Corticosteroid treatment can be continued if deemed necessary by the 
investigator and after consultation with the sponsor but doses should be tapered 
as quickly as feasible.  Close monitoring of blood glucose levels is recommended 
in such a case.  Further variations may be needed that should be discussed and 
agreed upon in a DLRM.   
Approved 
 
 


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6.3.2 
Infusion Interruption/Dose Modification due to Neurologic Events 
Patients with glioblastoma or malignant glioma may present with generalized symptoms 
(eg, headaches, cognition and personality changes) and focal signs (eg, hemiparesis, 
sensory loss, visual field disturbances) (Omuro and DeAngelis, 2013). 
Recommendations for management, including interventions and infusion interruptions for 
neurologic-related adverse events, are presented in Table 5.  As neurologic events may 
be anticipated in the study population, guidance regarding reporting of safety events, 
including disease-related and adverse events, is provided in Section 9 (Safety Data 
Collection, Recording, and Reporting). 
Table 5.  Management of Neurologic Events (by Severity) 
CTCAE 
Grade 
Intervention 
Instructions for Infusion 
Interruption or Permanent 
Discontinuation  
3 
Perform physical exam, assess vital 
signs and conduct safety laboratory 
tests 
Depending on the nature of the 
adverse event, additional measures 
(eg, CSF investigations, 
contrast-enhanced MRI of the head) 
can be taken upon discretion of the 
investigator 
MRI should also be considered for 
subjects who permanently 
discontinue treatment at the 
discretion of investigator 
Immediately interrupt AMG 596 
Restart AMG 596 infusion within 
2 weeks, but not earlier than 72 hours 
(3 days) after the infusion has 
stopped, if the event resolves to 
grade ≤ 1 within 7 days 
Delay AMG 404 dosing until day 8 
after AMG 596 restart if AMG 404 
dosing was scheduled during 
interruption 
Permanently discontinue AMG 596 
and AMG 404 if considered by the 
investigator related to study drug and 
if there is no improvement to grade 
≤ 1 within 7 days 
4 
Perform physical exam, assess vital 
signs and conduct safety laboratory 
tests 
Depending on the nature of the 
adverse event, additional measures 
(eg, CSF investigations, 
contrast-enhanced MRI of the head) 
can be taken upon discretion of the 
investigator 
Conduct MRI for subjects who 
permanently discontinue treatment 
Immediately interrupt AMG 596 
Permanently discontinue AMG 596 
and AMG 404 
CSF – cerebrospinal fluid, CTCAE – Common Terminology Criteria for Adverse Events,  
MRI – magnetic resonance imaging 
For subjects who experience serious neurologic adverse events leading to treatment 
interruption, if the event has decreased to at least CTCAE grade 1 within 1 week, 
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treatment may be restarted within 2 weeks, but not earlier than 72 hours (3 days) after 
the infusion was stopped.  
Seizure 
If the neurologic event was a seizure (CTCAE grade 2 or above), appropriate 
prophylactic anticonvulsant treatment (a therapeutic dose of eg, phenytoin or 
levetiracetam) can be administered during the next treatment cycle.  In case of 
occurrence of seizure grade 3, the investigational products will have to be stopped 
immediately and treatment will be permanently discontinued, and investigations 
associated with and previously described for a CTCAE grade 3 or higher 
neurologic-related adverse events, must also be performed.  
Depressed level of consciousness 
Depressed level of consciousness is a common neurological sign of intracranial 
pressure increase. AMG 596 may cause inflammation at the site of the tumor, leading to 
worsening of increased intracranial pressure resulting in neurological toxicity including a 
depressed level of consciousness. 
Prophylactic use of corticosteroids is mandated for any subject receiving a new cycle of 
AMG 596 (
), with dexamethasone 8 mg IV (or equivalent dose 
of other corticosteroids) given within 1 hour prior to administration of AMG 596 and the 
second dose of dexamethasone 8 mg IV given 12 hours after start of the infusion, and 
subsequent tapering at the discretion of the investigator. Prophylactic treatment with 
steroid (eg, dexamethasone) is also mandated before restarting of AMG 596 or 
otherwise clinically indicated (see Section 6.3).  
6.3.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, ALT, TBL) and/or 
international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described 
below) may meet the criteria for withholding or permanent discontinuation of Amgen 
investigational product or other protocol-required therapies as specified in the Guidance 
for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. 
Approved 
 
 


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6.3.4 
Criteria for Permanent Withholding of Amgen Investigational 
Product due to Potential Hepatotoxicity 
Both investigational products should be discontinued permanently, and the subject 
should be followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met: 
 
TBL > 2 × ULN or INR > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:  
- 
Baseline AST or ALT value: < ULN 
- 
AST or ALT elevation: > 3 × ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to:  
- 
Hepatobiliary tract disease 
- 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus)  
- 
Right sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia 
- 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms 
- 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir)  
- 
Alpha-one antitrypsin deficiency 
- 
Alcoholic hepatitis 
- 
Autoimmune hepatitis 
- 
Wilson’s disease and hemochromatosis 
- 
Nonalcoholic Fatty Liver Disease including steatohepatitis (NASH) 
- 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis)  
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if Amgen IP and other protocol-required therapies 
should be withheld or permanently discontinued, as deemed appropriate for the safety of 
the subject. 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132  
Date:  29 July 2019 
Page 68 of 169 
CONFIDENTIAL 
 
 
6.3.5 
Criteria for Conditional Withholding of Amgen Investigational 
Products due to Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational products outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational products and other protocol 
required therapies:  
 
Elevation of either AST or ALT according to the following schedule:  
- 
Baseline AST or ALT value: Any AST or ALT elevation: > 8 × ULN at any time 
- 
Baseline AST or ALT value: Any AST or ALT elevation: > 5 × ULN but 
< 8 × ULN for ≥ 2 weeks 
- 
Baseline AST or ALT value: Any AST or ALT elevation: > 5 × ULN but 
< 8 × ULN and unable to adhere to enhanced monitoring schedule 
- 
Baseline AST or ALT value: Any AST or ALT elevation: > 3 × ULN with 
clinical signs or symptoms which are consistent with hepatitis (such as right 
upper quadrant pain/tenderness, fever, nausea, vomiting, or jaundice).   
 
OR: TBL > 3 × ULN at any time 
 
OR: ALP > 8 × ULN at any time 
For transaminitis of CTCAE grade 3 or 4 suspected to be caused by cytokine release 
infusion interruption and discontinuation criteria should apply as defined in Appendix E. 
AMG 596 and AMG 404 should be withheld pending investigation into alternative causes 
of DILI.  If the investigational product is withheld, the subject is to be followed according 
to recommendations in Appendix A for possible DILI.  Rechallenge may be considered if 
an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL is 
discovered and the laboratory abnormalities resolve to normal or baseline 
(see Section 6.3.3 and Section 6.3.6.) 
6.3.6 
Criteria for Rechallenge of Amgen Investigational Product After 
Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject and investigator, after consultation with Sponsor. 
If signs or symptoms recur with rechallenge, then the investigational products should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.2.5) should never be rechallenged.  
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 69 of 169
CONFIDENTIAL
6.4
Other Protocol-required Therapies
There are no other protocol-required therapies.  All recommended therapies, including 
corticosteroids, 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 therapies.  Please also refer to Section 6.4 for concomitant 
therapy.
6.5
Concomitant Therapy
Throughout the study, subjects should be encouraged to remain well hydrated 
throughout the treatment period.
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 informed consent through to the SFUP.
Medications associated with AEs or SAEs occurring between the SFUP visit and End of 
Study must also be collected.  For all concomitant therapies collect therapy name, 
indication, dose, unit, frequency, route, start date, and stop date.  
Oxygen administration as supportive measure is permitted during study treatment.  
For symptomatic treatment of fever > 38.5°C, metamizole as infusion and/or 
paracetamol, ibuprofen, or acetylsalicylic acid are recommended.  
Patients should be closely monitored for any signs and symptoms that may be 
associated with CRS such as pyrexia, headache, nausea, vomiting, asthenia, 
hypotension, hypoxia and tachycardia during the initiation of AMG 596 and AMG 404
treatment (see Section 6.3). 
Recommendations for prophylactic anticonvulsant treatment for adverse events of 
seizure (CTCAE grade 2 or above) are provided in Section 6.3.2. 
Prophylactic use of corticosteroids is mandated for any subject receiving a new cycle of 
AMG 596 (
), with dexamethasone 8 mg IV (or equivalent dose 
of other corticosteroids) given within 1 hour prior to administration of AMG 596 and the 
second dose of dexamethasone 8 mg IV given 12 hours after start of the infusion, and 
subsequent tapering at the discretion of the investigator. Same prophylactic use of 
dexamethasone is mandated for AMG 596 in combination with AMG 404 prior to the 
start of the AMG 596 infusion.
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 70 of 169
CONFIDENTIAL
Prophylactic treatment with steroid (eg, dexamethasone) is also mandated before 
restarting of AMG 596 or otherwise clinically indicated (see Section 6.3.1 and 
Section 6.3.2). 
6.6
Medical Devices
The investigational products must be administered using infusion pumps approved for 
use by the appropriate regulatory authorities for the country in which the subject is 
undergoing treatment in both the inpatient and outpatient setting and as specified in 
Section 6.2.1 and Section 6.2.2. Investigational products, concentrates for solution for 
infusion, will be prepared in bags for IV infusion and AMG 596 will bedelivered through 
infusion lines with a 0.2 μm in-line filter. Both are compatible with the investigational 
product as described in the respective IPIM.  
Additional details for the use of the IV bag and infusion lines and their specifications are 
provided in the respective IPIM. Those devices that are commercially available are not 
usually provided or reimbursed by Amgen (except, for example, if required by local 
regulation). The investigator will be responsible for obtaining supplies of these devices.
6.7
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.
6.8
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period 
Any anti-tumor therapy other than the investigational products are not permitted, 
including cytotoxic and/or cytostatic drugs, hormonal therapy (unless treatment for 
endocrinopathy), immunotherapy or any biological response modifiers, any other 
investigational agent, other immunosuppressive therapies. Corticosteroids are
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132  
Date:  29 July 2019 
Page 71 of 169 
CONFIDENTIAL 
 
 
exceptions as described in Section 6.3 and Section 6.5 for management of CRS or 
neurologic adverse events.  
Subjects who received AMG 596 as monotherapy are not allowed to participate in the 
combination therapy with AMG 404.   
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the sponsor’s Medical Monitor first.  Investigators should ensure that the need for 
radiation does not indicate progressive disease and that for subjects with measurable 
disease, radiation is not to the sole site of measurable disease.  
The following procedures should also not be undertaken within the timeframes specified 
prior to enrollment and during the study:  
 
Participation in an investigational study (drug or device) within 21 days of study 
day 1  
 
Major surgery within 7 days of study day 1, with the exception of biopsy and long 
line insertion 
 
Enrollment into another investigational drug or device study 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 72 of 169
CONFIDENTIAL
Table 6. Schedule of Assessments-dose-escalation Cohort 
 Infusion Cycle 1
Optional Pre-
SCR
SCR
Treatment Period - Dose Escalation 
Cycle
1
Cycle Day
Pre-dose
Hours Relative to start of infusion
0.5
1
2
3
4 (+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
GENERAL AND SAFETY ASSESSMENTS
Informed consent
X
X
Hospitalizationa
X
Medical History
X
Concomitant Medications
X
X
Serious adverse events
X
X
Adverse events h
X
Clinical Evaluation b
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
Vital signs, pulse oximetry c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measurement
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy test d
X
X
Coagulation
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
Hepatitis Serology, HIV, HLA
X
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging g
X
Footnotes defined on next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 73 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 1 will be for a minimum of 8 days.
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle. 
Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
g Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
h Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history. 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 74 of 169
CONFIDENTIAL
Table 7. Schedule of Assessments-dose-escalation Cohort 
 Infusion Cycle 2 and all Subsequent Cycles
Treatment Period - Dose Escalation 
Cycle
2 and all subsequent cycles
Cycle Day
Pre-dose
Hours Relative to start of infusion
Every 
3 months 
(+/- 2 
weeks)
0.5
1
2
3
4 (+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
24
GENERAL AND SAFETY ASSESSMENTS
Informed consent
Hospitalizationa
X
Concomitant Medications
X
Serious adverse events
X
X h
Adverse events
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
X
Vital signs, pulse oximetryc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measurement
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy testd
X
Coagulation
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
Hepatitis Serology, HIV
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging e
X
X
X
Footnote defined on the next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 75 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycles 2 and subsequent cycles will be for a minimum of 72 hours until cycle 5 and 48 hours from cycle 6 onwards (per treating investigator’s 
discretion).
b Clinical evaluations will include physical exam, ECOG, and weight.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle. 
Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed every 10 to 12 weeks from start of treatment, and at SFUP if no scan was performed 
within 6 weeks.  Scans will in include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW (selected sites only) images of the brain.  All other known 
sites of disease should also be recorded and assessed. Earlier assessments can be made if clinically indicated at the discretion of the managing physician. If the subject is 
removed for any reason other than clinically significant disease progression, imaging should be collected during LTFU as long as subject consents to continue.
g Safety Follow Up to be performed 30 days (+/- 7 days) after EOT.
h Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected   
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 76 of 169
CONFIDENTIAL
Table 8. Schedule of Assessments-dose escalation Cohort 
 Infusion Cycle 1 (Arm 1, AMG 596 Monotherapy)
Optional
Pre-SCR
SCR
Treatment Period - Dose Escalation 
 C1
Cycle
1
Cycle Day
Any time prior
to SCR
Pre-
dose
Relative to start of infusion
Relative to end of infusion
0.5
1
2
3
4 (+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
GENERAL AND SAFETY ASSESSMENTS
Informed consent
X
X
Hospitalizationa 
X
X
Medical History
X
Concomitant Medications
X
X
Serious adverse events
X
X
Adverse events i
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
X
X
X
X
Vital signs, pulse oximetryc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measurement
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy testd
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
Hepatitis Serology, HIV, HLA
X
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging e
X
Treatment response
X
Footnote defined on next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 77 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 1 will be for a minimum of 7 days from the start of the infusion, and for at least 24 hours following completion of the infusion, and for 72 hours 
after a dose step at cycle 1 (if applicable).
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle. 
Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
h If a subject discontinues after C1 this visit assessments will be considered EOT assessments. After EOT, please perform SFUP assessments as in Table 9 Dose Escalation 
Cohort 
 Infusion Cycle 2 and all subsequent cycles.
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 78 of 169
CONFIDENTIAL
Table 9. Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 2, and all Subsequent Cycles (Arm 1,
AMG 596 Monotherapy)
Treatment Period - Dose Escalation 
C2 and subsequent cycles
Cycle
2 and all subsequent cycles
Cycle Day
Pre-
dose
Relative to start of infusion
Relative to EOI 
Every 3 
months 
(2+/-
weeks)
0.5
1
2
3
4
6
8
12
16
20
24
48
EOI
0.5
2
4
24
GENERAL AND SAFETY ASSESSMENTS
Informed consent
Hospitalizationa
X
Concomitant Medications
X
Serious adverse events
X
Xj
Adverse events
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
Xf
X
X
X
Neurological Evaluation
X
X
X
X
X
X
X
X
X
Vital signs, pulse oximetryc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
X
X
X
ECG triplicate measurement
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy testd
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
Xf
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
X
Hepatitis Serology, HIV
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging e 
X
X
X
Treatment response
X
X
X
Footnote defined on the next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 79 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 2 and all subsequent cycles and after dose step (if applicable) at cycle 2 and all subsequent cycles will be for a minimum of 72 hours until cycle 
5 and 48 hours from cycle 6 onwards (per treating investigator’s discretion).
b Clinical evaluations will include physical exam, ECOG, and weight.
c Vital Signs will be repeated every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle 
(see footnote a). Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed every 10 to 12 weeks from start of treatment, and at SFUP if no scan was performed 
within 6 weeks.  Scans will in include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW (selected sites only) images of the brain.  All other known 
sites of disease should also be recorded and assessed. Earlier assessments can be made if clinically indicated at the discretion of the managing physician. If the subject is 
removed for any reason other than clinically significant disease progression, imaging should be collected during LTFU as long as subject consents to continue.
g Safety Follow Up to be performed 30 days (+/- 7 days) after EOT.
j Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 80 of 169
CONFIDENTIAL
Table 10. Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 1 (Arm 2, Combination Therapy)
Optional
Pre-SCR
SCR
Treatment Period-Dose Escalation 
 AMG 596 Cycle1 (AMG 404 1st and 2nd Infusion)
Cycle -Day
Any time 
Prior to 
SCR
Pre-
Dose(
hr)
Hours Relative to Start of AMG 596 Infusion
Hours Relative to End 
of AMG 596 Infusion
0.5
1
2
3
4
(+1)
6
8
12
16
20
24
48
EO
I
0.5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to 
AMG 404 Infusion
GENERAL SAFETY ASSESSMENT
Informed Consent
X
X
Hospitalizationa
X
X
Medial History
X
Concomitant 
Medications
X
X
Serious Adverse 
Events
X
X
Adverse Eventsi
X
Clinical Ealuationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological 
Evatluation
X
X
X
X
X
X
X
X
Vital signs, pulse 
oximetryC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate 
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENT
Serum Pregnancy 
Testd
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, 
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines/CRP(Loc
al Lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
Hetatitis Serology, 
HIV, HLA
X
ACTH, ANA, 
ANCAk
X
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approved
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 81 of 169
CONFIDENTIAL
Table 10. Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 1 (Arm 2, Combination Therapy)
Optional
Pre-SCR
SCR
Treatment Period-Dose Escalation 
 AMG 596 Cycle1 (AMG 404 1st and 2nd Infusion)
Cycle -Day
Any time 
Prior to 
SCR
Pre-
dose(
hr)
Hours Relative to Start of AMG 596 Infusion
Hours Relative to End of 
AMG 596 Infusion
0.5
1
2
3
4
(+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to 
AMG 404 Infusion
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaginge
X
Page 2 of 2
Footnotes defined on next page of the table
 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 82 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 1 will be for a minimum of 8 days from the start of the AMG 596 infusion, whereby AMG 404 will be administered on 
 and for at least 
24 hours following completion of the AMG 596 infusion. All subjects will be hospitalized for at least 72 hours after a dose step of AMG 596 at cycle 1 (if applicable). Subjects 
should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
onwards.
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum hospitalization period in each cycle. Vital signs will 
also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
h If a subject discontinues after C1 this visit assessments will be considered EOT assessments. After EOT, please perform SFUP assessments as in Table 11
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
k ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically indicated.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 83 of 169
CONFIDENTIAL
Table 11. Schedule of Assessments Dose Escalation Cohort 
 AMG 596 Cycle 2 (AMG 404 3rd Infusion), Cycle 4 and all 
Subsequent Even Number Cycles (Arm 2, Combination Therapy)
Treatment Period-Dose Escalation 
AMG 596 Cycle 2 (AMG 404 3rd infusion), Cycle 4, and all Subsequent Even Number Cycles
Cycle -Day
Pre-
Dose(hr)
Hours Relative to Start of AMG 596 Infusion
Hours Relative to End of 
AMG 596 Infusion
Every 3 
Months 
(+/- 2 
weeks)
0.5
1
2
3
4 
(+1)
6
8
12
16
20
24
48
EOI
0.
5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to AMG 
404 Infusion
GENERAL AND SAFETY ASSESSMENT
Informed Consent
Hospitalizationa
X
X
Medial History
Concomitant 
Medications
X
Serious Adverse Events
X
XJ
Adverse Eventsi
X
Clinical Ealuationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evatluation
X
X
X
X
X
X
X
X
X
Vital signs, pulse 
oximetryC
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 triplicate 
Measurement
X
X
X
X
X
X
X
LABORATORY ASSESSMENT
Serum Pregnancy Testd
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines/CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
Hetatitis Serology, HIV, 
HLA
ACTH, ANA, ANCAk
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approve
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 84 of 169
CONFIDENTIAL
Table 11. Schedule of Assessments Dose Escalation Cohort 
 AMG 596 Cycle 2 (AMG 404 3rd Infusion), Cycle 4 and all 
Subsequent Even Number Cycles (Arm 2, Combination Therapy)
Treatment Period-Dose Escalation 
 AMG 596 Cycle 2 ( AMG 404 3rd infusion), Cycle 4, and all Subsequent Even Number Cycles
Cycle -Day
Pre-
dose(
hr)
Relative to start of AMG 596 infusion
Relative to End of AMG 
596 Infusion
Every 3 
Months 
(+/- 2 
weeks)
  
0.5
1
2
3
4 
(+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours relative to 
AMG 404 Iinfusion
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENT
Imaginge
X
X
X
Treatment Response
X
X
X
Page 2 of 2
Footnotes defined on next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 85 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a For combination therapy, Hospitalization at start of AMG 596 cycle 2 and all subsequent cycles, and after dose step (if applicable) at cycle 2 and all subsequent cycles, will be for a 
minimum of 72 hours after start of AMG 596 until cycle 5. Hospitalization will be at minimun of 48 hours after start of AMG 596 from cycle 6 onwards (per investigator’s discretion)., 
Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
onwards.
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum hospitalization period in each cycle. Vital signs will also be 
assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging evaluation 
(historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW 
(selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and treatment and 
cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
j Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected.
k ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically indicated.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 86 of 169
CONFIDENTIAL
Table 12. Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 3, and all Subsequent Odd Number Cycles 
(Arm 2, Combination Therapy) 
Treatment Period-Dose Escalation 
AMG 596 Cycle 3, and all subsequent Odd Number Cycles
Cycle -Day
Pre-
dose(
hr)
Hours Relative to Start of AMG 596 Infusion
Hours Relative to End 
of AMG 596 Infusion
Every 3 
Months 
(+/- 2 
weeks)
0.5
1
2
3
4
(+1)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to AMG 
404 Infusion
GENERAL SAFETY ASSESSMENT
Informed Consent
Hospitalizationa
X
X
X
Medial History
Concomitant 
Medications
X
Serious Adverse 
Events
X
Xj
Adverse Eventsi
X
Clinical Ealuationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological 
Evatluation
X
X
X
X
X
X
X
Vital signs, pulse 
oximetryC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate 
Measurement
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENT
Serum Pregnancy Testd
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines/CRP (Local 
lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
X
Hetatitis Serology, HIV, 
HLA
ACTH, ANA, ANCAk
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approve
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 87 of 169
CONFIDENTIAL
Table 12. Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 3, and all Subsequent Odd Number Cycles 
(Arm 2, Combination Therapy)
Treatment Period-Dose Escalation 
AMG 596 Cycle 3, and all Subsequent Odd Number Cycles
Cycle -Day
Pre-
dos
e(hr
)
Relative to start of AMG 596 infusion
Relative to End of 
AMG 596 Infusion
Every 3 
Months 
(+/- 2 
weeks)
0.
5
1
2
3
4(
+1
)
6
8
12
16
20
24
48
EOI
0.5
2
4
8
24
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to AMG 
404 Infusion
GENERAL SAFETY ASSESSMENT
DISEASE ASSESSMENT
Imaginge
X
X
X
Treatment Response
X
X
X
Page 2 of 2
Footnotes defined on next page of the table
 
 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 88 of 169
CONFIDENTIAL
a For combination therapy, hospitalization at start of AMG 596 cycle 2 and all subsequent cycles, and after dose step (if applicable) at cycle 2 and all subsequent cycles, will be 
for a minimum of 72 hours after start of AMG 596 until cycle 5. Hospitalization will be at minimun of 48 hours after start of AMG 596 from cycle 6 onwards (per investigator’s 
discretion)., Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
onwards
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle. 
Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
k ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically indicated.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 89 of 169
CONFIDENTIAL
Table 13. Schedule of Assessments Dose Expansion Cohort 28-day Infusion Cycle 1 (Arm 1, AMG 596 Monotherapy)
Optional
Pre-SCR
SCR
Treatment Period - Dose Expansion
Cycle
1
Cycle Day
Any time 
prior
to SCR
Pre-dose
Relative to start of infusion
EOI
0.5
1
2
3
4 (+1)
6
8
12
16
20
24
48
GENERAL AND SAFETY ASSESSMENTS
Informed consent
X
X
Hospitalizationa 
X
Medical History
X
Concomitant Medications
X
X
Serious adverse events
X
X
Adverse events i
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
Vital signs, pulse oximetryc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measurement
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy testd
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
Hepatitis Serology, HIV, HLA
X
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging e
X
Treatment response
X
Footnotes defined on next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 90 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 1 will be for a minimum of 7 days from the start of the infusion, and for at least 24 hours following completion of the infusion, and for 72 hours 
after a dose step at cycle 1 (if applicable).
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and following this every 6 hours during the minimum hospitalization period in each cycle. 
Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
g If a subject discontinues after C1 this visit assessments will be considered EOT assessments. After EOT, please perform SFUP assessments as in Table 14
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 91 of 169
CONFIDENTIAL
Table 14. Schedule of Assessments Dose Expansion Cohort 
 Infusion Cycle 2 and all Subsequent Cycles (Arm 1, 
AMG 596 Monotherapy)
Treatment Period - Dose Expansion
Cycle
2 and all subsequent cycles
Cycle Day
Pre-
dose
Hours Relative to Start of AMG 596 Infusion
EOI
Every 3 
months 
(+/- 2 
weeks) 
0.5
1
2
3
4
6
8
12
16
20
24
48
GENERAL AND SAFETY ASSESSMENTS
Informed consent
Hospitalizationa
X
Concomitant Medications
X
Serious adverse events
X
Xh
Adverse events
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
X
X
X
X
Vital signs, pulse oximetryc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG triplicate measurement
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum pregnancy testd
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines / CRP (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
X
Hepatitis Serology, HIV
INVESTIGATIONAL PRODUCT DOSING
AMG 596
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaging e
X
X
X
Treatment response
X
X
X
Footnotes defined on next page of the table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 92 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 2 and all subsequent cycles and after dose step at cycle 2 and all subsequent cycles (if applicable) will be for a minimum of 72 hours until 
cycle 5 and 48 hours from cycle 6 onwards (per treating investigator’s discretion).
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum hospitalization period in each cycle. Vital signs will 
also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed every 10 to 12 weeks from start of treatment, and at SFUP if no scan was performed 
within 6 weeks.  Scans will in include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW (selected sites only) images of the brain.  All other known 
sites of disease should also be recorded and assessed. Earlier assessments can be made if clinically indicated at the discretion of the managing physician. If the subject is 
removed for any reason other than clinically significant disease progression, imaging should be collected during LTFU as long as subject consents to continue.
f Safety Follow Up to be performed 30 days (+/- 7 days) after EOT.
h Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 93 of 169
CONFIDENTIAL
Table 15. Schedule of Assessment Dose Expansion Cohort 
 Cycle 1 and all Subsequent Odd Number Cycles (Arm 2, 
Combination Therapy)
Optional 
Pre-SCR
SCR
Treatment Period-Dose Expansion Cohorts-Cycle 1, Cycle3, and all Subsequent Odd Number Cycles
Cycle Day
Pre-
dose
Hours Relative to Start of AMG 596 Infusion
EOI
0.5
1
2
3
4 (+1)
6
8
12
16
20
24
48
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to MAG 
404 Infusion
GENERAL AND SAFETY ASSESSMENTS
Informed Consent
x
X
Hospitalizationa
x
Medial History
X
Concomitant Medications
X
X
Serious Adverse Events
X
X
Adverse Eventsi
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
Vital Signs, Pulse 
OximetryC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Triplicate 
Measurement
X
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum Pregnancy Testd
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine/CRP (Local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/Dipstick
X
X
X
X
X
X
X
X
Hepatitis Serology, HIV, 
HLA
X
ACTH, ANA, ANCAk
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approve
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 94 of 169
CONFIDENTIAL
Table 15. Schedule of Assessment Dose Expansion Cohort 
 Cycle 1 and all Subsequent Odd Number Cycles (Arm 2, 
Combination Therapy)
Optional 
Pre-SCR
SCR
Treatment Period-Dose Expansion Cohorts-Cycle 1, Cycle3, and all Subsequent Odd Number Cycles
Cycle Day
Pre-
dose
Hours Relative to Start of AMG 596 Infusion
EOI
0.5
1
2
3
4 
(+1)
6
8
12
16
20
24
48
INVESTIGATIONAL PRODUCT DOSING
AMG 596
AMG 404
Hours Relative to 
MAG 404 Infusion
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaginge
X
Treatment Response
X
Page 2 of 2
Footnotes defined on next page of the table
 
e
 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 95 of 169
CONFIDENTIAL
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of AMG 596 cycle 1 will be for a minimum of 8 days from the start of the AMG 596 infusion, whereby AMG 404 will be administered on 
, and for at 
least 24 hours following completion of the AMG 596 infusion. All subjects will be hospitalized for at least 72 hours after a dose step of AMG 596 at cycle 1 (if applicable). 
Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
onwards.
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum hospitalization period in each cycle. Vital signs will 
also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
g If a subject discontinues after C1 this visit assessments will be considered EOT assessments. After EOT, please perform SFUP assessments as in Table 16. 
Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
j ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically indicated.
 
Approved 
 
 


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Protocol Number:  20160132 
Date:  29 July 2019
Page 96 of 169
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Table 16. Schedule of Assessment Dose Expansion cohort 
 Cycle 2 and all Subsequent Even Number Cycles (Arm 2, 
Combination Therapy)
Treatment Period-Dose Expansion Cohorts-Cycle 2 and all Subsequent Odd Number Cycles
Cycle Day
Pre-
dose
Hours Relative to Start of AMG 596 Infusion
Every 3 
months 
( +/-2 
weeks)
0.5
1
2
3
4
(+1)
6
8
12
16
20
24
48
EOI
24
INVESTIGATIONAL DRUG DOSING
AMG 596
AMG 404
Hours Relative to AMG 
404 Infusion
GENERAL AND SAFETY ASSESSMENTS
Informed Consent
Hospitalizationa
X
Conconmitant 
Medications
X
Sevious Adverse Events
X
Xj
Adverse Eventsi
X
Clinical Evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Evaluation
X
X
X
X
X
X
X
X
X
Vital Signs, Pulse 
OximetryC
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 Triplicate 
Measurement
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum Pregnancy Testd
X
Cogulation
X
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
X
X
Blood Glucose Test
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines/ CRP (local 
Lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
Urianalysis/Dipstick
X
X
X
X
X
X
X
X
Hepatatis Serology, HIV, 
HLA
ACTH, ANA, ANCAk
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approve
 
 
 


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Protocol Number:  20160132 
Date:  29 July 2019
Page 97 of 169
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Table 16. Schedule of Assessment Dose Expansion cohort 
 Cycle 2 and all Subsequent Even Number Cycles (Arm 2, 
Combination Therapy)
Treatment Period-Dose Expansion Cohorts-Cycle 2 and all Subsequent Odd Number Cycles
Cycle Day
Pre-
Dose
Hours Relative to start of AMG 596 Infusion
Every 3 
months 
(+/-2 
weeks)
0.5
1
2
3
4
(+1)
6
8
12
16
20
24
48
EO
I
24
INVESTIGATIONAL DRUG DOSING
AMG 596
X
AMG 404
X
Hours Relative to AMG 
404 Infusion
Pre-
Dose
EOI
BIOMARKER ASSESSMENTS
DISEASE ASSESSMENTS
Imaginge
X
X
Treatment Response
X
X
X
Page 2 of 2
Footnotes defined on next page of the table
 
ed 
 
 


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a For combination therapy, hospitalization at start of AMG 596 cycle 2 and all subsequent cycles, and after dose step (if applicable) at cycle 2 and all subsequent cycles, will be 
for a minimum of 72 hours after start of AMG 596 until cycle 5. Hospitalization will be at minimun of 48 hours after start of AMG 596 from cycle 6 onwards (per investigator’s 
discretion)., Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
onwards
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum hospitalization period in each cycle. Vital signs will 
also be assessed prior to subject`s discharge from hospital in order to detect possible signs and symptoms of infusion reactions. 
d Serum pregnancy test will be performed for all females unless surgically sterile or 2 years postmenopausal
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If available, data from a prior imaging 
evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening. Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and 
post-contrast enhanced and DW (selected sites only) images of the brain.  All other known sites of disease should also be recorded and assessed.
Safety Follow Up to be performed 30 days (+/- 7 days) after EOT.
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after meeting all eligibility criteria and 
treatment and cohort have been assigned. Adverse events occurring during the screening period will be documented as medical history.
j Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected.
k ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically indicated.
 
Approved 
 
 


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7.2
General Study Procedures
A signed and dated IRB/IEC approved ICF must be obtained prior to performing any 
study-specific procedures.  All screening procedures must be performed within 14 days 
of day 1, unless otherwise noted.  Subjects who meet the inclusion and exclusion criteria 
will be eligible to be enrolled in the study.
A subject may be rescreened up to 3 additional times during the study at the discretion 
of the investigator.
During the study, every effort should be made to perform the study procedures as 
indicated on the Schedules of Assessments (Section 7.1, Table 6, Table 7, Table 8,
Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15 and Table 16). 
AMG 596 dose step can be introduced on 
 of a cycle, and assessments for the first 
week of the step dose (
) must follow assessments for 
 of a 
cycle except for the pregnancy test. In case of step dosing, AMG 404 will be 
administered 
 after the AMG 596 target dose is achieved in cycle 1.
AMG 404 will be given every 
 ECG triplicate measurements will be 
performed during first AMG 404 infusion at predose, EOI, and 4 hours after end of 
infusion for cycle 1. In all subsequent AMG 404 dose, ECG triplicate measurements will 
only be collected at predose and EOI. 
Subjects will be seen in the clinic for study evaluations.  When electrocardiograms 
(ECGs), vital signs, blood sample collections, biomarker sample collections, and biopsy 
sample collections occur on the same visit, ECGs and vital signs should be performed 
before samples (blood, biopsy) are collected.  Blood samples must not be taken/drawn 
from the catheter port used for AMG 596 or AMG 404 infusion.  If a permanent central 
line with more than one lumen is used, blood draws can be done via the lumen that is 
not used for drug administration. The time of blood sample collection must be recorded 
with the exact time of collection in the subject’s medical records and in the eCRF (do not 
use the time that the samples were frozen or any other time point).  If blood samples will 
be collected on the same day that the infusion bag is being changed, the blood samples 
must be collected before the infusion bag is changed.
The study specific manuals provide additional details regarding the requirements for 
these procedures.
Approved 
 
 


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Date:  29 July 2019 
Page 100 of 169 
CONFIDENTIAL 
 
 
Acceptable deviation windows are as follows: 
 
After completion of cycle 1 (AMG 596 and AMG 404), +/- 1 day for all visits if 
logistically necessary 
 
ECGs, biomarker 
 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 (or dose step, if applicable). 
- 
± 2-hour window if collected between 24 hours and 3 days after the start of 
an infusion (or dose step, if applicable).   
- 
Assessments after day 3 should be performed on the indicated study day, but 
not at a certain hour of the day.   
- 
± 1day window if collected at D8 or later, or at the EOI.   
 
PK blood draws in cycles 1 - 3:  
- 
within two hours prior to treatment start / dose step (if applicable) 
- 
± 15-minute window for samples taken within the first 24 hours after start of 
infusion and within 24 hours after EOI.  In case of a dose step, the 
± 15-minute window also applies to the samples taken within the first 
24 hours after dose step.   
Local laboratories should be used for the following assessments: hematology, clinical 
chemistry including cytokines, coagulation, urinalysis, hepatitis serology, HIV, and serum 
pregnancy tests.  Additional parameters can be explored locally and centrally for safety 
evaluations.  The following collections will be shipped to a central laboratory for analysis: 
blood samples for determination of plasma concentrations of 
 
 
.  Refer to the laboratory manual for detailed collection, 
processing, and shipping procedures. 
Approved 
 
 


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Table 17. List of Analytes
Chemistry
Hematology
Coagulation
Urinalysis
Other 
Sodium
Potassium
Chloride
Bicarbonate 
(HCO3) or carbon
dioxide
Total protein
Albumin
Calcium
Calcium corrected
Glucose
Blood urea 
nitrogen or Urea
Creatinine
Estimated CrCl
GFR, MDRD 
calculation
Total creatine 
kinase
Total bilirubin 
(TBL)
Direct bilirubin
Alkaline 
phosphatase 
(ALP)
Alanine 
aminotransferase 
(ALT)
Aspartate 
aminotransferase 
(AST)
TSH***
Free T4***
RBC
Hemoglobin
Hematocrit
Mean corpuscular 
volume (MCV)
Platelets
White blood cell 
differential

Total 
neutrophils

Eosinophils

Basophils

Lymphocytes

Monocytes
PT
PTT
INR
Fibrinogen
AT III
Specific gravity
pH
Blood
Protein
Glucose
BilirubinMicroscopic 
exam**
(performed at the
discretion of the 
Investigator)
C-reactive 
protein 
(CRP)
IL-6
Serum 
Pregnancy
HLA typing
Hepatitis B 
surface 
antigen
Hepatitis C 
antibody
HIV*
ACTH***
ANA***
ANCA***
(cytoplasmic 
and 
perinuclear)
* Hepatitis B surface antigen, Hepatitis C antibody, PCR for Hepatitis C RNA (if Hepatitis C antibody is 
positive), and HIV assessments are recommended.
** WBC, RBC, Epithelial Cells, Bacteria, Casts, and Crystals
*** Only applicable for AMG 404 infusion
ACTH = Adrenocorticotropic hormone; ANA = Antinuclear Antibodies; ANCA = Antineutrophil cytoplasmic 
antibodies;
A serum pregnancy test will be performed locally at each site on all female unless they 
are surgically sterile or ≥2 years postmenopausal. On visits where required, the serum 
pregnancy test must be performed prior to dosing with investigational product. If the 
pregnancy test is positive at day 1 of cycle 1, the subject should not be given 
investigational product.
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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.  This may 
include measurement of urine output, if deemed appropriate by the Investigator.
7.2.1
Pre-Screening and Screening 
The pre-screening evaluation is optional and serves to pre-determine 
EGFRvIII-positivity. Up to 500 subjects diagnosed with glioblastoma or malignant glioma
may undergo the pre-screening evaluation. Pre-screening can start after written 
informed consent for pre-screening has been obtained and should be completed prior to 
signing consent for study participation.
 After 
EGFRvIII-positivity has been reported and prior to signing consent for study 
participation, the subject may still receive one or more antitumor-treatments. During 
pre-screening, investigators may also provide the results of EGFRvIII positive testing 
from local testing for trial enrollment. If prescreening is used for enrollment, then plasma 
must be collected at screening or pre-dose for confirmation of mutation status when the 
plasma assay is ready. When the plasma test is ready, then patients will be enrolled 
using this plasma assay.
Subjects may also enter directly into the screening period without pre-screening.
Approved 
 
 


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The following assessments will be completed during Screening: 

Confirmation that the ICF for participation in the study has been signed

Demographic data including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety 
Approved 
 
 


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
Clinical evaluation
-
Physical examination as per standard of care. Physical examination findings 
should be recorded on the appropriate eCRF
-
Medical/surgical history (medical history data becoming available after the 
screening period will also have to be collected)
o
Including renal/urinary history (including urine output)
-
ECOG performance status
-
Height and weight

Neurological Evaluation

Vital signs (ie, blood pressure, heart rate, respiratory rate, temperature)

Pulse oximetry

ECG triplicate measurement

Laboratory assessments: hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test (females only), hepatitis serology, and HIV, cytokines/CRP, 
blood glucose test

Biomarker assessments:

Note: Test results confirming EGFRvIII positivity expire with start of any 
antitumor therapy between re-screenings and need to be repeated in this case. 

Imaging assessment collected at screening visit

Data from prior imaging evaluation (historical imaging) within 6 months of 
enrollment.

Serious adverse event reporting

Documentation of concomitant and rescue medications.  All prior cancer 
treatment therapies will be collected, and other prior therapies that were being 
taken as of signature of the informed consent should be collected.  For prior 
therapies, collect therapy name, indication, dose, unit, frequency, start date, 
and stop date.
7.2.2
Treatment
All subjects will be hospitalized for the following periods: 
Cycle 1: 

For the first 
 of AMG 596 monotherapy (Arm 1) 

For the first 
 of AMG 596 in combination with AMG 404 (Arm 2), hence 
AMG 404 will be administered on 

For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 
and Arm 2 

For additional 72 hours after AMG 596 step dose if necessary 
Approved 
 
 


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Protocol Number:  20160132 
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Cycle 2 and all subsequent cycles: 

For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2

For additional 72 hours after AMG 596 step dose if necessary.
Hospitalization may be shortened to 48 hours from the 6th cycle onwards at the 
discretion of the investigator. 
AMG 404 can be administered in an outpatient setting starting from cycle 1 
 
onwards. Subjects should be monitored intensely in hospital or outpatient clinic for at 
least 4 hours after start of each AMG 404 infusion from cycle 1 
 onwards.
Restart of the infusion should be performed in the clinic/hospital under the supervision of 
the investigator or designee and the subject should be hospitalized for a minimum of 
24 hours when the infusion interruption meets the following criteria:

associated to an AE, or

interruption > 24 hours due to a pump related issue.
Dosing with AMG 596 or AMG 596 in combination with AMG 404 can continue unless 
the subject becomes intolerant to investigational product, the signs and symptoms of 
clinical progression are evident as determined by the investigator, or the subject 
withdraws consent. Tumor evaluations by MRI will occur every 10 to 12 weeks from 
start of treatment. Earlier assessments can be made if clinically indicated at the 
discretion of the managing physician. Modified RANO criteria (Appendix D) will be used 
allowing subjects to stay on study until clinically significant disease progression if no 
other treatment discontinuation criteria apply.  Upon discussion with the Sponsor, 
subjects may continue to receive treatment after radiographic confirmation of 
progressive disease as long as they continue to derive clinical benefit in the opinion of 
the investigator and until further increase in tumor burden.  For analysis purposes, date 
of PD is the date of initial observed PD.
Investigational product is to be administered after all other protocol required pre-dose 
assessments have been performed on day 1 of each cycle.  
The results from laboratory tests taken on day prior to infusion start do not have to be 
available before start of treatment with AMG 596.  Laboratory assessments completed 
within 24 hours prior to treatment start do not have to be repeated on day 1 prior to 
infusion start. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Section 7.1). Treatment period starts when 
Approved 
 
 


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the first cIV infusion of AMG 596 is administered to a subject.  For a full list of study 
procedures, including the timing of each procedure, please refer to Section 7 and the 
Schedule of Assessments.

Hospitalization

Clinical evaluation
-
Physical examination as per standard of care.  Physical examination findings 
should be recorded on the appropriate eCRF.  
-
ECOG performance status
-
Weight

Neurological Evaluation

Vital signs (ie, blood pressure, heart rate, respiratory rate, temperature)

Pulse oximetry

ECG triplicate measurement

Laboratory assessments: hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test (females only), blood glucose test, cytokines/CRP

Biomarker assessments: 
 


Imaging Assessment

Serious adverse event reporting

Adverse event reporting

Documentation of concomitant and rescue medications
7.2.3
End of Treatment (EOT)
The EOT visit will occur upon documented clinically significant disease progression, 
intolerable adverse event, or withdrawal of consent (see Section 8) for a complete list of 
reasons for permanent treatment discontinuation.  For subjects who choose to 
discontinue investigational product treatment, the EOT visit should occur as soon as 
possible after the last dose of investigational product is administered.  Medically 
significant adverse events that are considered related to the investigational product will 
be followed until resolved or considered stable.  The following procedures will be 
completed during the EOT visit as designated in the Schedules of Assessments 
(Section 7.1):
Approved 
 
 


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
Clinical evaluation
-
Physical examination as per standard of care Physical examination findings 
should be recorded on the appropriate eCRF. 
-
ECOG performance status
-
Weight

Neurological evaluation

Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature)

Pulse oximetry 

ECG triplicate measurement

Laboratory assessments: hematology, chemistry, coagulation, urinalysis, blood 
glucose test, cytokines/CRP

Biomarker assessments:

Serious adverse event reporting

Adverse event reporting

Documentation of concomitant and rescue medications
7.2.4
Safety Follow Up Visit
The safety follow-up visit (SFUP) is to be performed 30 days (+/- 7 days) after the last 
dose of AMG 596 and AMG 404 even if the subject begins another therapy.  All efforts 
should be made to conduct this visit.  If it is not possible to conduct the SFUP visit, 
documentation of the efforts to complete the visit should be provided in the source 
documents and noted as not done in the eCRF.
The following procedures will be completed at the SFUP visit as designated in the 
Schedules of Assessments (Section 7.1) 

Clinical evaluation
-
Physical examination as per standard of care. Physical examination findings 
should be recorded on the appropriate eCRF.
-
ECOG performance status
-
Weight

Neurological evaluation

Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature)

Pulse oximetry

ECG triplicate measurements

Laboratory assessments: hematology, chemistry, coagulation, urinalysis, blood 
glucose test, cytokines/CRP
Approved 
 
 


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
Biomarker assessments: 


Imaging assessment if last assessment was done more than 6 weeks prior to 
this visit 

Treatment response (not applicable to Cohort 
)

Serious adverse event reporting

Adverse event reporting

Documentation of concomitant and rescue medications
7.2.5
Long Term Follow Up
The long term follow up visit (LTFU) is to be performed via clinical visit or telephone 
every 3 months (+/- 2 weeks) after their SFUP visit and until a maximum of 12 months 
from start of treatment, until start of a new therapy or until death has been reported, 
whichever occurs first. 
Subjects will allow Amgen continued access to medical records for up to 12 months from 
start of treatment, so that information related to subject’s disease status may be 
obtained.  All efforts should be made to conduct this visit.  If it is not possible to conduct 
the LTFU visit, documentation of the efforts to complete the visit should be provided in 
the source documents and noted as not done in the eCRF. 
The following procedures will be completed at the LTFU visit as designated in the 
Schedules of Assessments (Section 7.1):

Method of contact (clinical study visits or telephone contact)

Adverse Events and Serious Adverse Events with respective Concomitant 
Medications

Imaging assessments (if collected as part of SoC) and treatment response 
(if available)
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. 
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7.3.2
Demographic Data
Demographic data collection including sex, date of birth, 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, Current Malignancy and Prior Therapy
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening and through screening until start of treatment.  Medical 
history will include information on the subject’s concurrent medical conditions.  Record 
all findings on the Medical History eCRF or Current Malignancy eCRF as appropriate.
Relevant medical history, including renal/urinary history (including urine output), previous 
chemotherapy or radiotherapy, antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, bleeding, and infection (resolved and ongoing) will 
be collected.  The history of glioblastoma or malignant glioma must date back to the 
initial diagnosis and any response duration.  The current toxicity grade will be collected 
for each condition that has not resolved.
7.3.4
Concomitant Medications
Concomitant therapies are to be collected from informed consent through to the SFUP.
Medications associated with AEs or SAEs occurring between the SFUP visit and End of 
Study must also be collected. Collect therapy name, indication, dose, unit, frequency, 
route, start date, and stop date.
7.3.5
Weight Measurements
Weight in kilograms should be measured without shoes.
7.3.6
Height Measurements
Height in centimeters should be measured without shoes at screening only.
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.
The 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 most recumbent position as possible.  The 
Approved 
 
 


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position selected for a subject should be the same that is used throughout the study and 
documented on the vital signs eCRF.
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs 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
Electrocardiogram 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.
Electrocardiograms should be performed in a standardized method, in triplicate, and 
approximately 30 seconds apart, prior to blood draws or other invasive procedures.  
Each ECG must include the following measurements: QRS, QT, QTc, RR, and PR 
intervals.
Electrocardiograms will be performed as follows:

Three baseline ECGs will be collected ≥ 30 minutes apart, with each baseline ECG 
in triplicate run consecutively (ie, approximately 30 seconds apart; 2 sets collected 
at screening, and 1 set collected pre-dose on day 1 [ie, total ≥ 9 ECGs])

Triplicate ECGs at time points after dosing
Baseline is defined as pre-dose assessments from cycle 1 day 1.  The principal 
investigator or designated site physician will review all ECGs.  Electrocardiograms will 
be transferred electronically to an ECG central reader for analysis per Amgen 
instructions.  Once signed, the original ECG tracing will be retained with the subject’s 
source documents.  At the request of 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.
7.3.10
Physical Examination
A complete physical examination as per standard of care (rectal and vaginal examination 
not required) will be performed by the investigator or designee at screening and at the 
time points specified in the Schedules of Assessments (Section 7.1, Table 6, Table 7, 
Approved 
 
 


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Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, and 
Table 16.
The physical examination will include general appearance, including examination of the 
skin, spleen, 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 Adverse Event eCRF.
7.3.11
Eastern Cooperative Oncology Group (ECOG)
Subjects will be graded according to the Eastern Cooperative Oncology Group (ECOG) 
Performance Status.  The ECOG criteria for this protocol are further defined in 
Appendix F.  
7.3.12
Clinical Laboratory Tests
The tests listed Table 17 (List of Analytes) will be conducted on samples collected and 
analyzed by standard laboratory procedures at the time points specified in the Schedule 
of Assessments (Section 7.1, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, 
Table 12,Table 13, Table 14, Table 15 and Table 16).  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.
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.  
7.3.13
Serum Pregnancy Test
A serum qualitative pregnancy test will be performed locally at each site on all females 
unless they are surgically sterile or 2 years postmenopausal.  On visits where required, 
the serum pregnancy test must be performed prior to dosing with investigational product.  
If the pregnancy test is positive at day 1 of cycle 1, the subject should not be given 
investigational product.  If the pregnancy test is positive at any other visit, then 
investigational product must be held, and a confirmatory quantitative serum pregnancy 
test must be done.  If the confirmatory quantitative serum pregnancy test is positive, the 
investigational product (AMG 596) must be discontinued.  If the quantitative pregnancy 
test is negative the subject should restart infusion per the criteria in Section 6.2.4.  
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7.3.14
Adverse Events
Adverse event and serious adverse 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 9.2.  Determination of the severity of all adverse events will be 
consistent with the CTCAE, version 4.0 (Appendix A) unless specified otherwise.
7.4
Pharmacokinetic Blood Sampling
Blood samples will be obtained for determination of serum concentrations of AMG 596 in 
the monotherapy and for the determination of serum concentrations of AMG 596 and 
AMG 404 in the combination therapy at the time points specified in the Schedules of 
Assessments (Section 7.1, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, 
Table 12,Table 13, Table 14, Table 15 and Table 16).  Blood must not be drawn from the 
port catheter.  Sample collection, processing, storage, and shipping instructions are 
provided in a separate laboratory manual.
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7.8
Sample Storage and Destruction
Any blood, tissue or CSF sample collected according to the Schedule of Assessments 
(Section 7.1) can be analyzed for any of the tests outlined in the protocol and for any 
tests necessary to minimize risks to study subjects.  This includes testing to ensure 
analytical methods produce reliable and valid data throughout the course of the 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 
glioblastomas and malignant gliomas, the dose response and/or prediction of response 
to AMG 596 and in combination with AMG 404, 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 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent.
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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, CSF, or tumor samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen.
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
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.
7.9
Imaging Assessment of Disease Burden
7.9.1
Magnetic Resonance Imaging (MRI)
MRI of the brain will be done at screening, every 10 to 12 weeks from start of treatment 
and at SFUP or until the signs and symptoms of clinical progression are evident as 
determined by the investigator, radiographic progression is confirmed in 2 scans 
≥4 weeks apart without signs of clinical benefit, start of a new treatment, death or the 
subject withdraws consent (see Section 7.1 Schedule of Assessment).  Upon discussion 
with the Sponsor, subjects may continue to receive treatment after radiographic 
confirmation of progressive disease as long as they continue to derive clinical benefit 
and until further increase in tumor burden. For analysis purposes, date of PD is the date 
of initial observed PD.  All scans for each subject will be performed in the same manner 
as at baseline, at the same field strength, preferably on the same scanner.  The same 
contrast agent should be used through the study; macrocyclic gadolinium agents are 
preferred.  Scans should be acquired with a slice thickness ≤5 mm.  At each imaging 
timepoint, the following sequences will be performed:

Axial Pre Contrast (2D) T1

Axial T2

Axial T2/FLAIR

Axial Post Contrast (2D) T1
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
Axial diffusion-weighted magnetic resonance imaging (DWI) (at selected sites)

Sagittal Post Contrast (3D) T1 (selected sites if part of site protocol)
Subjects who demonstrate an objective response or disease progression will have a 
confirmatory MRI performed at least 4 weeks after the initial observation scan.  
7.9.2
Tumor Assessment by MRI
The Response Assessment in Neuro-Oncology (RANO) Working Group published 
recommendations that extend the Macdonald Criteria, and specifically incorporate 
T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) sequences to better capture 
non-enhancing components that may be present in high grade gliomas 
(Wen et al, 2010).  The modified RANO criteria for this protocol are further defined in 
Appendix D.
Imaging data may be submitted to a central laboratory for archival and/or additional 
analysis. Additional MRI endpoints reflecting tumor biology, eg, functional diffusion 
maps and three-dimensional tumor volume, and alternate response criteria, eg,
Macdonald, RANO or iRANO, may also be evaluated.
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY
8.1
Subjects’ Decision to Withdraw
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution.
Subjects can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product, device or other 
protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments (Section 7.1) including different options of 
follow-up (eg, in person, by phone/mail, through family/friends, in correspondence/
communication with other treating physicians, from the review of medical records) and 
collection of data, including endpoints, adverse events, disease related events, and 
device related events, as applicable.  Subjects who have discontinued investigational 
product and/or protocol required therapies or procedures should not be automatically 
removed from the study.  Whenever safe and feasible it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data.  The 
investigator must document the level of follow-up that is agreed to by the subject.  
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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  

safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy)

death

lost to follow-up

decision by sponsor (other than subject request, safety concern, lost to follow-up)

disease progression confirmed by 2 scans ≥4 weeks apart without signs of 
clinical benefit
8.3.2
Reasons for Removal From Study
Reasons for removal of a subject from the study are:

decision by sponsor (eg, product quality issue)

withdrawal of consent from study

death

lost to follow-up

start of any other antitumor therapy
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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. Such events do not meet the definition 
of an adverse event unless assessed to be more severe than expected for the subject’s 
condition.  
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 
reported 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 
reported as an Adverse Event or Serious Adverse Event.
Table 18 outlines the expected Disease-Related Events by System Organ Class.
Table 18. Disease-Related Adverse Events by System Organ Class
System Organ Class
Preferred Term(s)
Gastrointestinal disorders
Nausea
Vomiting
Nervous system disorders
Aphasia
Brain edema
Cognitive impairment1
Headache
Hemiparesis
Intracranial pressure increased
Lethargy
Seizure
Sensory loss
Visual field defect
HLT = high level term
1 Represents preferred terms in the Mental impairment (excluding dementia and memory loss) HLT 
(MedDRA version 19.0).
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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, and 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.  
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event eCRF.  
For situations when an adverse event or serious adverse event is due to glioblastoma or 
malignant glioma 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). If a new primary malignancy appears, it 
will be considered as an adverse event.
Note:  The term “disease progression” should not be used to describe the 
disease-related event or adverse event.  
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device.
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.  
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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 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 End of 
Study 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.
Disease-related events assessed by the investigator to be more severe than expected
and/or related to the investigational product(s)/study treatment/protocol-required
therapies, and determined to be serious, must be reported on the Event CRF as 
seriousadverse events and recorded and reported per section 9.2.1 and Appendix I.
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Disease-related events pre-defined for this study are listed in Table 18.
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 the first dose of investigational 
product through the End of Study are reported using the Event eCRF.
The investigator must assign the following adverse event attributes:

Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms),

Dates of onset and resolution (if resolved),

Severity,

Assessment of relatedness to investigational product, medical devices or other 
protocol-required therapy, 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, medical 
device(s), and/or other protocol-required therapies.  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?
The investigator must assess whether the adverse event is possibly related to any study 
mandated activity (eg, administration of investigational product, protocol-required 
therapies, use of medical device(s) and/ or procedure (including any screening 
procedure(s)).  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by administration 
of investigational product?”
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the Investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
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or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event.
The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2.2
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 30 days after the last day of the dosing interval of the investigational 
product or the end of study visit (whichever is later) are recorded in the subject’s medical 
record and are submitted to Amgen.  All serious adverse events must be submitted to 
Amgen within 24 hours following the investigator’s knowledge of the event via the Event 
eCRF.
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event. See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form. 
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available.
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product, medical devices(s), and/or protocol-required therapies. This 
relationship is indicated by a “yes” or “no” response to the question: Is there a 
reasonable possibility that the event may have been caused by the investigational 
product. Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
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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 and that are considered related to the investigational 
product by the investigator.  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. 
In addition to the attributes listed in Section 9.2.2.1, the investigator must also complete 
the serious adverse event section of the Event eCRF.
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.
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In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 30 days after the last dose of AMG 596 or through
4 months (120 days) after the last dose of AMG 404.
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 (see 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 30 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:

Dose limiting toxicities (DLT), treatment-emergent adverse events, 
treatment-related adverse events and changes in vital signs, physical 
examinations, and clinical laboratory tests
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Secondary Endpoint(s):

PK parameters for monotherapy AMG 596 including, but not limited to, average 
steady-state concentration (Css), area under the concentration-time curve (AUC), 
clearance, volume of distribution and half-life (t1/2) for serum AMG 596 

PK parameters of AMG 404 including, but not limited to, maximum abserved 
serum concentration (Cmax), time to achieve Cmax (tmax), and AUC 

PK parameters for AMG 596 dosed in combination with AMG 404 including, but 
not limited to, average steady-state concentration (Css), area under the 
concentration-time curve (AUC), clearance, volume of distribution and half-life 
(t1/2) for serum AMG 596

Objective response (OR) as per modified RANO, time to response, response 
duration and time to progression (TTP); progression free survival (PFS) at 6 and 
12 months after treatment initiation with AMG 596 monotherapy or AMG 596 in 
combination with AMG 404
Exploratory Endpoint(s):  
10.1.2
Analysis Sets
Safety Analysis Set
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 one 
administration of AMG 596.
RANO Evaluable Analysis Set
The RANO Evaluable Analysis Set includes all subjects that are enrolled and receive at 
least one administration of AMG 596 with measurable disease at enrollment per RANO.
DLT Evaluable Analysis Set

The DLT Evaluable Analysis Set includes subjects who are DLT-evaluable and 
will be used to summarize incidence of dose limiting toxicity (DLT) (see 
Section 3.3 for definition of DLT-evaluable). 
10.1.3
Covariates and Subgroups
Due to the small sample size, the impact of baseline characteristics on study outcomes 
will not be explored, and no subgroup analyses will be performed.
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10.2
Sample Size Considerations
It is anticipated that up to 190 subjects will be enrolled in the study. It is anticipated that 
up to 100 subjects will be enrolled to Arm 1 in this study and up to 90 subjects will be 
enrolled to Arm 2 in this study.
For Group 1 (recurrent disease), the following are the planned sample sizes.

In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to 
monotherapy Arm 1 and up to 30 DLT-evaluable subjects to combination Arm 2 

In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and 
up to 15 subjects to combination Arm 2. 
For Group 2 (maintenance setting), the following are the planned sample sizes.

In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to 
monotherapy Arm 1 and up to 20 DLT-evaluable subjects to combination Arm 2 

In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and 
up to 25 subjects to combination Arm 2 
The sample sizes in dose escalation are based on practical considerations and it is 
consistent with conventional oncology studies with the objective to identify the 
RP2D/MTD.  With 2 subjects per cohort, there is a 19-56% probability of observing at 
least one DLT for a cohort if the true DLT rate is 10-33% and with 6 subjects per cohort, 
the probability is 47-91%. 
For Group 1 (recurrent disease) in each respective arm (monotherapy and combination), 
the respective sample sizes of the dose expansion cohorts are based on practical 
considerations. With 21 subjects treated at the RP2D/MTD (6 from dose escalation and 
15 from dose expansion) in an arm, there is a 66% probability of observing an adverse 
event with 5% incidence rate.  For an ORR of 20%, the probability of observing the OR 
in at least 4 subjects would be 63%. The estimated ORR and exact 80% CI for 4 
responses is 19% and 9%-35% respectively.
For Group 2 (maintenance setting) in each respective arm (monotherapy and 
combination), the sample sizes in the respective dose expansion arm are based on a 
Bayesian predictive probability design (Lee, 2008). For both arms, the ORR of interest 
is 20% or higher while an ORR of 5% or less is considered insufficient antitumor-activity. 
The maximum sample size per arm is 31 subjects (6 from dose escalation and 25 from 
dose expansion).  Futility will be assessed initially after treating 10 subjects for at least 
6 months and continuously for each additional subject afterwards. If ORR is lower than 
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5%, enrollment may be terminated due to futility.  The guidelines for early termination 
due to futility are as follows:
Number of Treated Subjects
Futility Termination Guideline
10
0 responders
19
1 or fewer responders
26
2 or fewer responders
31
3 or fewer responders
With this design, the probability of accepting the treatment is 0.05 (type I error) when 
ORR=5% and 0.8 (power) when ORR=20%. If the ORR is 5%, the probability of 
stopping the trial early at the interim with 10 evaluable subjects for futility is 60% and the 
expected additional subjects to be assessed in dose expansion is 9.6. 
During dose expansion and separately for the monotherapy arm (combining data from 
Groups 1 and 2) and for the combination arm (combining data from Groups 1 and 2), 
Amgen will conduct evaluations of the ongoing grade 4 or higher treatment-related 
adverse event rate to assess if the threshold for possible early trial termination has been 
reached. If this threshold is met, enrollment to dose expansion will be halted pending 
review of safety data by the DLRT. After receiving the DLRT recommendation, Amgen 
will choose to take one of the following actions.
1) Terminate the trial 
2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication)
3) Continue dose expansion without any changes
The stopping rules use a Bayesian approach proposed by Thall, Simon, and Estey 
(1995) to terminate the study if the posterior probability that the grade 4 or higher 
treatment-related adverse event rate is greater than 20% is > 80%. The stopping 
boundaries assume a prior distribution of Beta (0.40, 1.60) are presented in Table 19
and the operating characteristics with pre-specified batch size of 10 new subjects per 
batch are presented in Table 20. Subjects included in a batch may come from different 
study groups. The evaluations could occur more frequently if necessary to address 
emerging safety concerns. The operating characteristics in Table 19 provide the 
probability of stopping the trial early for given hypothetical true rate of grade 4 or higher 
treatment-related adverse events, whereas the stopping criteria in Table 20 are based 
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on situations where the empirical evidence would result in a posterior probability of 
≥80% that the true grade 4 or higher treatment-related adverse event rate is ≥20%.
Table 19. Stopping Boundary for Dose Expansion
Number of subjects
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events
10
≥4
20
≥6
30
≥9
40
Study Complete
Table 20. Operating Characteristics with Batch Size of 10 Subjects
True grade 4 or higher 
treatment-related 
adverse event rate
Probability of early stopping 
of dose expansion
Average dose expansion sample size
0.10
2.0%
39.5
0.15
9.7%
37.6
0.20
25.8%
33.9
0.25
47.7%
28.8
0.30
69.2%
23.4
10.3
Adaptive Design
During dose escalation for both Arm 1 and Arm 2, a two-parameter Bayesian logistic 
regression model (BLRM, Neuenschwander et al, 2008) 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 DLT endpoint at dose level di is 
assumed to follow a Bernoulli distribution with probability pi where the logit of pi
increases linearly with the log of the standardized dose in the following 2-parameter 
logistic model:
log [pi / (1-pi)] = logit(pi) = log[a] + exp( log[b]) log (di / dref)
where a and b are random variables and dref is one of the planned doses selected as the 
reference dose.  
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For both Arm 1 and Arm 2 , a bi-variate normal prior distribution (Neuenschwander, 
Branson and Gsponer; 2008) is used to select for θ = (log a, log b) where the probability 
that the true DLT rate is ≤ 0.40 at the lowest monotherapy planned dose (
 μg/day) is 
0.90 and the probability the true DLT rate is ≤0.05 at the reference dose (
 μg/day) 
is 0.05. These values were selected such that pi is 0.05 for the starting dose and 0.25 for 
the reference dose. Model sensitivity to the prior will also be investigated and in 
particular the BLRM will be examined using a prior having a lower reference dose (eg,
 μg/day) and using a prior having a higher reference dose (eg,
 μg/day).
10.4
Planned Analyses
10.4.1
Interim Analyses
Arm 1
In dose escalation, the DLRT will review the safety data after each cohort and make a 
decision on the next dose level to be explored for the estimate of RP2D/MTD based on a 
BLRM design. The RP2D/MTD will be established separately for Group 1 (recurrent 
disease) and Group 2 (maintenance setting) subjects.  The interim analysis will include 
the establishment of RP2D/MTD and the estimate of ORR.

The first interim of safety data analysis in Part 1 dose escalation will happen at 
the earlier of 
-
When 15 subjects enrolled and completed DLT observation or
-
Completion of dose escalation of Group 1.  Efficacy data will also be 
analyzed for subjects who have had at least one imaging evaluation after 
start of treatment or have dropped out before that.
Interim safety analyses during dose expansion will occur once 1) 5 subjects with 
recurrent disease have been enrolled and 2) after enrollment of 10 subjects with 
maintenance setting. The BLRM will estimate the RP2D/MTD using available data from 
dose escalation and dose expansion.  Based on this revised RP2D/MTD estimate and 
reviewing all available safety data, the dose level for dose expansion may be revised.
In Part 2 dose expansion, the ORR will be evaluated after treating n=10 Group 
2 subjects for at least 6 months. The futility will be assessed initially for N=10 and 
continuously afterwards using a Bayesian predictive probability design.  Enrollment may 
be terminated if insufficient antitumor-activity is observed.  
Arm 2
In dose escalation, the DLRT will review the safety data after each cohort and make a 
decision on the next dose level to be explored for the estimate of RP2D/MTD based on a 
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BLRM design.  The RP2D/MTD will be established separately for Group 1 (recurrent 
disease) and Group 2 (maintenance setting) subjects.   
Interim safety analyses during dose expansion will occur once 1) 5 subjects with 
recurrent disease have been enrolled and 2) after enrollment of 10 subjects with 
maintenance setting.  The BLRM will estimate the RP2D/MTD using available data from 
dose escalation and dose expansion.  Based on this revised RP2D/MTD estimate and 
reviewing all available safety data, the dose level for dose expansion may be revised. 
In Part 2 dose expansion, the ORR will be evaluated after treating n=10 Group 
2 subjects for at least 6 months.  The futility will be assessed initially for N=10 and 
continuously afterwards using a Bayesian predictive probability design.  Enrollment may 
be terminated if insufficient antitumor-activity is observed. 
10.4.2 
Dose Level Review Team (DLRT) 
Dose level review meetings (DLRMs) will be held to review data, monitor safety, and 
make dose escalation/change decisions.  The review team will be composed of the 
investigators, Amgen Medical Monitor/ Early Development Leader, Amgen Global Safety 
Officer or designated safety scientist, Amgen Clinical Research Study Manager and 
Biostatistics representative.  Additional members may be added as needed 
(eg, Biomarker Scientist, PK Scientist).  A quorum, defined as > 50% of the participating 
investigators or their qualified designee [ie, sub-PI or research nurse or study 
coordinator possessing hard copy documentation (eg, email) of the PI’s vote regarding 
the dose level review], must be in attendance for DLRM.  The following DLRT members 
are responsible for dosing decisions: investigators, Amgen Medical Monitor, Early 
Development Leader, and Amgen Global Safety Officer.  The DLRM will be rescheduled 
if a quorum is not reached.  
The DLRT members are responsible for dosing decisions, which may include escalation 
to the next planned dose, escalation to an intermediate dose (a dose lower than the next 
planned dose), de-escalation to a lower dose; continuation, delay, or termination of 
dosing; or repetition or expansion of a cohort or start of step-dosing.  All available study 
data, including demographics, investigational product administration, medical history, 
concomitant medications, adverse events, ECGs, vital signs, laboratory results, and 
PK/PD information will be reviewed.  In addition to DLTs, all ≥ grade 3 toxicities not 
meeting DLT criteria (including hematologic) will be reviewed by the team and can be 
considered in the DLRT’s decisions.  Data to be reviewed will be queried. 
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10.4.3
Primary Analysis
A primary analysis will be performed for each group separately when target enrollment in 
Part 1 and Part 2 is complete and each subject either completes 6 months on study or 
withdraws from the study.  
10.4.4
Final Analysis
A final analysis for each group is planned after all subjects in each group have ended the 
study (parts 1 and 2).
10.5
Planned Methods of Analysis
10.5.1
General Considerations
The analyses described below will be reported separately for subjects enrolled to Arm 1
and for subjects enrolled to Arm 2. Unless otherwise specified, the analyses will be done 
using the Safety Analysis Set.
Descriptive statistics will be provided for selected demographics, safety, PK, PD, efficacy 
and biomarker data by dose, dose schedule, and time as appropriate. Descriptive 
statistics on continuous data will include means, medians, standard deviations and 
ranges, while categorical data will be summarized using frequency counts and 
percentages. ORR will be presented with 80% Clopper-Pearson exact CI using the 
RANO Evaluable Analysis Set. PFS will be summarized using Kaplan-Meier method. 
Graphical summaries of the data may also be presented.
10.5.2
Primary Endpoint(s)
Dose Limiting Toxicities (DLT)
The DLT endpoint will be analyzed using the DLT Evaluable Analysis Set. The 
probability of each TPI and of a DLT from the BLRM will be summarized by dose and 
group along with the estimated dose-toxicity curve. Subject incidence of DLT by dose 
level and group will be summarized.
Adverse Events
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term. The number and percentage of subjects reporting 
adverse events will be evaluated overall and by dose level and will also be tabulated by 
relationship to study drug.
Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required therapies, and 
significant treatment-emergent adverse events will also be provided.
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Disease-Related Event (DREs)
Safety endpoints (eg, mortality and morbidity) that are study endpoints are reported on 
an eCRF.  A negatively adjudicated safety endpoint will be reported to the investigator 
and treated by Amgen as appropriate.  This could include no action, or a report on the
eCRF as a Disease-Related event, an adverse event, or a serious adverse event.
Clinical Laboratory Tests
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each 
subject.  Values outside the normal laboratory reference ranges will be flagged as high 
or low on the listings.  Depending on the size and scope of changes in laboratory data, 
summaries of laboratory data over time and/or changes from baseline over time may be 
provided. Tables of maximum shifts from baseline for selected laboratory values may 
also be provided.
Vital Signs
Vital signs data will be listed and reviewed for each subject. Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline 
over time may be provided.
Electrocardiograms
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.
Subjects’ maximum change from baseline in QTc will be categorized and the number 
and percentage of subjects in each group will be summarized.
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized.
All on-study ECG data will be listed and select parameters of interest may be plotted. 
10.5.3
Secondary Endpoint(s)
For all subjects in part 1 and part 2 listings will be produced indicating the time to 
progression, time to response, and duration of response.
Using the RANO Evaluable Analysis Set, an exact 80% CI will be estimated for the OR 
rate for all subjects in part 2 and those in part 1 treated at RP2D/MTD for each group. 
Among these subjects, the proportion of subjects that are progression free at 6 months 
and 12 months with corresponding exact 80% CI will be calculated. A Kaplan-Meier 
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curve may be presented for time to progression with estimates for rates and 80% CI at 
selected weeks.
Pharmacokinetic Analyses
The serum PK parameters of AMG 596 as monotherapy or in combination therapy with 
AMG 404 including, but not limited to, average Css, area under the concentration-time 
curve (AUC), clearance, volume of distribution, half-life (t1/2), 
 
and serum PK parameters of AMG 404 including, but not limited to, Cmax, 
tmax, and AUC will be estimated using non-compartmental methods and summarized by 
dose level using means, standard deviations, medians, minimums, and maximums.  
 Summary 
statistics will be computed for each sampling time and parameter as appropriate.  
10.5.4
Exploratory Endpoints
11.
REGULATORY OBLIGATIONS
11.1
Informed Consent
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Study Manager to the investigator.  
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The written informed consent form is to be prepared in the language(s) of the potential 
subject population.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational product(s) is/ are 
administered.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/ her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician is 
to be documented in the subject’s medical records, and the informed consent form is to 
be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject.
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  
11.2
Institutional Review Board/Independent Ethics Committee
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product.
The investigator must submit and, where necessary, obtain approval from the IRB/IEC
for all subsequent protocol amendments and changes to the informed consent 
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document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures.
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen.
11.3
Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained:  

Subjects are to be identified by a unique subject identification number.  

Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations.  

On the demographics page, in addition to the unique subject identification 
number, include the age at the time of enrollment.  

For Serious Adverse Events reported to Amgen, subjects are to be identified by 
their unique subject identification number, initials (for faxed reports, in 
accordance with local laws and regulations), and date of birth (in accordance with 
local laws and regulations).

Documents that are not submitted to Amgen (eg, signed informed consent forms) 
are to be kept in strict confidence by the investigator, except as described below.
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC, direct access to review the subject’s original medical 
records for verification of study related procedures and data.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named such individuals to have access to 
his/her study related records, including personal information.
11.4
Investigator Signatory Obligations
Each clinical study report is to be signed by the investigator or, in the case of 
multi- center studies, the coordinating investigator.
The coordinating investigator, identified by Amgen, will be any or all of the following:

a recognized expert in the therapeutic area

an investigator who provided significant contributions to either the design or 
interpretation of the study

an investigator contributing a high number of eligible subjects
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12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments and Study Termination
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site.
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen.
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially.
12.2
Study Documentation and Archive
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
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Elements to include:

Subject files containing completed eCRF, informed consent forms, and subject 
identification list.

Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the 
IRB/IEC and Amgen.

Investigational product-related correspondence including Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable.

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 CRFs 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, CRFs and other 
pertinent data) provided that subject confidentiality is respected.
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study related 
records needed to verify the entries on the eCRFs.
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.
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Data capture for this study is planned to be electronic:

All source documentation supporting entries into the eCRFs must be maintained 
and readily available.

Updates to eCRFs will be automatically documented through the software’s 
“audit trail”.

To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During 
this review, subject data are checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data are reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries are created in the EDC system 
database for site resolution and subsequently closed by the EDC system or by 
an Amgen reviewer.

The investigator signs only the Investigator Verification Form for this electronic 
data capture study.  This signature indicates that the investigator inspected or 
reviewed the data on the eCRF, the data queries, and agrees with the content.
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the eCRF Standard 
Instructions and the eCRF Specific Instructions, both of these will be available through 
the EDC system.  Examples of obvious data errors that may be corrected by Amgen (or 
designee) include deletion of obvious duplicate data (ie, the same results sent twice with 
the same date with different visit, [eg, week 4 and early termination]) and updating a 
specific response if the confirming datum is provided in the “other, specify” field (eg, for 
race, reason for ending study).
12.4
Investigator Responsibilities for Data Collection
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (see Section 7.1) the investigator can search publically 
available records [where permitted]) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible.  
12.5
Language
Electronic CRFs must be completed in English. TRADENAMES/® (if used) for 
concomitant medications may be entered in the local language. Consult the 
country-specific language requirements.
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All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  
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 (ICMJE, 2017). 
Recommendations for the Conduct of Reporting, Editing, and Publication of Scholarly 
Work in Medical Journals, which states:

Authorship credit should be based on (1) substantial contributions to conception 
and design, acquisition of data, or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final 
approval of the version to be published; and (4) agreement to be accountable for 
all aspects of the work in ensuring that questions related to the accuracy or 
integrity of any part of the work are appropriately investigated and resolved.  
Authors should meet conditions 1, 2, and 3 and 4.

When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should fully meet the criteria for authorship defined above.

Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship.

All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed.

Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.
Additional information on the current guidelines for publications can be found at the 
following location:  http://www.icmje.org.
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications.
12.7
Compensation
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.
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13. 
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AMG 596 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
AMG 211 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
AMG 404 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Statistics in medicine. 1998: 17(10):1103-1120 
Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, Dieckmann K, Filipits 
M, Brandstetter A, Weller M, Kurscheid S, Hegi ME, Zielinski CC, Marosi C, Hainfellner 
JA, Preusser M, Wick W. Programmed death ligand 1 expression and tumor-infiltrating 
lymphocytes in glioblastoma. Neuro Oncology. 2015 Aug;17(8):1064-75.  
Brown, C. E., D. Alizadeh, R. Starr, L. Weng, J. R. Wagner, A. Naranjo, J. R. Ostberg, 
M. S. Blanchard, J. Kilpatrick, J. Simpson, A. Kurien, S. J. Priceman, X. Wang, T. L. 
Harshbarger, M. D’Apuzzo, J. A. Ressler, M. C. Jensen, M. E. Barish, M. Chen, J. 
Portnow, S. J. Forman and B. Badie. "Regression of Glioblastoma after Chimeric 
Antigen Receptor T-Cell Therapy." New England Journal of Medicine 2016;375(26): 
2561-2569. 
Burstein AH, Zhao Q, Ross J, Styren S, Landen JW, McCush F, et al. Safety and 
pharmacology of ponezumab (PF-0436035) after a single 10-minute intravenous infusion 
in subjects with mild to moderate Alzheimer disease. Clin Neruropharmacol. 
2013;36(1):8-13. 
Chen, J. R., H. Z. Xu, Y. Yao and Z. Y. Qin (2015). "Prognostic value of epidermal 
growth factor receptor amplification and EGFRvIII in glioblastoma: meta-analysis." Acta 
Neurol Scand 2015;132(5): 310-322. 
Choi, B. D., C. T. Kuan, M. Cai, G. E. Archer, D. A. Mitchell, P. C. Gedeon, L. 
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survival benefit with intratumoral and systemic immune responses in recurrent 
glioblastoma. Nat Med. 2019 Mar;25(3):477-486.  
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Gedeon, P. C., B. D. Choi, T. R. Hodges, D. A. Mitchell, D. D. Bigner and J. H. 
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“Pathogenesis-Based Development of Potential Mitigation Strategies for 
Blinatumomab-Associated Neurologic Events (NEs)”, Blood 2016 (ASH abstract). 
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Kischel, R., A. Sternjak, J. Wahl, I. Herrmann, O. Thomas, M. Balazs, M. Voelkel, S. 
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an EGFRvIII/CD3 specific BiTE® antibody construct for the treatment of glioblastoma 
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Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Kohnke T, Vick B, Jeremias 
I, Metzeler KH, Altmann T, Schneider S, Fiegl M, Spiekermann K, Bauerle 
PA, Hiddemann W, Riethmüller G, Subklewe M. Blockade of the PD-1/PD-L1 axis 
augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: 
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Lee, D. W., R. Gardner, D. L. Porter, C. U. Louis, N. Ahmed, M. Jensen, S. A. Grupp 
and C. L. Mackall. "Current concepts in the diagnosis and management of cytokine 
release syndrome." Blood 2014;124(2): 188-195. 
Lee, Bioinformatics. 2008 Nov 1;24(21):2542-3.  
Louis, D. N., A. Perry, G. Reifenberger, A. von Deimling, D. Figarella-Branger, W. K. 
Cavenee, H. Ohgaki, O. D. Wiestler, P. Kleihues and D. W. Ellison. "The 2016 World 
Health Organization Classification of Tumors of the Central Nervous System: a 
summary." Acta Neuropathol 2016;131(6): 803-820. 
Mellinghoff, I. K., M. Y. Wang, I. Vivanco, D. A. Haas-Kogan, S. Zhu, E. Q. Dia, K. V. Lu, 
K. Yoshimoto, J. H. Huang, D. J. Chute, B. L. Riggs, S. Horvath, L. M. Liau, W. K. 
Cavenee, P. N. Rao, R. Beroukhim, T. C. Peck, J. C. Lee, W. R. Sellers, D. Stokoe, M. 
Prados, T. F. Cloughesy, C. L. Sawyers and P. S. Mischel. "Molecular determinants of 
the response of glioblastomas to EGFR kinase inhibitors." N Engl J Med 2005;353(19): 
2012-2024. 
Mendelsohn, J. and J. Baselga. "Epidermal growth factor receptor targeting in cancer." 
Semin Oncol 2006;33(4): 369-385. 
Mehta, M., Wen, P., Nishikawa, R., Reardon, D., & Peters, K. Critical review of the 
addition of tumor treating fields (TTFields) to the existing standard of care for newly 
diagnosed glioblastoma patients. Crit Rev Oncol Hematol, 2017;111, 60-65.  
Neuenschwander, B., M. Branson and T. Gsponer. "Critical aspects of the Bayesian 
approach to phase I cancer trials." Stat Med 2008;27(13): 2420-2439. 
Okada, H., M. Weller, R. Huang, G. Finocchiaro, M. R. Gilbert, W. Wick, B. M. Ellingson, 
N. Hashimoto, I. F. Pollack, A. A. Brandes, E. Franceschi, C. Herold-Mende, L. Nayak, 
A. Panigrahy, W. B. Pope, R. Prins, J. H. Sampson, P. Y. Wen and D. A. Reardon.  
"Immunotherapy response assessment in neuro-oncology: a report of the RANO working 
group." Lancet Oncol 2015;16(15): e534-542. 
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., & 
Carbone, P. P. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol, 1982;5(6), 649-655. 
Omuro, A. and L. M. DeAngelis. "Glioblastoma and other malignant gliomas: a clinical 
review." JAMA 2013;310(17): 1842-1850. 
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A., Ramkissoon, S.H., Ligon, K.L.,Latek,R. ,Zwirtes, R. Strauss,L., Paliwal, P., Harbison, 
C.T., Reardon, D.A.,Sampson, J.H.,Nivolumab with or without ipilimumab in patients with 
recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. 
Neuro Oncol. 2018;20(5):674-686 
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Ostrom Q T, L. Bauchet, F. G. Davis, I. Deltour, J. L. Fisher, C. E. Langer, M. Pekmezci, 
J. A. Schwartzbaum, M. C. Turner, K. M. Walsh, M. R. Wrensch and J. S. 
Barnholtz-Sloan. "The epidemiology of glioma in adults: a "state of the science" review." 
Neuro Oncol 2014;16(7): 896-913. 
Osada T, Patel SP, Hammond SA, Osada K, Morse MA, Lyerly HK.CEA/CD3-bispecific 
T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by 
inhibition of both PD1 and PD-L1. Cancer Immunol Immunother. (2015) 64:677–88. 
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Immunol Immunother 2016 Jul 26. 
Reardon, D.A., Omuro, A., Brandes, A.A., Rieger, J., Wick,A., Sepulveda,J., 
Phuphanich,S., de Souza, P., Ahluwalia, M.S., Lim,M., Vlahovic, G., Sampson, J., et al., 
2017a. OS10.3: randomized phase 3 study evaluating the efficacy and safety of 
nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. 
Neuro Oncol. 2017 V19 Page iii21 
Reardon, D.A, Kim, T.,Frenel, J.S.,Santoro, A., Lopez, J., Subramaniam, D.S., Siu, 
L.L.,Rodon,J., Tamura, K.,Saraf, S., Morosky, A., Stein, K., Soria, J.C., ATIM-35. 
Results of the phase Ib Keynote-028 multi-cohort trial of pembrolizumab monotherapy in 
patients with recurrent PD-L1 positive Glioblastoma Multiforme (GBM), Neuro Oncology. 
2016 V18, P25-26 
Reardon, D. A., Nayak, L., Peters, K.B., Clarke, J.L., Jordan, J. T., Groot, J. F., 
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Bahavsar, C., Molinaro, A. M., Smith, T., Severgnini, M., Wen, P. Y., Phase II study of 
pembrolizumab or pembrolizumab plus bevacizumab for recurrent glioblastoma (rGBM) 
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Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate 
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Espindola F, Choi J, Gúrpide A, Giraldez M, Goicoechea I Gallego Perez-Larraya 
J, Sanmamed MF, Perez-Gracia JL, Melero I. Neoadjuvant nivolumab modifies the 
tumor immune microenvironment in resectable glioblastoma.Nat Med. 2019 
Mar;25(3):470-476 
Stewart, L.A. "Chemotherapy in adult high-grade glioma: a systematic review and 
meta-analysis of individual patient data from 12 randomised trials." Lancet 
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Chamberlain, M. C., Stupp, R., Lamborn, K. R., Vogelbaum, M. A., van den Bent, M. J. 
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Wong, A. J., J. M. Ruppert, S. H. Bigner, C. H. Grzeschik, P. A. Humphrey, D. S. Bigner 
and B. Vogelstein. "Structural alterations of the epidermal growth factor receptor gene in 
human gliomas." Proc Natl Acad Sci U S A 1992;89(7): 2965-2969. 
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D, Samanamud J, Mahajan A, Filip I, Orenbuch R, Goetz M, Yamaguchi JT, Cloney 
M, Horbinski C, Lukas RV, Raizer J, Rae AI, Yuan J, Canoll P, Bruce JN, Saenger 
YM, Sims P, Iwamoto FM, Sonabend AM, Rabadan R “Immune and genomic correlates 
of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med. 2019; 25(3):462-469.  
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14.
APPENDICES
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Appendix A.  Additional Safety Assessment Information
Adverse Event Grading Scale
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE V 4.0) is 
available at the following location:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_
40
If the Amgen standard scoring system is used, insert the following table:
Grade
Amgen Standard Adverse Event Grading Scale
1
MILD:  Aware of sign or symptom, but easily tolerated
2
MODERATE:  Discomfort enough to cause interference with usual activity
3
SEVERE:  Incapacitating with inability to work or do usual activity
It is recommended that teams use the same version of CTCAE throughout a 
program instead of migrating to a newer version in order to avoid the potential for 
introducing discrepancies between studies within a program.] 
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 6.3 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 as defined in Section 9.1.3.
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 6.3.3, Section 6.3.4, Section 6.3.5 and Section 6.3.6. 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 
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abnormalities return to normal or to the subject’s baseline levels.  Assessments that are 
to be performed during this period include: 

Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 

In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve

Testing frequency of the above laboratory tests may decrease if the 
abnormalities stabilize or the investigational product(s) or protocol-required 
therapies has/have been discontinued AND the subject is asymptomatic.

Initiate investigation of alternative causes for elevated AST or ALT and/or 
elevated TBL.  The following are to be considered depending on the clinical 
situation:
-
Complete blood count (CBC) with differential to assess for eosinophilia
-
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess 
for autoimmune hepatitis
-
Serum acetaminophen (paracetamol) levels
-
A more detailed history of: 

Prior and/or concurrent diseases or illness

Exposure to environmental and/or industrial chemical agents 

Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever

Prior and/or concurrent use of alcohol, recreational drugs and special 
diets

Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms
-
Viral serologies
-
Creatine phosphokinase (CPK), haptoglobin, Lactate dehydrogenase (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.  Electronic Serious Adverse Event Contingency Form
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Appendix C.  Pregnancy and Lactation Notification Worksheets
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Appendix D.  Modified Response Assessment In Neuro-Oncology (RANO) 
The RANO criteria are extentions to the Macdonald criteria that incorporate T2/ FLAIR 
images to better capture lesion response (Wen et al, 2010).  Here, the RANO criteria are 
further modified to capture pseudoprogression and delayed responses which may be 
observed in response to immunotherapies (Okada et al, 2015). 
Patients require at least 1 bi-dimensionally measurable contrast-enhancing lesion that 
can be accurately assessed at baseline by magnetic resonance imaging (MRI) to be 
included in this a study. 
Definitions:

Measurable lesions contrast-enhancing lesions that can accurately be measured 
bidimensionally with ≥10mm longest diameter and ≥10mm perpendicular 
diameter and noted on more than one imaging slice.

Non-measurable lesions – all other lesions, including small lesions, ie, bone 
lesions, leptomeningeal disease and cystic lesions that are not confirmed and 
followed by imaging techniques.
Documentation of index and non-index lesions:

Index Lesions
-
All measureable lesions (up to 5) should be identified as index lesions, 
measured and recorded during screening.
-
Enhancing lesions should be selected based on size (largest cross-sectional 
area) and suitability for accurate repeat measure (clearly defined borders)
-
The sum of bidimensional products (total cross-sectional area of measurable 
lesions) for all enhancing measurable lesions at screening will be calculated 
and reported as the baseline disease burden.  
-
Baseline disease burden will be the reference used to characterize 
radiographic objective tumor response. 
-
Baseline or nadir, whichever is smaller, is used to calculate PD.

Non-Index Lesions
-
All other lesions (or sites of disease) should be identified and recorded as 
non-index lesions during screening.  
-
Measurable lesions located in previously irradiated sites that have not since 
shown documented progression are non-index lesions.
-
Incidental new lesions will be recorded and tracked as non-index lesions.
-
Measurement of non-index lesions is not required, but absence or presence 
and qualitative changes (unequivocal response, stable, unequivocal 
progression) should be recorded throughout the study.
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Table 21.  Measurement Summary 
Imaging modality 
MRI  
Sequences for this protocol 
- 
Axial Pre Contrast (2D) T1 
- 
Axial T2/FLAIR 
- 
Axial T2 
- 
Axial Post Contrast (2D) T1 
- 
Axial DWI (at selected sites) 
- 
Sagittal Post Contrast (3D) T1 (at selected sites) 
Measurement technique 
Bidimensional; sum of products of perpendicular diameters 
Imaging intervals 
Screening, every 10-12 weeks, SFUP, LTFU 
Measurable lesions  
Contrast-enhancing lesions with ≥ 10mm longest diameter and 
≥ 10mm perpendicular diameter 
Measurable disease 
One to five index lesions 
Table 22.  Response Assessment 
All % changes are calculated as change from baseline burden, except PD which is 
baseline or nadir. 
Complete response (CR) 
• 
Disappearance of all enhancing disease  
• 
no new lesions  
• 
stable or improved T2/FLAIR 
• 
no more than physiological steroids 
• 
clinically stable or improved 
• 
Disappearance confirmed with follow-up scan after ≥ 4 weeks 
Partial response (PR) 
• 
≥ 50% decrease in the sum of perpendicular diameters of 
enhancing disease from baseline 
• 
stable or improved T2/FLAIR 
• 
stable or decreased steroid dose 
• 
clinically stable or improved 
• 
Decrease confirmed with follow-up scan after ≥ 4 weeks 
Stable disease (SD) 
• 
Changes do not qualify for CR, PR or PD  
• 
stable or improved T2/FLAIR 
• 
stable or decreased steroid dose 
• 
clinically stable or improved 
Progressive disease (PD) 
Any of the below 
• 
≥ 25% increase in the sum of perpendicular diameters of 
enhancing disease from the lesser of baseline or nadir 
• 
or substantially worsened T2/FLAIR  
• 
or unequivocal progression in new lesions 
• 
or substantial clinical decline  
• 
Increase confirmed with follow-up scan ≥ 4 weeks after initial 
observation.   
Reponses (CR and PR) are dated at time of confirmation scan. 
Progression (PD) is backdated to initial observation, if confirmed. 
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Patients with a neurological decline attributable to their underlying tumor requiring 
discontinuation of treatment without objective evidence of measurable radiographic 
disease progression at that time should be classifies as having “clinical deterioration.” 
Every effort should be made to document the radiographic progression even after 
discontinuation of treatment.
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Appendix E.  Grading and Management of Cytokine Release Syndrome (CRS)
CRS 
Grade
Description of Severitya
Minimum Expected 
Intervention
Instructions for 
Interruption of Dosing
1
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea,
fatigue, headache, 
myalgias, malaise
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 
earlier.
N/A
2
Symptoms require and 
respond to moderate 
intervention
Oxygen requirement
< 40%, OR
Hypotension responsive to 
fluids or low dose of one
vasopressor, OR
Grade 2 organ toxicity
or grade 3 transaminitis 
per
CTCAE criteria
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.
For subjects with extensive
co-morbidities or poor 
performance status, 
manage per grade 3 CRS 
guidance below.
Immediately interrupt 
dosing until event resolves 
to CRS grade ≤ 1 but for 
no less than 72 hours.
Permanently discontinue
AMG 596 and AMG 404 if 
there is no improvement to 
CRS ≤grade 1 within 
7 days.
Footnotes defined on the next page of the table
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Appendix E. Grading and Management of Cytokine Release Syndrome (CRS)
(Continue)
CRS 
Grade
Description of Severitya
Minimum Expected 
Intervention
Instructions for 
Interruption of Dosing
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
Admit to intensive care 
unit for close clinical and 
vital sign monitoring per 
institutional guidelines.
Administer 
dexamethasone (or 
equivalent) IV at a dose 
maximum of 3 doses of 
8 mg (24 mg/day).  The 
dose should then be 
reduced step-wise.
Investigators may also 
consider use of 
Tocilizumab as an 
additional therapy in this 
setting at a dose of 
4-8 mg/kg as a single 
dose.
Immediately interrupt 
dosing until event resolves
to CRS grade ≤ 1 but for 
no less than 72 hours.
Permanently discontinue
AMG 596 if there is no 
improvement to CRS 
≤grade 2 within 5 days or 
CRS ≤ grade 1 within 
7 days.
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 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, Tocilizumab 
can be considered 
administered at a dose of 
4-8 mg/kg as a single dose 
and may be repeated once 
within 24 to 48 hours 
based on clinical 
assessment.
Immediately stop the 
infusion and permanently 
discontinue
AMG 596 and AMG 404
therapy.
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
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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.
Reference: (Oken et al., 1982)
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Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Pneumonitis
Grade 2 (symptomatic, involves 
more than one lobe of the lung of 
25-50% of lung parenchyma, 
medical intervention indicated, 
limiting instrumental ADL)
Withhold
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d
prednisone (or equivalent) followed 
by taper. Consider additional 
immunosuppressive agent (eg, 
infliximab, mycophenolate, 
cyclophosphamide) if refractory to 
corticosteroids.
Monitor subjects for signs and 
symptoms of pneumonitis.  
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging. Add prophylactic 
antibiotics for opportunistic 
infections.
Grade 3 (severe symptoms, 
hospitalization required, involves 
all lung lobes or >50% of lung 
parenchyma, limiting self-care 
ADL, oxygen indicated)
Permanently 
discontinue
Grade 4 (life-threatening 
respiratory compromise, urgent 
intervention indicated [intubation])
Page 1 of 8
Footnotes defined on last page of this table
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 161 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Colitis/Diarrhea
Grade 2 (increase of 4-6 stools 
per day over baseline; moderate 
increase in ostomy output 
compared with baseline)
Withhold
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider infliximab if 
symptoms refractory to 
corticosteroids within 2-3 days.
Monitor subjects for signs and 
symptoms of enterocolitis (eg, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(eg, peritoneal signs and ileus). 
For subjects with grade ≥2 
diarrhea suspecting colitis, 
consider GI consultation and 
endoscopy to rule out colitis.
Grade 3 (increase of 7 or more 
stools per day over baseline, 
incontinence; hospitalization 
indicated, severe increase in 
ostomy output compared with 
baseline, limiting self-care ADL)
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated)
Permanently 
discontinue
Page 2 of 8
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Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 162 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Hepatitis
Grade 2 (asymptomatic, AST or 
ALT > 3.0 to ≤5 x ULN and/or
total bilirubin > 1.5 to ≤ 3 x ULN 
[for patients with values < ULN at 
baseline])
Withhold
Administer corticosteroids at an 
initial dose of 0.5 to 1 mg/kg/d 
prednisone (or equivalent) followed 
by taper.
Monitor with liver function tests 
more frequently until returned to 
baseline or stable.
Grade 3 (symptomatic liver 
dysfunction, fibrosis by biopsy, 
compensated cirrhosis, 
reactivation of chronic hepatitis 
[AST or ALT 5-20 x ULN and/or
total bilirubin 3-10 x ULN])
Permanently 
discontinue
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider mycophenolate 
mofetil if refractory to corticosteroids 
or no improvement after 3 days.
Grade 4 (decompensated liver 
function eg, ascites, 
coagulopathy, encephalopathy, 
coma [AST or ALT > 20 x ULN 
and/or total bilirubin > 10 x ULN])
Administer corticosteroids at an 
initial dose of 2 mg/kg/d prednisone 
(or equivalent) followed by taper.
Consider mycophenolate mofetil if 
refractory to corticosteroids or no 
improvement after 3 days.
Page 3 of 8
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Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 163 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Hypophysitis
Grade 3 or 4 (severe symptoms, 
medically significant or 
life-threatening consequences, 
unable to perform ADL)
Withhold
Administer corticosteroids at an 
initial dose of 1 mg/kg/d prednisone 
(or equivalent) followed by taper. In 
addition, initiate hormonal 
replacement therapy as clinically 
indicated.
Monitor for signs and symptoms 
of hypophysitis. Consider 
endocrine consultation.
Adrenal 
Insufficiency
Grade 3 or 4 (severe symptoms, 
medically significant or 
life-threatening consequences, 
unable to perform ADL)
Withhold
Initiate IV stress-dose 
corticosteroids on presentation 
(hydrocortisone 100 mg or 
dexamethasone 4 mg [if the
diagnosis is not clear and ACTH 
stimulation testing will be needed]). 
Taper stress-dose corticosteroids 
down to maintenance doses 
(prednisone 5 to 10 mg daily) over 
1-2 weeks after discharge. 
Monitor for signs and symptoms 
of adrenal insufficiency.
Consider endocrine consultation.
Hypothyroidism 
Grade 3 or 4 (severe symptoms, 
medically significant or 
life-threatening consequences, 
unable to perform ADL)
Withhold
Initiate thyroid hormone 
supplementation.
Monitor subjects for signs and 
symptoms of hypothyroidism. 
Consider endocrine consultation.
Hyperthyroidism
Grade 3 or 4 (severe symptoms, 
medically significant or 
life-threatening consequences, 
unable to perform ADL)
Withhold
Initiate β-Blocker (eg, atenolol, 
propranolol) for symptomatic relief. 
For severe symptoms or concern for 
thyroid storm, initiate prednisone 
1-2 mg/kg/d (or equivalent) tapered 
over 1-2 weeks. Consider use of 
SSKI or thionamide (methimazole or 
PTU).
Monitor subjects for signs and 
symptoms of hyperthyroidism. 
Consider endocrine consultation.
Page 4 of 8
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Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 164 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Diabetes Mellitus
Grade 3 hyperglycemia (> 250 to 
500 mg/dL [> 13.9 to 
27.8 mmol/L])
Withhold
Initiate insulin therapy.
Monitor subjects for 
hyperglycemia or other signs and 
symptoms of diabetes. Consider 
endocrine consultation.
Grade 4 hyperglycemia 
(> 500 mg/dL [> 27.8 mmol/L])
Nephritis and 
Renal 
Dysfunction
Grade 2 (serum creatinine >1.5 -
3.0 x baseline; >1.5 - 3.0 x ULN)
Withhold
Administer corticosteroids at an 
initial dose of 0.5 to 1 mg/kg/d 
prednisone (or equivalent) followed 
by taper. If worsening or no 
improvement occurs, increase dose 
of corticosteroids to 1 to 2 mg/kg/d 
prednisone (or equivalent).
Monitor changes in renal 
function. Evaluate for other 
causes of renal dysfunction (eg,
recent IV contrast, medications, 
fluid status, etc)
Grade 3 (serum creatinine >3.0 x 
baseline; >3.0 - 6.0 x ULN)
Permanently 
discontinue
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper.
Grade 4 (serum creatinine > 6 x 
ULN; dialysis indicated)
Page 5 of 8
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Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 165 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Skin
Grade 3 rash or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN)
Withhold
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Treat with topical 
emollients, oral antihistamines, and 
high-potency topical corticosteroids 
as indicated.
Monitor subjects for suspected 
severe skin reactions and 
exclude other causes (eg,
infection, an effect of another 
drug, a skin condition linked to 
another systemic disease, etc). 
For signs or symptoms of SJS or 
TEN, withhold study drug and 
refer the patient for specialized 
care for assessment and 
treatment.
Grade 4 rash or confirmed SJS
or TEN
Permanently 
discontinue
Encephalitis
Grade 2 (moderate symptoms, 
some interference with ADL)
Withhold
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider empirical antiviral 
(IV acyclovir) and antibacterial 
therapy until CSF results obtained 
and negative for aseptic meningitis.
Monitor subjects for neurologic 
symptoms and exclude other 
etiologies (eg, infectious). 
Evaluation of patients with 
neurologic symptoms may 
include, but not be limited to, 
consultation with a neurologist, 
brain MRI, and lumbar puncture.
Grade 3 or 4 (severe symptoms, 
limiting self-care and aids 
warranted)
Permanently 
discontinue
Page 6 of 8
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Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132  
Date:  29 July 2019 
Page 166 of 169 
CONFIDENTIAL 
 
 
Appendix G.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
4.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Myocarditis 
Grade 1 (abnormal cardiac 
biomarker testing, including 
abnormal ECG)  
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. 
Monitor patients with 
cardiovascular symptoms. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Grade 2 (abnormal screening 
tests with mild symptoms) 
Grade 3 (moderately abnormal 
testing or symptoms with mild 
activity) 
Permanently 
discontinue 
Grade 4 (moderate to severe 
decompensation, IV medication 
or intervention required, 
life-threatening conditions) 
All Other 
Immune-Related 
Adverse 
Reactions 
Grade 3 adverse reaction 
involving a major organ 
Withhold 
Based on type and severity of 
adverse reaction, administer 
corticosteroids. Refer to ASCO 
Clinical Practice Guidelines for 
additional recommendations. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Life-threatening or Grade 4 
adverse reaction involving a 
major organ 
Permanently 
discontinue 
Page 7 of 8 
Footnotes defined on last page of this table 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132 
Date:  29 July 2019
Page 167 of 169
CONFIDENTIAL
Appendix G. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404*
Immune-Related
Adverse 
Reactions
Severity (CTCAE Grade Version 
4.0 or Specific Conditions)
AMG 404 Dose 
Modification
Management with Corticosteroids 
and/or Other Therapies
Monitor & Follow-up
Recurrent or 
Persistent 
Immune-Related
Adverse 
Reactions
Recurrence of same Grade 3 or 
Grade 4 adverse reaction
Permanently 
discontinue
Based on type and severity of 
adverse reaction, administer 
corticosteroids. Additional 
immunosuppressive treatment may 
be required.
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes.
Requirement for ≥10 mg/day 
prednisone (or equivalent) for 
more than 12 weeks
Persistent grade 2 or 3 adverse 
reactions lasting 12 weeks or 
longer after last dose (ie, does 
not resolve to grade 0 or 1 within 
12 weeks)
General considerations: 

Corticosteroid taper should be initiated upon improvement of signs/symptoms and/or laboratory values to Grade 1 or less. Continue 
corticosteroid taper over the course of at least 4 to 6 weeks. 

If AMG 404 has been withheld, treatment with AMG 404 may be resumed after adverse event (or associated signs/symptoms/laboratory 
parameters) has been reduced to Grade 1 or less and corticosteroid has been tapered to prednisone < 10 mg (or equivalent). 

For severe and life-threatening immune-related adverse reactions, IV corticosteroids should be initiated first followed by oral corticosteroids. 
Other immunosuppressive treatment should be initiated if the event cannot be controlled by corticosteroids. 
Page 8 of 8
* Recommendations adapted from the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines for the Management of Immune-Related Adverse 
Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (JCO 2018)
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132  
Date:  29 July 2019 
Page 168 of 169 
CONFIDENTIAL 
 
 
Appendix H.  Management of Infusion Related Reactions With AMG 404 
Severity (CTCAE 
Grade Version 4.0) 
AMG 404 Dose 
Modification 
Management 
Premedication at 
Subsequent 
Dosing 
Grade 1 (mild transient 
reaction; infusion 
interruption not 
indicated; intervention 
not indicated) 
Interrupt or 
slow the rate of 
the infusion. 
• Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
• Treat per institutional 
guidelines. 
None 
Grade 2 (therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDS,  
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours) 
Interrupt or 
slow the rate of 
the infusion.  
For subjects 
who develop 
grade 2 
infusion-related 
reaction despite 
adequate 
premedication, 
permanently 
discontinue 
AMG 404. 
• Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
• Treat per institutional 
guidelines. Additional 
appropriate medical 
therapy may include but 
is not limited to 
IV fluids, 
antihistamines, 
NSAIDs, 
acetaminophen, and 
narcotics. 
Subject may be 
premedicated 
1.5 hours  
(± 30 minutes) prior 
to infusion of  
AMG 404 with:  
• Diphenhydramine 
50 mg orally (or 
equivalent dose of 
antihistamine). 
• Acetaminophen 
500-1000 mg 
orally (or 
equivalent dose of 
antipyretic). 
Grade 3 (prolonged [eg, 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion]; recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae) 
 
OR 
 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
study drug. 
• Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
• Hospitalization may be 
indicated. 
• Treat per institutional 
guidelines. Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, 
narcotics, oxygen, 
vasopressors, 
corticosteroids, and 
epinephrine. In cases of 
anaphylaxis, 
epinephrine should be 
used immediately. 
No subsequent 
dosing 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132  
Date:  29 July 2019 
Page 169 of 169 
CONFIDENTIAL 
 
 
Appendix I.  Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting 
Disease-related Event Definition 
• 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease. See [Section 9.2.3.1.1.1 / Section 12.8] for 
the list of disease-related events.  All serious disease-related events will be recorded and 
reported to the sponsor or designee within 24 hours. 
• 
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 reported as 
an adverse event or serious adverse event. 
• 
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 reported 
as a disease-related event.    
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 1 of 86 
CONFIDENTIAL 
 
 
Amendment 5 
Protocol Title:  Phase 1
Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 596 as a Monotherapy and in 
Combination With AMG 404 in Subjects With Glioblastoma or Malignant Glioma 
Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) 
Amgen Protocol Number 20160132 
IND Number 134352 
EudraCT number 2017-001658-32 
 
Amendment Date: 
29 July 2019 
Rationale: 
The combination of AMG 596 with the checkpoint inhibitor AMG 404 is seen as a 
promising approach in the treatment of glioblastomas and can now be supported by 
preclinical data and available initial safety data for AMG 596 and for AMG 404. Also, a 
first objective response has been observed with AMG 596 monotherapy in a subject with 
recurrent glioblastoma and there is a high interest of study investigators to enroll 
subjects in the study. In order to extent the opportunity with the potential for an even 
more effective combination therapy we are amending the ongoing FIH study protocol.  
Protocol Amendment 5 includes adding combination therapy of AMG 596 and AMG 404, 
and also to start enrollment of Group 2 subjects (newly diagnosed glioblastoma) after 
observation of a first partial response in separate cohorts.   
Revisions to Protocol Amendment 5 include: 
• 
Adding combination therapy of AMG 596 and AMG 404 in protocol synopsis and 
main protocol text.  
• 
Add background information, mechanism of action of AMG 404, dosing rational 
and risk evaluation for AMG 596 in combination with AMG 404.  
• 
Add terminology of Arm 1 and Arm 2. Arm 1 refers to AMG 596 monotherapy. 
Arm 2 refers to AMG 596 and AMG 404 combination therapy.  
• 
Allow newly diagnosed glioblastoma to enroll at current highest safe dose from 
Group 1 subjects.  
• 
Update the treatment schema to reflect the addition of AMG 596 and AMG 404 
combination therapy in both recurrent glioblastoma (group 1) and in maintenance 
of newly diagnosed Glioblastoma after standard of care therapy.  
• 
Update sample size in both dose escalation phase and dose expansion phase in 
monotherapy and combination therapy in Group 1 and Group 2.  
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 2 of 86 
CONFIDENTIAL 
 
 
• 
Add appendix G for Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Reactions Associated with AMG 404* 
• 
Add appendix H for Management of infusion-related reactions with AMG 404 
• 
Update ECG triplicate collection upon AMG 404 infusion.  
• 
Update exclusion criteria to add AMG 404 exclusion criteria  
• 
Added language for prophylactic use of corticosteroid prior to C1D1 of treatment  
In addition, clarifications and corrections of inconsistencies, and administrative and 
typographical changes were made throughout the protocol. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 3 of 86 
CONFIDENTIAL 
 
 
Below are Description of changes:  
Section 
Amended text 
Global, Key 
Sponsor 
Contacts 
Replace 
 
Clinical Research Study Manager 
Phone
Email:
 
With 
, PhD  
Clinical Research Study Manager 
Phone: 
  
Email: 
 
Global 
The version is updated to Amendment 5 and the date is updated to 29 July 2019.  
Investigators 
agreement 
Replace: 
Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 in Subjects 
with Glioblastoma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) 
 
With 
Phase 1
Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 as 
Monotherapy and in Combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma Expressing 
Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) 
Investigators 
agreement 
Replace  
11 March 2019 
 
With 
29 July 2019 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 4 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P3, Protocol 
Synopsis, 
Primary 
Objective 
Replace 
Evaluate the safety and tolerability of AMG 596 administered by continuous intravenous (cIV) infusion in subjects 
with EGFRvIII-positive glioblastoma or malignant glioma in the recurrent setting (Group 1) and afterwards in the 
maintenance treatment phase of newly diagnosed glioblastoma (maintenance setting) (Group 2) 
 
With 
Evaluate the safety and tolerability of AMG 596 administered by continuous intravenous (cIV) infusion in 
monotherapy (Arm 1) and in combination with AMG 404 (anti-programmed cell death-1 (PD-1) antibody  
(Arm 2) in subjects with EGFRvIII-positive glioblastoma or malignant glioma in the recurrent setting (Group 1) and in 
the maintenance treatment phase of newly diagnosed glioblastoma (maintenance setting, Group 2).  
P3, Protocol 
Synopsis, 
Secondary 
Objective 
Replace 
Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by cIV infusion  
 
With 
Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by cIV infusion either in 
monotherapy or in combination with AMG 404 
P3, Protocol 
Synopsis, 
Secondary 
Objective 
Add 
Evaluate the pharmacokinetics (PK) of AMG 404 in serum when administered by short term infusion in 
combination with AMG 596 
P3, Protocol 
Synopsis, 
Secondary 
Objective 
Replace  
Evaluate the clinical benefit of AMG 596 as determined by objective response rate (ORR) per modified Response 
Assessment in Neuro-Oncology Criteria (RANO) in subjects with EGFRvIII-positive glioblastoma or malignant glioma 
in the recurrent and in the maintenance setting 
 
With 
Evaluate the clinical benefit of AMG 596 or AMG 596 in combination with AMG 404 as determined by objective 
response rate (ORR) per modified Response Assessment in Neuro-Oncology Criteria (RANO) in subjects with 
EGFRvIII-positive glioblastoma or malignant glioma in the recurrent and in the maintenance setting 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 5 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P3, Protocol 
Synopsis, 
Secondary 
Objective 
Replace: 
Evaluate progression free survival (PFS) at 6 and 12 months after initiation of treatment 
 
With:  
Evaluate progression free survival (PFS) at 6 and 12 months after initiation of treatment for any Part, Arm and 
Group of the study 
P3, Protocol 
Synopsis, 
Exploratory 
Objective 
Replace 
Evaluate the pharmacokinetics (PK) of AMG 596 in cerebrospinal fluid (CSF) 
 
With 
Evaluate the pharmacokinetics (PK) of AMG 596 and AMG 404 in cerebrospinal fluid (CSF) 
P3, Protocol 
Synopsis, 
Exploratory 
Objective 
P3, Protocol 
Synopsis, 
Exploratory 
Objective 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 6 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P3, Protocol 
Synopsis, 
Hypotheses 
Replace 
AMG 596 is safe and well tolerated in at least one dose level when administered in subjects with EGFRvIII-positive 
glioblastoma, or malignant glioma in the recurrent (Group 1) and thereafter in the maintenance setting (Group 2) 
With 
AMG 596 monotherapy and in combination with AMG 404 are safe and well tolerated in at least one dose level 
when administered in subjects with EGFRvIII-positive glioblastoma, or malignant glioma in the recurrent (Group 1) 
and in the maintenance setting (Group 2) 
 
Replace 
AMG 596 can induce objective tumor shrinkage and/or overcome lack of response to SoC in subjects with  
EGFRvIII-positive glioblastoma or malignant glioma in either recurrent or in the maintenance setting at a tolerable 
dose 
With 
AMG 596 monotherapy and/or AMG 596 in combination with AMG 404 can induce objective tumor shrinkage 
and/or overcome lack of response to SoC in subjects with EGFRvIII-positive glioblastoma or malignant glioma in 
either recurrent or in the maintenance setting at a tolerable dose 
P4, Protocol 
Synopsis, 
Secondary 
Endpoint 
Add 
PK parameters of AMG 404 including, but not limited to, maximum observed serum concentration (Cmax), 
time to achieve Cmax (tmax), and AUC 
P4, Protocol 
Synopsis, 
Secondary 
Endpoint 
Add 
PK parameters for AMG 596 dosed in combination with AMG 404 including, but not limited to, average 
steady-state concentration (Css), area under the concentration-time curve (AUC), clearance, volume of 
distribution and half-life (t1/2) for serum AMG 596  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 7 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P4, Protocol 
Synopsis, 
Secondary 
Endpoint 
Replace 
Objective response (OR) as per modified RANO, time to response, response duration and time to progression (TTP); 
progression free survival (PFS) at 6 and 12 months after treatment initiation  
 
With 
Objective response (OR) as per modified RANO, time to response, response duration and time to progression (TTP); 
progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 monotherapy or 
AMG 596 in combination with AMG 404 
P4, Protocol 
Synopsis, 
Exploratory 
Endpoints 
P4, Protocol 
Synopsis, 
Exploratory 
Endpoints 
P4, Protocol 
Synopsis, 
Study Design 
Replace 
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive 
glioblastoma or malignant glioma. The study consists of 2 parts, dose escalation (Part 1) and dose expansion 
(Part 2).  This study will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and 
maintenance treatment after SoC in newly diagnosed disease (Group 2).  
 
With 
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive 
glioblastoma or malignant glioma exploring AMG 596 monotherapy (Arm 1) and in combination with AMG 404 
(Arm 2). Both Arm 1 and Arm 2 consist of 2 parts, dose escalation (Part 1) and dose expansion (Part 2).  Both 
Arm 1 and Arm 2 will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and 
maintenance treatment after SoC in newly diagnosed disease (Group 2).  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 8 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P4, Protocol 
Synopsis, 
Study Design 
Replace 
The purpose of dose escalation is to make a preliminary estimate of the Recommended Phase 2 Dose (RP2D)/ 
Maximum Tolerated Dose (MTD) of AMG 596. 
 
With 
Part 1, Dose Escalation:  The purpose of dose escalation is to make a preliminary estimate of the Recommended 
Phase 2 Dose (RP2D)/ Maximum Tolerated Dose (MTD) of AMG 596 monotherapy and in combination with 
AMG 404.   
P4, Protocol 
Synopsis, 
Study Design 
Replace 
Treatment is divided into 2 periods: (1) DLT period 1 for 
 of AMG 596 infusion and (2) DLT period 2 for 
 of infusion. 
With 
Treatment is divided into 2 periods: (1) DLT period 1 for 
 of AMG 596 infusion and (2) DLT period 2 for 
 of infusion (applies for both Arms). 
P4, Protocol 
Synopsis, 
Study Design 
Add 
resulting in the utilization of 
P4, Protocol 
Synopsis, 
Study Design 
Replace 
Further pre-specified nominal doses for use in the dose escalation are 
, 
 µg/day.   
With 
Further pre-specified nominal AMG 596 doses for potential use in any dose escalation Arms are 
 
µg/day.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 9 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P4, Protocol 
Synopsis, 
Study Design, 
(beginning of 
page 4)  
Replace 
The preliminary estimate of the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent disease 
(Group 1) and subsequently in subjects with maintenance treatment after SoC in newly diagnosed disease 
(Group 2). In the multiple subject cohorts a safety observation window of at least 72 hours must apply between start 
of subjects 1, 2 and 3 of each dose escalation cohort. Intra-subject dose escalation will be allowed to higher dose 
levels in subsequent treatment cycles once a higher dose has been deemed safe by the DLRT. Subjects who do not 
proceed to a higher dose may continue at the original dose.  
With  
The preliminary estimate of the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent disease 
(Group 1) and separately in subjects with maintenance treatment after SoC in newly diagnosed disease (Group 2) 
and separately for AMG 596 monotherapy and in combination with AMG 404.  
If the same AMG 596 doses are to be explored in monotherapy and in combination, the monotherapy cohort 
must be completed before enrollment in the combination cohort. In the multiple subject cohorts, a safety 
observation window of at least 72 hours must apply between start of subjects 1, 2 and 3 of each dose escalation 
cohort. Intra-subject dose escalation will be allowed to higher AMG 596 dose levels in subsequent treatment cycles 
once a higher dose has been deemed safe by the DLRT. Subjects who do not proceed to a higher dose may 
continue at the original dose. 
P4, Protocol 
Synopsis, 
Study Design 
Delete 
Dose Escalation in Group 1 will proceed using 2 phases 
P5, Protocol 
Synopsis, 
Group 1, 
Recurrent 
Disease, 
Replace 
Dose Escalation phase 1in single subject cohorts 
With 
Dose Escalation in single subject cohorts 
P5, Protocol 
Synopsis, 
Group 1, 
Recurrent 
Disease,  
Add 
Combination of AMG 596 and AMG 404: The starting dose of AMG 596 is 
 ug/day administered in 
 
 cycles and the defined AMG 404 dose is 
 mg every 4 weeks.  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 10 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P5, Protocol 
Synopsis, 
Group 1, 
Recurrent 
Disease 
Delete 
The DLT period is 28 days; DLT period 1 is from 
 of AMG 596 infusion, and DLT period 2 is from 
 
 of infusion (including cycle 2). 
P5, Protocol 
Synopsis, 
Group 1, 
Recurrent 
Disease 
Replace 
The cohort size will be increased to N=2-4 subjects (ie, Start of Dose Escalation Phase 2, multiple subject cohorts) 
after observation of  
 
With 
The cohort size will be increased to N=2-4 subjects (ie, Start of multiple subject cohorts) after observation of  
P5, Protocol 
Synopsis, 
Dose 
Escalation 
phase 2 
Replace 
Dose Escalation Phase 2, multiple subject cohorts 
 
With 
Dose Escalation in multiple subject cohorts 
P5, Protocol 
Synopsis, 
Dose 
Escalation 
phase 2 
Replace 
All subjects receive 
 treatment break until treatment discontinuation criteria apply.  
 
With 
All subjects receive AMG 596 in 
 infusion cycles until treatment discontinuation criteria apply 
P5, Protocol 
Synopsis, 
Dose 
Escalation in 
multiple subject 
cohorts 
Delete 
In the first cycle, DLT period 1 is from 
 of AMG 596 infusion and DLT period 2 is from 
 
infusion.  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 11 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P5 Protocol 
Synopsis, 
Group 1, 
Recurrent 
Disease  
Replace 
The maximum total sample size of N=30 DLT evaluable subjects (including single subject cohorts) is reached 
 
With 
The maximum total sample size of N=45 DLT evaluable subjects (including single subject cohorts) is reached for 
AMG 596 monotherapy and N=30 DLT evaluable subjects for AMG 596 in combination with AMG 404 
P6, Protocol 
Synopsis, 
Group 2, 
Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Replace 
A first cohort will start after RP2D/MTD has been established in Group 1 subjects with recurrent EGFRvIII-positive 
glioblastoma or malignant glioma.  The starting dose in Group 2 will be decided by the DLRT and will be the MTD of 
Group 1, or will be no higher than a 2-fold increase of the Group 1 RP2D if no MTD was reached and no DLT was 
observed at the highest dose administered in Group 1 dose escalation.   
 
With 
A first cohort will start after observation of a first objective anti-tumor response in Group 1 subjects with 
recurrent EGFRvIII-positive glioblastoma or malignant glioma. The starting dose of AMG 596 monotherapy in 
Group 2 will be decided by DLRT and will be the highest dose deemed safe of Group 1.  
P6, Protocol 
Synopsis, 
Group 2,  
Replace 
The BLRM will be used to guide dose level selection.  The cohort size will be N=4-6 subjects.  
  
With 
The BLRM will be used to guide dose level selection. The cohort size will be N=2-4 subjects. 
P6, Protocol 
Synopsis, 
Group 2,  
Replace 
The maximum sample size of N=12 DLT evaluable subjects is reached 
 
With 
The maximum sample size of N=15 DLT evaluable subjects is reached for AMG 596 monotherapy or N=20 DLT 
evaluable subjects for the AMG 596 in combination with AMG 404. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 12 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P6, Protocol 
Synopsis, 
Sample Size 
Replace 
It is anticipated that around 82 subjects will be enrolled in the study.  Up to 30 DLT-evaluable subjects will be 
enrolled in dose escalation in Group 1 (recurrent disease) and up to 12 subjects in dose escalation Group 2 
(maintenance setting).  Up to 40 subjects will be enrolled in the dose expansion cohorts (15 subjects in Group 1 and 
up to 25 subjects in Group 2) at 9 or more sites across US, Australia and Europe. 
 
With 
It is anticipated that around 190 subjects will be enrolled in the study, up to 100 subjects will be enrolled to Arm 1 
and up to 90 subjects will be enrolled to Arm 2. Enrollment for Arm 1 and Arm 2 will occur at 12 or more 
sites across US, Australia and Europe.  
P6, Protocol 
Synopsis, 
Sample Size 
Add 
For Group 1 (recurrent disease), the following are the planned sample sizes. 
• 
In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up to 30 
DLT-evaluable subjects to combination Arm 2  
• 
In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and up to 15 subjects to 
combination Arm 2. 
For Group 2 (maintenance setting), the following are the planned sample sizes. 
• 
In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up to 20 
DLT-evaluable subjects to combination Arm 2  
• 
In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and up to 25 subjects to 
combination Arm 2 
P6, Protocol 
Synopsis, 
Sample Size 
Replace  
The sample size for Group 1 dose expansion is based on practical considerations.   
 
With 
For both Arm 1 and Arm 2, the sample size for Group 1 dose expansion is based on practical considerations.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 13 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P6, Protocol 
Synopsis, 
Sample Size 
Replace 
With 21 subjects treated at Group 1 RP2D/MTD (6 from dose escalation and 15 from dose expansion), 
 
With 
With 21 subjects treated at the respective Group 1 RP2D/MTD (6 from dose escalation and 15 from dose 
expansion), 
P6, Protocol 
Synopsis, 
Sample Size 
Replace 
The sample size for Group 2 dose expansion is based on a Bayesian predictive probability design 
 
With 
For both Arm 1 and Arm 2, the sample size for Group 2 dose expansion is based on a Bayesian predictive 
probability design 
P7, Protocol 
Synopsis, 
Investigational 
Product (IP) 
Add 
AMG 404 
P7 Protocol 
Synopsis 
Investigational 
Product 
Add 
AMG 404 is supplied in a 3 mL Type 1 glass tubing vial containing 1 mL deliverable 
volume of 70 mg/mL. The drug product is formulated with 10 mM acetate (sodium 
counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2 and will be prepared for IV 
administration by dilution. 
P7, Protocol 
Synopsis 
Investigational 
Product 
Delete 
Dose escalation Phase 1 only 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 14 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P7, Protocol 
Synopsis 
Investigational 
Product 
Add 
AMG 404 will be delivered using infusion pumps approved for use by the appropriate regulatory authority for 
the country in which the subject is undergoing treatment. AMG 404 solution for infusion will be prepared in 
bags for IV infusion and delivered through infusion lines.  The drug will be administered as an IV infusion at 
a constant flow rate over 30 minutes every 
. 
P7, Protocol 
Synopsis 
Investigational 
Product 
Replace 
All subjects will be hospitalized for the first 
 of infusion and for at least 24 hours following completion of the 
infusion in cycle 1, and for 72 hours after a dose step in cycle 1, and at least for the first 72 hours of infusion in any 
subsequent cycle and after a dose step in any subsequent cycle. Hospitalization may be shortened to 48 hours from 
the 6th cycle onwards at the discretion of the investigator 
 
With 
All subjects will be hospitalized for the following periods:  
Cycle 1:  
• 
For the first 
 of AMG 596 monotherapy (Arm 1)  
• 
For the first
 of AMG 596 in combination with AMG 404 (Arm 2), hence AMG 404 will be 
administered on 
 
• 
For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 and Arm 2  
• 
For additional 72 hours after AMG 596 step dose if necessary  
Cycle 2 and all subsequent cycles:  
• 
For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2 
• 
For additional 72 hours after AMG 596 step dose if necessary.  
Hospitalization may be shortened to 48 hours from the 6th cycle onwards at the discretion of the 
investigator.  
AMG 404 can be administered in an outpatient setting starting from cycle 1 
 onwards. Subjects should 
be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each AMG 404 
infusion from cycle 1 
 onwards. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 15 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P8, Protocol 
Synopsis 
Procedure 
Add 
or the combination of AMG 596 and AMG 404 
P8, Protocol 
Synopsis 
Procedure 
Replace 
managing physician 
 
With 
Investigator 
P8, Protocol 
Synopsis 
Procedure 
Replace 
including serum pregnancy test, if applicable, coagulation, hematology, chemistry, urinalysis, hepatitis serology, 
human immunodeficiency virus (HIV) test, 
 
 
With 
including serum pregnancy test, if applicable, coagulation, hematology, chemistry, urinalysis, hepatitis serology, 
human immunodeficiency virus (HIV) test, 
 
P8, Protocol 
Synopsis 
Statistical 
considerations 
Replace 
In dose escalation, the DLRT will review the safety data after each cohort and make a decision on the next dose 
level to be explored for the estimate of RP2D/MTD based on a BLRM design.  In dose expansion for Group 2, futility 
will be assessed initially for N=10 and continuously afterwards using a Bayesian predictive probability design.   
 
With 
For both Arm 1 and Arm 2, in dose escalation, the DLRT will review the safety data after each cohort and make a 
decision on the next dose level to be explored for the estimate of RP2D/MTD based on a BLRM design.  For both 
Arm 1 and Arm 2, in dose expansion for Group 2, futility will be assessed initially for N=10 and continuously 
afterwards using a Bayesian predictive probability design.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 16 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P10.  
Protocol 
Synopsis, 
Figure one, 
study design 
and treatment 
schema 
Replace 
 
 
 
 
 
 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 17 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
 
With 
 
P13, 
Abbreviation 
Add 
mAb, Monoclonal antibody 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 18 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P22, 
Section 1.1  
Replace 
Evaluate the safety and tolerability of AMG 596 administered by continuous intravenous (cIV) infusion in subjects 
with EGFRvIII-positive glioblastoma or malignant glioma in the recurrent setting (Group 1) and in the maintenance 
treatment phase of newly diagnosed glioblastoma (maintenance setting) (Group 2) 
With 
Evaluate the safety and tolerability of AMG 596 administered by continuous intravenous (cIV) infusion in 
monotherapy (Arm 1) and in combination with AMG 404 (Arm 2) in subjects with EGFRvIII-positive glioblastoma 
or malignant glioma in the recurrent setting (Group 1) and in the maintenance treatment phase of newly diagnosed 
glioblastoma (maintenance setting, Group 2) 
P22, 
Section 1.2 
Secondary 
Objective 
Replace 
Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by cIV infusion 
With 
Evaluate the pharmacokinetics (PK) of AMG 596 in serum when administered by cIV infusion either in 
monotherapy or in combination with AMG 404 
P22, Section 
1.2 Secondary 
Objective 
Add 
Evaluate the pharmacokinetics (PK) of AMG 404 in serum when administered by short term infusion in 
combination with AMG 596 
P22, 
Section 1.2 
Secondary  
Replace 
Evaluate the clinical benefit of AMG 596 as determined by objective response rate (ORR) per modified Response 
Assessment in Neuro-Oncology Criteria (RANO) 
 
With 
Evaluate the clinical benefit of AMG 596 monotherapy or AMG 596 in combination with AMG 404 as determined 
by objective response rate (ORR) per modified Response Assessment in Neuro-Oncology Criteria (RANO) 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 19 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P22, 
Section 1.2 
Secondary  
Replace 
Evaluate progression free survival rate at 6 and 12 months after initiation of treatment 
 
With 
Evaluate progression free survival rate at 6 and 12 months after initiation of treatment for any Part, Arm and Group 
of the study 
P22, Section 
1.3 Exploratory  
Replace 
 
With 
P23, Epidermal 
Growth Factor 
Receptor 
Variant 
EGFRvIII 
Add 
Kischel et al., 2016 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 20 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P23, Epidermal 
Growth Factor 
Receptor 
Variant 
EGFRvIII 
Add 
and potent 
P23, Epidermal 
Growth Factor 
Receptor 
Variant 
EGFRvIII 
Add 
Cytotoxicity 
P24-26, 
Checkpoint 
inhibits for 
treatment of 
GBM 
Add 
Checkpoint inhibitors for treatment of Glioblastoma (GBM) 
Immunotherapies with checkpoint inhibitors have been explored in GBM with limited success (Omuro et al., 
2018) and response rates have been rarely above 10 percent (Wang et al., 2019). Reasons for failure are 
associated with (1) genetic patterns supporting immunosuppressive tumor microenvironment, eg PTEN 
mutations leading to cell clustering and lack to increase T cell infiltration, (2) evolutionary patterns 
promoting negative selection of immunogenic neoepitopes, and (3) greater increase in T cell diversity 
leading to failure of selective recruitment of lymphocytes to tumor (Zhao et al., 2019).   
Nivolumab, a fully human IgG4 subtype programmed death-1 (PD-1) immune checkpoint inhibitor was 
evaluated in a large randomized clinical trial (Reardon et al., 2017) in monotherapy or combination with 
ipilimumab and monotherapy was compared versus bevacizumab in 369 patients with first recurrence of 
GBM in the phase 3 part (NCT02017717). At baseline, most patients in the nivolumab (nivo, 83%) and 
bevacizumab (bev, 84%) arms had measurable disease, and 40% (nivo) and 43% (bev) of patients required 
corticosteroids, receiving up to ≥ 4 mg/day. The 12-month OS was 42% in both monotherapy arms and 
median OS for nivolumab was 9.8 months compared to 10 months for bevacizumab. ORRs were 8% (nivo) 
and 23% (bev); median duration of response was 11.1 months (nivo) and 5.3 months (bev). Most common 
treatment-related AEs (≥ 10% of patients in either arm; nivo vs bev) were fatigue (21% vs 14%) and 
hypertension (1% vs 22%). Serious AEs (all causalities) were reported in 46% (nivo) and 35% (bev) of 
patients. Seizure (8% vs 6%) and malignant neoplasm progression (11% vs 7%) were the only serious AEs 
reported in ≥ 5% of patients in either arm.  
Pembrolizumab, a humanized IgG4 anti PD-1 monoclonal antibody (mAb), was explored in GBM in a basket 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 21 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
trial (Keynote-028) with the GBM basket of patients with any recurrence including two-thirds being treated 
after their first recurrence (Reardon et al., 2016). One partial response (ORR 4%) was observed within 
25 patients and 12 patients (48%) presented with SD. Treatment-related AEs occurred in 19 (73.1%) patients, 
most commonly fatigue and rash (n=6 each, 23.1%). Four (15.4%) patients experienced grade  
3–4 treatment-related AEs (lymphopenia, type 2 diabetes mellitus, arthritis, and syncope). Pembrolizumab in 
combination with bevacizumab was compared with pembrolizumab in 80 patients with recurrent GBM for the 
primary endpoint of 6-month PFS per RANO (NCT02337491). At a median follow-up of 25 months the 
6-month PFS was 6.7% for pembrolizumab monotherapy and 25.3% for the combination (Reardon et al., 
2018). Most commonly observed treatment-related AEs were headache (30%) and fatigue (17%) for 
pembrolizumab monotherapy. 
Although PD-L1 expression has been reported in GBM specimen, the observed clinical results were 
discouraging (Berghoff et al., 2015). Emerging evidence of relevant immune cell activation through blockade 
of PD-1/PD-L1 axis comes from most recently published studies with neoadjuvant checkpoint blockade. 
Patients with recurrent GBM receiving neoadjuvant pembrolizumab prior to surgical debulking experienced 
significantly longer overall survival versus those receiving adjuvant, postsurgical pembrolizumab simply. In 
the neoadjuvant group, focal induction of PD-L1 in the tumor microenvironment and activation of tumor 
infiltrating lymphocytes, linked with upregulation of interferon gamma related genes suggesting relevant 
immune cell activation, were observed. Moreover, expanded T cell receptor clones correlating between 
tumor and blood with high overlap, and a decreasing monocytic population in the peripheral blood were 
associated with neoadjuvant pembrolizumab but not seen with adjuvant treatment only. Interestingly, 
dexamethasone was not found to impact upregulation of interferon gamma and T cell activation genes. 
Hence, only patients with baseline 4 mg/day or less dexamethasone was allowed to enroll. The authors 
concluded that an immune response leading to prolonged survival was induced by repeated PD-1 blockade 
whereby maintaining functionality of tumor-specific T cell clones, and by down-regulation of cell cycle 
related gene expression within tumor cells through T cell-mediated interferon gamma response (Cloughesy 
et al., 2019). A similar approach with neoadjuvant administration of nivolumab to patients undergoing 
surgery for GBM indicates the onset of antitumor-directed immune pharmacodynamic effects after treatment 
with neoadjuvant nivolumab (Schalper et al., 2019).  
Ultimately, to overcome hurdles for success of immunotherapies in GBM such as a limited number of 
infiltrated T cells and an upregulated immunosuppressive signature, the combination of checkpoint 
blockade with BiTE® treatment may be an alternative approach to achieve clinically meaningful tumor 
regression. The combination of checkpoint inhibitors with various BiTE® molecules in preclinical studies 
showed that cytotoxic potential, T cell activation and proliferation are strongly enhanced upon blockade of 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 22 of 86 
CONFIDENTIAL 
Section 
Amended text 
the PD-1/PD-L1 axis (Kufer et al., 2016, Osada et al., 2015). The addition of AMG 404, an anti-PD-1 mAb that is 
being developed by Amgen, to AMG 596 may support maintaining T cell activation by blocking PD-1 
upregulation on T cells and avoid T cell exhaustion facilitated by the immunosuppressive 
microenvironment. The current study with AMG 404 will enable a deeper understanding of synergistic 
efficacy, toxicity, and pharmacodynamic profiles of the combination of AMG 404 and AMG 596.  
P26, Section 
2.2 Amgen 
Investigational 
Product 
Background 
AMG 596 
Add 
AMG 596 
P26, Section 
2.2 Amgen 
Investigational 
Product 
Background 
AMG 596 
Replace 
 
With 
 
P28-29, 
Section 2.3 
Add 
2.3 
Amgen Investigational Product Background AMG 404 
2.3.1 
Nonclinical Pharmacology 
AMG 404 is an IgG1 antibody; however, the Fc region has been modified to eliminate undesired interactions 
with Fc gamma receptors. The ligand blocking activity of AMG 404 was evaluated in three different assays 
using three different readouts and both cell-expressed, as well as recombinant, soluble ligands.  In each 
assay, AMG 404 demonstrated the expected dose-dependent activity, indicating it is a potent inhibitor of 
human and cynomolgus monkey PD-1 binding.   
2.3.2 
Nonclinical Pharmacokinetics 
The toxicokinetics (TK) of AMG 404 were characterized in a Good Laboratory Practice (GLP) study after 
weekly IV administration of 
 mg/kg or SC administration of 
 mg/kg for four consecutive weeks.  
Following repeat dose administration, AMG 404 exposure increased approximately dose-proportionally from 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 23 of 86 
CONFIDENTIAL 
Section 
Amended text 
 mg/kg as measured by Cmax and AUC over 6 days.  AMG 404 exposures were similar between male 
and female animals.   
2.3.3 
Toxicology 
The potential for AMG 404 to cause acute release of cytokines from human peripheral blood leukocytes 
(PBL) in the presence of human endothelial cells (HUVECs) was evaluated in vitro.  Under the conditions 
tested, AMG 404 did not induce cytokine release above background levels. 
AMG 404 was evaluated in a 
 GLP toxicology study in cynomolgus monkeys.  Doses of 
 
 mg/kg were administered by slow IV bolus, and doses of 
 mg/kg were administered SC 
(3 animals/sex/group).  Animals were dosed once weekly (4 total doses).  There were no AMG 404-related 
clinical signs or effects on body weight, food consumption, respiratory rate, body temperature, organ 
weights, or urinalysis parameters and no AMG 404-related ocular, electrocardiographic, neurologic, or 
macroscopic findings.  AMG 404-related clinical pathology changes were limited to mild decreases in 
lymphocytes for females at all dose levels on Day 2 that were generally similar to control and/or baseline 
values on Day 9 and throughout the remainder of the study, and mildly increased C-reactive protein in some 
animals.  
In conclusion, administration of AMG 404 by once weekly IV bolus or SC injection was well tolerated in 
cynomolgus monkeys at levels of 
 mg/kg IV and 
 mg/KG IV and SC. 
Refer to AMG 404 Investigators Brochure for more information. 
P29, 
Section 2.4.1 
AMG 596 
Monotherapy 
Replace 
At this time, there is no clinical experience with AMG 596 in humans 
With 
At this time, there is limited clinical experience with AMG 596 in humans derived from first 15 subjects treated in 
this study and data are summarized in the AMG 596 Investigator’s Brochure.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 24 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P29, Section 
2.4.1 AMG 596 
Monotherapy 
Add 
AMG 596 
P28-31 
Section 2.4.1 
AMG 596 
Monotherapy 
Add 
 
 
 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 25 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 26 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P32, Section 
2.5 Rationale 
Add 
2.5.1 Rationale for AMG 596 Monotherapy 
P32, Section 
2.5 Rationale 
Replace  
After establishing the maximum tolerated dose (MTD) or recommended phase dose (RP2D) in the recurrent setting 
 
With 
After the observation of a first objective response (partial or complete) in the recurrent setting, 
P33-34, 
Section 2.5.2 
Rationale for 
the 
Combination of 
AMG 596 with 
AMG 404 
Add 
2.5.2 Rationale for the Combination of AMG 596 with AMG 404 
BiTE treatment helps T cells to infiltrate tumor and become activated independent of the 
immunosuppressive microenvironment. However, preclinical evaluations showed that BiTE induced T cell 
activation is associated with upregulation of PD-1 on T cells, a known immune-regulatory mechanism that 
may lead to diminished T cell cytolytic activity resulting in impaired ability of T cells to eradicate the tumor. 
Anti-PD-1 therapy is intended to reverse this T cell exhaustion. Indeed, in vitro combination of AMG 596 with 
AMG 404 demonstrated more cytotoxic activity than AMG 596 alone. 
We hypothesize that the addition of an anti-PD-1 antibody, such as AMG 404, may help maintain 
AMG 596-induced tumor cell killing by T cells resulting in improved antitumor activity in the clinical setting.  
Initial signs of clinically meaningful antitumor effect with AMG 596 monotherapy in subjects with recurrent 
glioblastoma have been observed. In addition, monotherapy administration of both novel products, AMG 596 
and AMG 404, has been well tolerated, to date. Moreover, tolerability of anti-PD-1 antibodies has been 
demonstrated in subjects with glioblastoma in various clinical trials (Reardon et al., 2017, Schalper et al., 
2019, Kufer et al., 2016, Osada et al., 2015). Considering the devastating nature of glioblastoma, the addition 
of AMG 404 to AMG 596, even in this early stage of the development of both investigational products, can be 
justified and can contribute to enrichment of treatment opportunities. 
P34, Section 
2.5.3 Dose 
Rationale  
Add 
2.5.3.1 AMG 596 Monotherapy 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 27 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Delete 
currently in development 
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Add 
Clinical PK data for AMG 596 can be found in the AMG 596 Investigator’s Brochure.   
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Replace 
The predicted human steady-state concentration of AMG 596 after a 
 µg/day IV infusion was also found to be 
20600-fold lower than the observed exposure in cynomolgus monkeys at the 6.6 mg/kg/day dose, accounting for a  
7-fold difference in potency between human and monkey effector cells.   
 
With 
At the starting dose of 
 µg/day, the safety margins based on the observed Css were 13 400-fold before 
potency adjustment and 1910-fold after correction for a 7-fold difference in AMG 596 potency between 
human and cynomolgus monkey effector cells. 
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Delete 
The predicted human steady-state concentration of AMG 596 after a 
 µg/day IV infusion was also found to be 
20600-fold lower than the observed exposure in cynomolgus monkeys at the 6.6 mg/kg/day dose, accounting for a 7-
fold difference in potency between human and monkey effector cells.   
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Add 
A pharmacodynamic drug interaction study showed that AMG 596-induced cytokine release could be 
reduced by dexamethasone, but dexamethasone might result in a reduced cytotoxic potency of AMG 596 
when co-administered to patients. 
P34, Section 
2.5.3.1 
AMG 596 
Monotherapy 
Add 
Dose escalation in Group 2 subjects can start at the highest AMG 596 monotherapy dose deemed to be 
tolerated by DLRT for Group 1 subjects.  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 28 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P36-37, 
Section 2.5.3.2 
AMG 596 in 
Combination 
with AMG 404 
Add 
2.5.3.2 AMG 596 in Combination with AMG 404 
No clinical safety information is available for the combination of AMG 596 with AMG 404.  Based on biological 
mechanism of action and initial clinical safety information for monotherapies with AMG 596 and AMG 404, adverse 
events caused by synergistic activation of T cells are expected.  
The first-in-human dose exploration and expansion study evaluating AMG 404 in subjects with advanced solid tumors 
is currently ongoing. Preliminary PK results of AMG 404 in 11 subjects with advanced solid tumors after AMG 404 
administration as short-term IV infusions (approximately 0.5 hours) 
 were available for dose levels of 
 mg 
(3 subjects, first and second dosing intervals) and 
 mg (8 subjects, first dosing interval).  The nonclinical 
pharmacology findings and preliminary human PK results from the FIH study provide increased confidence towards 
achieving an efficacious dose with doses planned in the study and results were consistent with those for other 
therapeutic anti-PD-1 mAbs. Moreover, no dose-limiting toxicities (DLTs) were observed in any of the 12 subjects who 
have received AMG 404 doses up to 
 mg 
 Treatment-emergent adverse events were reported in 9 subjects 
(75.0%); the most frequently reported adverse events (≥ 3 subjects) were fatigue (4 subjects, 33.3%) and nausea 
(3 subjects, 25.0%). Three subjects (25.0%) had 5 adverse events that were grade 3 in severity (dehydration, edema, 
fatigue, urinary tract infection, and vomiting); no grade 3 adverse event preferred term was reported in > 1 subject. 
Since AMG 404 doses up to 
 mg administered every 4 weeks have been shown to be tolerable, with the only 
treatment-related adverse event occurring in > 1 subject of nausea in 2 subjects (16.7%), the highest dose explored 
(
 mg) will be used for combination therapy with AMG 596. If a higher AMG 404 dose will be declared as 
recommended phase 2 dose in the ongoing Phase 1 study (Study 20180143), such a dose can be explored in additional 
cohort(s) in combination with AMG 596 whereby using the highest AMG 596 dose shown to be tolerated in the 
combination cohorts with AMG 404.  
For AMG 596, the start dose in combination with AMG 404 treatment is based on the observation of pharmacodynamic 
effects observed at 
 µg/day in Group 1 subjects with recurrent malignant glioma. For Group 1 subjects, a dose of 
 µg/day administered in 
 infusion cycles will therefore be selected as first dose. The next AMG 596 pre-defined 
doses will be used for further dose escalation. 
For Group 2 subjects, the starting dose of AMG 596 in combination with AMG 404 will be one dose level below the 
selected start dose for AMG 596 monotherapy (eg a start dose of 
 µg/day for AMG 596 monotherapy in Group 2 
subjects leads to the selection of 
 µg/day as start dose for AMG 596 in combination with AMG 404 in Group 2 
subjects). The next AMG 596 pre-defined doses will be used for further dose escalation. 
To avoid cumulative toxicity associated with initial T cell activation after treatment start, a first dose of AMG 404 will 
not be given until 
 after start of the AMG 596 infusion. Prophylactic dexamethasone treatment as described in 
Section 6.5, should be given before starting any AMG 596 infusion. Dose escalation will start with single subject 
cohorts as a pharmacodynamic effect is expected resulting in a reduced cytotoxic potency of AMG 596 when 
co-administered with dexamethasone. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 29 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P37, 
Section 2.6 
Hypotheses 
Add 
monotherapy and in combination with AMG 404  
P37, 
Section 2.6 
Hypotheses 
Add 
monotherapy and/or in combination with AMG 404 
P37, 
Section 3.1 
Study Design 
Replace 
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive 
glioblastoma or malignant glioma. The study consists of 2 parts, dose escalation (Part 1) and dose expansion 
(Part 2).   
With 
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive 
glioblastoma or malignant glioma exploring AMG 596 monotherapy (Arm 1) and combination of AMG 596 and 
AMG 404 (Arm 2).  Each arm of the study consists of 2 parts, dose escalation (Part 1) and dose expansion (Part 2). 
P38, 
Section 3.1 
Part 1: Dose 
Escalation 
Replace 
The purpose of dose escalation is to make a preliminary estimate of the RP2D /MTD of AMG 596. Treatment is 
divided into 2 periods: (1) DLT period 1 for 
 of AMG 596 infusion and (2) DLT period 2 for day
 
 of infusion.  
With 
The purpose of dose escalation is to make a preliminary estimate of the RP2D /MTD of AMG 596 monotherapy and 
in combination with AMG 404. Treatment is divided into 2 periods: (1) DLT period 1 for 
 of AMG 596 
infusion and (2) DLT period 2 for 
 of AMG 596 infusion (applies for both Arms). 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 30 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P38, 
Section 3.1 
Study Design, 
Part 1, Dose 
Escalation 
Replace 
The start dose based on preclinical evaluations for the estimation of the MABEL is 
 µg/day. Further pre-specified 
nominal doses for use in the dose escalation are 
 µg/day. 
With 
The AMG 596 start dose based on preclinical evaluations for the estimation of the MABEL is 
 µg/day. Further  
pre-specified nominal AMG 596 doses for potential use in any dose escalation Arms are 
 
 µg/day. 
P38, 
Section 3.1 
Study Design, 
Part 1, Dose 
Escalation 
Replace 
The preliminary estimate of the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent disease 
(Group 1) and in subjects with maintenance treatment after SoC in newly diagnosed disease (Group 2)  
With 
The preliminary estimate of the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent disease 
(Group 1) and separately in subjects with maintenance treatment after SoC in newly diagnosed disease (Group 2) 
and separately for AMG 596 monotherapy and in combination with AMG 404.  
P38, 
Section 3.1 
Study Design 
Part 1, Dose 
Escalation 
Add 
If same AMG 596 doses are to be explored in monotherapy and in combination, the monotherapy cohort 
must be completed before enrollment in the combination cohort. 
P38, 
Section 3.1 
Study Design 
Part 1, Dose 
Escalation 
Add 
AMG 596 
P39, 
Section 3.1 
Study Design, 
Group 1, 
Recurrent 
Disease 
Delete 
Dose Escalation in Group 1 will proceed using 2 phases 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 31 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Replace 
Dose Escalation Phase 1, single subject cohorts 
With 
Dose Escalation in single subject cohorts 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Add 
AMG 596 monotherapy 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Add 
Combination of AMG 596 with AMG 404: The starting dose of AMG 596 is 
 ug/day administered in 
 
 cycles and the defined AMG 404 dose is 
 mg every 4 weeks.  
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Delete 
The DLT period is 
; DLT period 1 is from 
 of AMG 596 infusion, and DLT period 2 is from 
 
 of infusion (including cycle 2). 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 32 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease  
Replace  
• 
The cohort size will be increased to N=2-4 subjects (= Start of Dose Escalation Phase 2, multiple subject 
cohorts) after observation of  
• 
Treatment-related adverse events of common terminology criteria for adverse events (CTCAE) grade 
2 or higher and/or 
• 
Quantifiable cytokine levels in blood or CSF above baseline 
With 
• 
The cohort size will be increased to N=2-4 subjects (= Start of multiple subject cohorts) after observation of  
• 
Treatment-related adverse events of common terminology criteria for adverse events (CTCAE 4.0) 
grade 2 or higher and/or 
• 
Quantifiable cytokine levels in blood or CSF above baseline 
P39, 
Section 3.1 
Study Design, 
Group 1, 
Recurrent 
Disease 
Replace 
Dose Escalation Phase 2, multiple subject cohorts:  
• 
Subjects in the first multiple subject cohort receive the same dose as the last single subject cohort. 
• 
All subjects receive 28-day infusion cycles with 14-day treatment break until treatment discontinuation criteria 
apply. 
With 
Dose Escalation in multiple subject cohorts:  
• 
Subjects in the first multiple subject cohort receive the same dose as the last single subject cohort. 
• 
All subjects receive AMG 596 in 
 infusion cycles until treatment discontinuation 
criteria apply. 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Delete 
In the first cycle, DLT period 1 is from 
 of AMG 596 infusion and DLT period 2 is from 
 
of infusion. 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 33 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P39, Section 
3.1 Study 
Design, Group 
1, Recurrent 
Disease 
Replace 
The maximum total sample size of N=30 DLT evaluable subjects (including single subject cohorts) is reached. 
With 
The maximum total sample size of N=45 DLT evaluable subjects (including single subject cohorts) is reached for 
AMG 596 monotherapy or N=30 DLT evaluable subjects for AMG 596 in combination with AMG 404. 
P40, Section 
3.1, Study 
Design Group 
2, Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Replace 
A first cohort will start after RP2D/MTD has been established in Group 1 subjects with recurrent EGFRvIII-positive 
glioblastomas or malignant glioma.  The starting dose in Group 2 will be decided by DLRT and will be the MTD of 
Group 1, 
 
With 
A first cohort will start after observation of a first objective antitumor response in Group 1 subjects with recurrent 
EGFRvIII-positive glioblastomas or malignant glioma.  The starting dose of AMG 596 monotherapy in Group 2 will 
be decided by DLRT and will be the current highest dose deemed safe of Group 1, 
P40, Section 
3.1, Study 
Design Group 
2, Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Delete 
or will be no higher than a 2-fold increase of the Group 1 RP2D if no MTD was reached and no DLT was observed at 
the highest dose administered in Group 1 dose escalation.   
P40, Section 
3.1, Study 
Design Group 
2, Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Add 
The starting dose of AMG 596 in combination with AMG 404 for Group 2 will be one dose level below the 
selected start dose for AMG 596 monotherapy and an AMG 404 dose of 
 mg.  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 34 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P40, Section 
3.1, Study 
Design Group 
2, Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Replace 
The cohort size will be N=4-6 subjects 
 
With 
The cohort size will be N=2-4 subjects 
P40, Section 
3.1, Study 
Design Group 
2, Maintenance 
Treatment after 
SoC in Newly 
Diagnosed 
Disease 
Replace 
The maximum sample size of N=12 DLT evaluable subjects is reached 
 
With 
The maximum sample size of N=15 DLT evaluable subjects is reached for AMG 596 monotherapy or N=20 DLT 
evaluable subjects for the AMG 596 in combination with AMG 404. 
P40, 
Section 3.1, 
Study Design, 
Dose 
Expansion 
Replace 
It is anticipated that 15 subjects will be enrolled to Group 1 and up to 25 subjects will be enrolled to Group 2. 
 
With 
It is anticipated that 15 subjects will be enrolled to Group 1 in Arm1 and Arm 2, respectively. Up to 25 subjects will 
be enrolled to Group 2 in Arm 1 and Arm 2, respectively.  
P41, 
Section 3.1, 
Study Design 
Dose 
Expansion 
Replace 
In Group 2, the objective response rate (ORR) of interest is 20% or higher while an ORR of 5% or less is considered 
insufficient antitumor-activity.   
 
With 
In Group 2 both for Arm 1 and Arm 2, the objective response rate (ORR) of interest is 20% or higher while an ORR 
of 5% or less is considered insufficient antitumor-activity.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 35 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P41, 
Section 3.1, 
Study Design 
Dose 
Expansion 
Replace 
The ORR in Group 2 will be initially evaluated after 10 subjects are treated and have been evaluated at the first 
imaging scan or have dropped out before that.   
 
With 
For each arm, the ORR in Group 2 will be initially evaluated after 10 subjects are treated and have been evaluated 
at the first imaging scan or have dropped out before that.   
P41, 
Section 3.1, 
Study Design 
Dose 
Expansion 
Replace 
During dose expansion, Amgen will conduct evaluations of the ongoing grade 4 or higher treatment-related adverse 
event rate to assess if the threshold for possible early trial termination has been reached. 
 
With 
During dose expansion and separately for the monotherapy arm (combining data from Groups 1 and 2) and for 
the combination arm (combining data from Groups 1 and 2), Amgen will conduct evaluations of the ongoing 
grade 4 or higher treatment-related adverse event rate to assess if the threshold for possible early trial termination 
has been reached. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 36 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P41, 
Section 3.1, 
Study Design, 
Dose 
Expansion 
Replace 
Number of subjects 
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
35 
Study Complete 
 
With 
Number of subjects 
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Study Complete 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 37 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P42, 
Section 3.1, 
Study Design, 
Dose 
Expansion, 
Figure 1.  
Schema of 
Study Design 
and Dosing 
Examples  
Delete 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 38 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P42,  
Section 3.1, 
Study Design, 
Dose 
Expansion, 
Figure 2.  
Schema of 
Study Design 
and Dosing 
Examples  
Add 
 
P43,  
Section 3.2 
Number of 
Sites 
Replace 
This study will be conducted at 12 sites in the United States, Australia and Europe.  
 
With 
This study will be conducted at approximately 12 or more sites in the United States, Australia and Europe.   
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 39 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P43, 
Section 3.3 
Number of 
Subjects 
Replace 
It is anticipated that around 82 subjects will be enrolled in the study.  Up to 30 DLT-evaluable subjects will be 
enrolled in dose escalation in Group 1 (recurrent disease) and up to 12 subjects in Group 2 (maintenance treatment 
after SoC in newly diagnosed disease).  Up to 40 subjects will be enrolled in the dose expansion cohorts at 9 or 
more sites in US, Australia and Europe. 
 
With 
It is anticipated that up to 190 subjects will be enrolled in the study. It is anticipated that up to 100 subjects will be 
enrolled to Arm 1 in this study and up to 90 subjects will be enrolled to Arm 2 in this study.   
For Group 1 (recurrent disease), the following are the planned sample sizes. 
• 
In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up to 
30 DLT-evaluable subjects to combination Arm 2.  
• 
In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and up to 15 subjects to 
combination Arm 2.  
For Group 2 (maintenance setting), the following are the planned sample sizes. 
• 
In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up to 
20 DLT-evaluable subjects to combination Arm 2  
• 
In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and up to 25 subjects to 
combination Arm 2.  
P44, Section 
3.4, Estimated 
Study Duration 
Replace 
The duration of this study will be approximately 3.5 years, with about 36 months for enrollment (a maximum of 
24 months for the dose escalation cohorts, and 12 months for the dose expansion cohort) and 6 months protocol 
treatment period. 
 
With 
The duration of this study will be approximately 4.5 years, with about 42 months for enrollment (a maximum of 
30 months for the dose escalation cohorts, and 12 months for the dose expansion cohort) and 12 months protocol 
treatment period 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 40 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P46, Section 
4.2, Exclusion 
Criteria # 209 
Add 
Pembrolizumab 
P47, Section 
4.2, Exclusion 
Criteria # 210 
Replace 
Treatment with non-topical systemic corticosteroids within 14 days before enrollment (day 1) (exemption: systemic 
corticosteroid doses of ≤ 2 mg of dexamethasone (or equivalent) per day after consultation with Sponsor, exemption 
does not apply for Part 1 Dose Escalation Phase 1 subjects) 
 
With 
Treatment with non-topical systemic corticosteroids within 14 days before enrollment (day 1) (exemption: 
prophylactic treatment with dexamethasone as defined in section 6.5, and systemic corticosteroid doses of ≤ 2 
mg of dexamethasone (or equivalent) per day after consultation with Sponsor,) 
P47, Section 
4.2, Exclusion 
Criteria # 214 
Replace 
Male and female of reproductive potential who are unwilling to practice highly effective method(s) of birth control 
while on study through 1 week (5 half-lives) after receiving the last dose of study drug 
 
With 
Male and female of reproductive potential who are unwilling to practice highly effective method(s) of birth control 
while on study through 30 days after receiving the last dose of AMG 596 and through 4 months (120 days) after 
receiving the last dose of AMG 404 
P47, Section 
4.2, Exclusion 
Criteria # 215 
Replace 
Female who is lactating/breastfeeding or who plans to breastfeed while on study through 1 week (5 half-lives) after 
receiving the last dose of study drug. 
 
With 
Female who is lactating/breastfeeding or who plans to breastfeed while on study through 30 days after receiving the 
last dose of AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 41 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P47, Section 
4.2, Exclusion 
Criteria # 217 
Replace 
Female planning to become pregnant while on study through 1 week (5 half-lives) after receiving the last dose of 
study drug. 
 
With 
Female planning to become pregnant while on study through 30 days after receiving the last dose of AMG 596 and 
through 4 months (120 days) after receiving the last dose of AMG 404.  
P48, Section 
4.2, Exclusion 
Criteria # 218 
Replace 
Male who is unwilling to abstain from sperm donation while on study through 1 week (5 half-lives) after receiving the 
last dose of study drug. 
 
With 
Male who is unwilling to abstain from sperm donation while on study through 30 days after receiving the last dose of 
AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404. 
P48,  
Section 4.2 
Exclusion 
Criteria 
Add 
The following Exclusion Criteria apply in addition for enrollment in combination cohorts with AMG 404  
220.    History of solid organ transplantation.  
221.    Prior treatment with anti-PD-1, anti-PD-L1, CTLA-4 or other checkpoint inhibitor drugs 
222. Prior treatment with AMG 596 monotherapy arm is not eligible to enroll in the combination therapy arm.  
223.    Live vaccine therapies within 4 weeks prior to study drug administration 
224.    Evidence of interstitial lung disease or active, non-infectious pneumonitis 
225.    History of any immune-related colitis. Infectious colitis is allowed if evidence of adequate treatment 
and clinical recovery exists and at least 3 months interval observed since diagnosis of colitis.  
226.    Active or history of any autoimmune disease or immunodeficiencies. Subjects with Type I diabetes, 
vitiligo, psoriasis, hypo-or hyper-thyroid disease not requiring immune-suppressive treatment are permitted.  
227.    Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York 
Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 42 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P50, Section 
5.1 Treatment 
Assignment 
Delete 
Study Part 1, dose escalation, will start in Group 1 subjects and after establishing the RP2D in Group 1 dose 
escalation will proceed in Group 2 subjects.  In Part 1 Dose escalation Phase 1, the initial dose escalation cohorts, 
only a single subject will be enrolled to a cohort because the dose level is not anticipated to be clinically active.  The 
cohort size will be extended to 2 to 4 subjects, on a limited basis up to 5 subjects, in Part 1 Dose escalation Phase 2, 
when treatment-related adverse events of CTCAE grade 2 of higher and/or quantifiable cytokine levels in blood or 
CSF and above baseline are observed. 
Next cohorts (which are expected to be pharmacodynamically or clinically efficacious based on nonclinical models), 
will enroll up to 4 evaluable subjects.  When a first DLT is observed, the BLRM will be used to guide dose level 
selection.  The cohort size will be N=4-6 subjects for dose escalation in Group 2. 
Add 
Subjects will be treated either with AMG 596 monotherapy or with the combination of AMG 596 and AMG 404 
in the respective treatment arm according their individual eligibility and availability of treatment slots. If 
AMG 596 dose are different, mono- and combination therapy cohorts can run in parallel. If same AMG 596 
doses will be explored in monotherapy and in combination, the monotherapy cohort must be completed 
before enrollment in the combination cohort.  Enrollment of Group 2 subjects can start after observation of a 
first objective response during Group 1 dose escalation.   
 
P50, Section 
5.1 Treatment 
Assignment 
Add 
or AMG 596 in combination with AMG 404 
P50, Section 
5.1 Treatment 
Assignment 
Add 
The Sponsor will provide the exact treatment assignment (cohort) to sites including AMG 596 or AMG 596 
and AMG 404 doses and schedule. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 43 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P51, 
Section 6.1, 
Classification 
of Product(s), 
Medical 
Device(s), 
and/or 
Combination 
Product(s)  
Replace 
The Amgen IPs used in this study include AMG 596 and intravenous solution stabilizer (IVSS). 
 
With 
The Amgen IPs used in this study include AMG 596, AMG 404 and intravenous solution stabilizer (IVSS). 
P51, 
Section 6.1, 
Classification 
of Product(s), 
Medical 
Device(s), 
and/or 
Combination 
Product(s) 
Replace 
The Investigational Product Instruction Manual (IPIM), a document external to this protocol, contains detailed 
information regarding the storage, preparation, destruction, and administration of AMG 596.  
 
With 
The Investigational Product Instruction Manual (IPIM), a document external to this protocol, contains detailed 
information regarding the storage, preparation, destruction, and administration of AMG 596 and AMG 404. 
P52, Section 
6.2.1.1 
Dosage, 
Administration 
and Schedule 
for AMG 596 
Replace 
Dosage, Administration and Schedule 
 
With 
Dosage, Administration and Schedule for AMG 404 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 44 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P52, Section 
6.2.1.1 
Dosage, 
Administration, 
and Schedule 
for AMG 596 
Add 
AMG 596 administration can cause dose dependent increase of peritumoral edema leading to 
development or worsening of depressed level of consciousness, a disease related event, which can be 
prevented by prophylactic administration of dexamethasone. Prophylactic use of corticosteroids is 
mandated for any subject receiving a new cycle of AMG 596 (28 day on and 14 days off), with 
dexamethasone 8 mg IV (or equivalent dose of other corticosteroids) given within 1 hour prior to 
administration of AMG 596 and a second dose of dexamethasone given 8 mg IV 12 hours after start of 
the infusion. Subsequently, corticosteroids can be tapered at the discretion of the investigator based 
on clinical judgement. Same prophylactic use of dexamethasone is mandated for AMG 596 in 
combination with AMG 404 prior to the start of the AMG 596 infusion. 
 
Prophylactic treatment with steroid (eg, dexamethasone) is also mandated before restarting of AMG 596 or 
otherwise clinically indicated (see Section 6.2.4.1 and Section 6.3.2).  
P52, Section 
6.2.1.1 
Dosage, 
Administration, 
and Schedule 
for AMG 596 
 
Replace 
Subjects will be hospitalized for the first 7 days of infusion and for at least 24 hours following completion of the 
infusion in cycle 1, and for 72 hours after a dose step in cycle 1, and at least for the first 72 hours of infusion in any 
subsequent cycle and after a dose step in any subsequent cycle.  
With 
Subjects will be hospitalized for the following periods:  
Cycle 1:  
• 
For the first 
 of AMG 596 monotherapy (Arm 1)  
• 
For the first 
 of AMG 596 in combination with AMG 404 (Arm 2), hence AMG 404 will be 
administered on 
 
• 
For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 and Arm 2  
• 
For additional 72 hours after AMG 596 step dose if necessary  
Cycle 2 and all subsequent cycles:  
• 
For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2 
• 
For additional 72 hours after AMG 596 step dose if necessary.  
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 45 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P53, Section 
6.2.1.1 
Dosage, 
Administration, 
and Schedule 
for AMG 596 
Replace 
The start dose based on preclinical evaluations for the estimation of the MABEL is 
 µg per day.  Further 
pre-planned dose levels are 
µg per day; step-dosing can be 
introduced.  
 
With 
The start dose for AMG 596 based on preclinical evaluations for the estimation of the MABEL is 
 µg per day.  
Further AMG 596 pre-planned dose levels are 
 µg per day; 
step-dosing can be introduced.  
P53, Section 
6.2.1.1 
Dosage, 
Administration, 
and Schedule 
for AMG 596 
Replace 
Intra-subject dose escalation will be allowed to higher dose levels in subsequent treatment cycles once a higher 
dose has been deemed safe by the DLRT 
 
With 
Intra-subject dose escalation for AMG 596 will be allowed to higher dose levels in subsequent treatment cycles once 
a higher dose has been deemed safe by the DLRT. 
P52, Section 
6.2.1.1 
Dosage, 
Administration, 
and Schedule 
for AMG 596 
Replace 
A new cycle may begin +/- 2 days from the scheduled day 1 of the new cycle for logistical reasons. 
With 
A new cycle for AMG 596 may begin +/- 2 days from the scheduled day 1 of the new cycle for logistical reasons. 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 46 of 86
CONFIDENTIAL
Section
Amended text
P55, Section
6.2.2. Amgen
Investigational
Product
AMG 404
Add
6.2.2
Amgen Investigational Product AMG 404
AMG 404 is supplied in a 3 mL Type 1 glass tubing vial containing 1 mL deliverable volume of 70 mg/mL. The
drug product is formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate
80, pH 5.2 and will be prepared for IV administration by dilution.
6.2.2.1
Dosage, Administration, and Schedule
The investigational product will be dispensed at the research facility by a qualified staff member.
At the beginning of a treatment cycle a physician or nurse trained in emergency medical care must be available
when the infusion of investigational product is started for immediate intervention in case of complications.
AMG 404 will be delivered using infusion pumps approved for use by the appropriate regulatory authority for the
country in which the subject is undergoing treatment.
AMG 404 solution for infusion will be prepared in bags for IV infusion and delivered through infusion lines.
The drug will be administered as an IV infusion at a constant flow rate over 30 minutes every 
Subjects will be hospitalized for 24 hours after first administration of AMG 404 in Cycle 1 
 of the AMG 596
infusion and should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each
following AMG 404 infusion. Assessments should be performed as indicated in the Schedule of Activities.
The planned dose, start date, start time, stop date, stop time, dose administered, reason for dose change, and
package lot number of AMG 404 are to be recorded on each subject's eCRF(s) and/or the site’s study files.
6.2.2.2
Overdose
The effect of overdose of this product are not known.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 47 of 86
CONFIDENTIAL
Section
Amended text
P56, Section
6.2.3 Dose
Escalation,
Stopping Rules
and
Dose-Limiting
Toxicities (DLTs)
Replace
6.2.3 Dose-cohort study Escalation, Stopping Rules and Dose-Limiting Toxicities (DLTs)
With
6.2.3 Dose Escalation, Stopping Rules and Dose-Limiting Toxicities (DLTs)
P56, Section
6.2.3 Dose
Escalation,
Stopping Rules
and
Dose-Limiting
Toxicities (DLTs)
Replace
A DLT will be defined as any of the following occurring in a subject during the DLT period and regarded to be
related to AMG 596.
With
A DLT will be defined as any of the following occurring in a subject during the DLT period (first 
 treatment days
for both AMG 596 monotherapy and in combination with AMG 404) and regarded to be related to AMG 596
and/or AMG 404.
P56, Section
6.2.3 Dose
Escalation,
Stopping Rules
and
Dose-Limiting
Toxicities (DLTs)
Add
Lymphopenia of any grade is not considered a DLT
P56, Section
6.2.3 Dose
Escalation,
Stopping Rules
and
Dose-Limiting
Toxicities (DLTs)
Add
Laboratory parameters of grade ≥ 3, not considered clinically relevant, and improved to grade ≤ 2 within 
72 hours will not be considered DLT (for ALT and GGT elevations grade ≥ 3, not considered clinically
relevant, and improved to grade ≤ 2 within 7 days due to the long half-life of these parameters)
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 48 of 86
CONFIDENTIAL
Section
Amended text
P56, Section
6.2.3 Dose
Escalation,
Stopping Rules
and
Dose-Limiting
Toxicities (DLTs)
Add
Any grade 3 endocrinopathy that cannot be adequately controlled by hormonal replacement
P57, Section
6.2.4, Dosage
Adjustments,
Delays, Rules for
Withholding or
Restarting,
Permanent
Discontinuation
Replace
Prophylactic treatment with steroid (eg, dexamethasone) is recommended before restarting of AMG 596 if clinically
indicated.
With
Prophylactic treatment with steroid (eg, dexamethasone) is mandated before restarting of AMG 596.
P59, Table 3,
Hematological
Criteria for Dose
Reduction
Replace
Table 2.  Hematological Criteria for Dose Reduction
With
Table 3.  Hematological Criteria for Dose Reduction
P60, Table 4,
Non-
hematological
Criteria for Dose
Reduction
Replace
Table 3, Non-hematological Criteria for Dose Reduction
With
Table 4, Non-hematological Criteria for Dose Reduction
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 49 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P60,  
Section 6.2.4.2 
AMG 404 Dose 
Delay or Dose 
Reduction 
Add 
6.2.4.2 
AMG 404 
Dose Delay or Dose Reduction 
Each subject will stay on the dose level assigned until treatment needs to be stopped. The reason for dose 
withholds and dose delays is to be recorded on each subject’s CRF. Specific guidance for management of 
adverse events associated with AMG 404 are provided in Appendix G 
Immune-related Adverse Reactions 
Adverse events following the administration of AMG 404 may represent an immunologic etiology. Based 
on clinical experience with other anti-PD-L1 therapies, these immune-related toxicities may occur shortly 
after the first dose to several months after the last dose of treatment and may affect more than one body 
system simultaneously. Early recognition and management is critical to reduce complications.  
Most immune-related adverse events require adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests, such as bronchoscopy, endoscopy, or skin biopsy, may be 
included as part of the evaluation.  
Based on the type and severity of the immune-related adverse event, withholding or permanent 
discontinuation of AMG 404 may be required, in addition to treatment with corticosteroids and/or other 
therapies. Dose modification and toxicity management guidelines for immune-related adverse reactions 
are provided in Appendix G.  
Infusion-related Reactions 
Infusion-related reactions may occur with the administration of AMG 404. Monitor patients for signs and 
symptoms of infusion-related reactions, including pyrexia, chills, rigors, flushing, urticaria, hypotension, 
dyspnea, wheezing, headache, back pain, and abdominal pain. If an infusion-related reaction is suspected, 
perform a physical examination, monitor vital signs, monitor pulse oximetry, and perform and ECG if the 
patient is experiencing chest pain or sustained tachycardia.  
For mild or moderate infusion-related reactions, interrupt or slow the rate of infusion.  For severe or 
life-threatening infusion-related reactions, permanently discontinue AMG 404. Treatment guidelines for 
infusion reactions associated with the administration of AMG 404 are provided in Appendix H. 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 50 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P61, 
Section 6.2.5 
Permanent 
Discontinuation 
Replace 
Dose-limiting or other unmanageable toxicity. If a DLT occurs in a subject with a clear clinical benefit from 
treatment, a restart at a lower dose can be considered if the toxicity has resolved and after consultation with the 
sponsor (see Section 6.3 and Appendix E). 
 
With 
Dose-limiting or other unmanageable toxicity. For exemption, please see section 6.2.3.  
P61, Section 
6.2.5 Permenant 
Discontinuation 
Replace 
Occurrence of neurologic-related adverse event considered related to AMG 596 by the investigator and meeting 
one or more of the following criteria: 
 
With 
Occurrence of neurologic-related adverse event considered related to AMG 596 and/or AMG 404 by the 
investigator and meeting one or more of the following criteria 
P61, Section 
6.2.5 Permenant 
Discontinuation 
Replace 
Occurrence of acute kidney injury considered related to AMG 596 by the investigator.  
 
With 
Occurrence of acute kidney injury considered related to AMG 596 and/or AMG 404 by the investigator  
P61, Section 
6.2.5 Permanent 
Discontinuation 
Add 
Pregnancy 
P61, Section 
6.2.5 Permanent 
Discontinuation 
Add 
• 
A DLT leads to permanent discontinuation unless the following criteria apply, in which case a 
restart of treatment at the same or a lower dose may be allowed: 
− 
The AE (including relevant lab values) is reversible and improves to grade ≤ 1 or baseline within 
14 days 
− 
The patient is experiencing clinical benefit as assessed by the investigator 
− 
There is agreement between the investigator and the Amgen Medical Monitor that treatment may 
be restarted 
− 
The subject is willing to continue treatment after the investigator has led an appropriate 
discussion of potential risks and benefits with the subject 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 51 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P61, Section 
6.2.5 
Permanent 
Discontinuation 
Delete 
Male with pregnant partners or whose partners become pregnant while the subject is on study through 5 half-lives 
after receiving the dose of study drug must practice sexual abstinence or use a condom while on study through 5 
half-lives after receiving the last dose of study drug.  
Female who becomes pregnant while on study through 5 half-lives after receiving the last dose of study drug will 
not receive subsequent scheduled doses and will be followed for safety until the safety follow up visit. 
P62, Section 
6.3.1, Cytokine 
Release 
Syndrome 
Replace 
Subjects may be at an increased risk for cytokine release syndrome during the first few days following the initial 
infusion of AMG 596.    
 
With 
Subjects may be at an increased risk for cytokine release syndrome during the first few days following the initial 
infusion of AMG 596 and/or AMG 404.   
P62, Section 
6.3.1, Cytokine 
Release 
Syndrome 
Replace 
Throughout the infusion with AMG 596, monitor subjects for clinical signs 
 
With 
Throughout the infusion with AMG 596 and/or AMG 404, monitor subjects for clinical signs 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 52 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P65, Table 5, 
Management of 
Neurologic 
Events 
(by Severity)  
Replace  
Table 4. Management of Neurologic Events (by Severity) 
CTCAE Grade 
Intervention 
Instructions for Infusion Interruption or 
Permanent Discontinuation  
3 
Perform physical exam, assess vital signs and 
conduct safety laboratory tests 
Depending on the nature of the adverse event, 
additional measures (eg, CSF investigations, 
contrast-enhanced MRI of the head) can be 
taken upon discretion of the investigator 
MRI should also be considered for subjects who 
permanently discontinue treatment at the 
discretion of investigator 
Immediately interrupt AMG 596 
Restart within 2 weeks, but not earlier than 
72 hours (3 days) after the infusion has stopped, if 
the event resolves to grade ≤ 1 within 7 days 
Permanently discontinue AMG 596 and AMG 404 
if considered by the investigator related to study 
drug and if there is no improvement to grade  
≤ 1 within 7 days 
4 
Perform physical exam, assess vital signs and 
conduct safety laboratory tests 
Depending on the nature of the adverse event, 
additional measures (eg, CSF investigations, 
contrast-enhanced MRI of the head) can be 
taken upon discretion of the investigator 
Conduct MRI for subjects who permanently 
discontinue treatment 
Immediately interrupt AMG 596 
Permanently discontinue AMG 596.  
 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 53 of 86
CONFIDENTIAL
Section
Amended text
With
Table 5. Management of Neurologic Events (by Severity)
CTCAE
Grade
Intervention
Instructions for Infusion Interruption or Permanent
Discontinuation
3
Perform physical exam, assess vital signs and
conduct safety laboratory tests
Depending on the nature of the adverse event,
additional measures (eg, CSF investigations,
contrast-enhanced MRI of the head) can be
taken upon discretion of the investigator
MRI should also be considered for subjects
who permanently discontinue treatment at the
discretion of investigator
Immediately interrupt AMG 596
Restart AMG 596 infusion within 2 weeks, but not
earlier than 72 hours (3 days) after the infusion has
stopped, if the event resolves to grade ≤ 1 within 7 days
Delay AMG 404 dosing until day 8 after AMG 596
restart if AMG 404 dosing was scheduled during
interruption
Permanently discontinue AMG 596 and AMG 404 if
considered by the investigator related to study drug and
if there is no improvement to grade ≤ 1 within 7 days
4
Perform physical exam, assess vital signs and
conduct safety laboratory tests
Depending on the nature of the adverse event,
additional measures (eg, CSF investigations,
contrast-enhanced MRI of the head) can be
taken upon discretion of the investigator
Conduct MRI for subjects who permanently
discontinue treatment
Immediately interrupt AMG 596
Permanently discontinue AMG 596 and AMG 404
P64, Section
6.3.2, Infusion
Interruption/Dose
Modification due
to Neurologic
Events,
Depressed Level
of
Consciousness
Replace
In case of occurrence of seizure grade 3, the infusion of AMG 596 will have to be stopped immediately
With
In case of occurrence of seizure grade 3, the investigational products will have to be stopped immediately
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 54 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P64, Section 
6.3.2, Infusion 
Interruption/Dose 
Modification due 
to Neurologic 
Events, 
Depressed Level 
of 
Consciousness 
Add 
Depressed level of consciousness 
Depressed level of consciousness is a common neurological sign of intracranial pressure increase. 
AMG 596 may cause inflammation at the site of the tumor, leading to worsening of increased intracranial 
pressure resulting in neurological toxicity including a depressed level of consciousness. 
Prophylactic use of corticosteroids is mandated for any subject receiving a new cycle of AMG 596 (
 
), with dexamethasone 8 mg IV (or equivalent dose of other corticosteroids) given within 
1 hour prior to administration of AMG 596 and the second dose of dexamethasone 8 mg IV given 12 hours 
after start of the infusion, and subsequent tapering at the discretion of the investigator. Prophylactic 
treatment with steroid (eg, dexamethasone) is also mandated before restarting of AMG 596 or otherwise 
clinically indicated (see Section 6.3).  
P67, Section 
6.3.4 
Criteria for 
Permanent 
Withholding of 
Amgen 
Investigational 
Product due to 
Potential 
Hepatotoxicity 
Replace 
Investigational product 
 
With 
Both investigational products 
P67, Section 
6.3.4 
Criteria for 
Conditional 
Withholding of 
Amgen 
Investigational 
Product due to 
Potential 
Hepatotoxicity 
Replace 
Investigational product 
 
With 
Investigational products 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 55 of 86
CONFIDENTIAL
Section
Amended text
P69, Section
6.3.5, Criteria for
Conditional
Withholding of
Amgen
Investigational
Products due to
Potential
Hepatotoxicity
Replace
AMG 596 should be withheld pending investigation into alternative causes of DILI.
With
AMG 596 and AMG 404 should be withheld pending investigation into alternative causes of DILI.
P69, Section 6.5
Concomitant
Therapy
Add
Prophylactic use of corticosteroids is mandated for any subject receiving a new cycle of AMG 596 
), with dexamethasone 8 mg IV (or equivalent dose of other corticosteroids) given within 1 hour
prior to administration of AMG 596 and the second dose of dexamethasone 8 mg IV given 12 hours after start of
the infusion, and subsequent tapering at the discretion of the investigator. Same prophylactic use of
dexamethasone is mandated for AMG 596 in combination with AMG 404 prior to the start of the AMG 596
infusion.
Prophylactic treatment with steroid (eg, dexamethasone) is also mandated before restarting of AMG 596 or
otherwise clinically indicated (see Section 6.3.1 and Section 6.3.2).
P70, Section 6.6
Medical Device
Delete
Preprogrammed
P70, Section 6.6
Medical Device
Replace
The investigational product must be administered using preprogrammed infusion pumps approved for use by the
appropriate regulatory authorities for the country in which the subject is undergoing treatment in both the inpatient and
outpatient setting.  Investigational product, concentrate for solution for infusion, will be prepared in bags for IV infusion
and delivered through infusion lines with a 0.2 μm in-line filter.  Both are compatible with the investigational product as
described in the IPIM.
Additional details for the use of the IV bag and infusion lines and their specifications are provided in the IPIM.
With
The investigational products must be administered using infusion pumps approved for use by the appropriate regulatory
authorities for the country in which the subject is undergoing treatment in both the inpatient and outpatient setting and as
specified in Section 6.2.1 and Section 6.2.2 Investigational products, concentrates for solution for infusion, will be
prepared in bags for IV infusion and AMG 596 will be delivered through infusion lines with a 0.2 μm in-line filter.  Both
are compatible with the investigational product as described in the respective IPIM
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 56 of 86
CONFIDENTIAL
Section
Amended text
P70, Section 6.6
Medical Device
Add
respective
P70, Section 6.8
Excluded
Treatments
Replace
Any anti-tumor therapy other than the investigational product, including cytotoxic and/or cytostatic drugs, hormonal
therapy, immunotherapy or any biological response modifiers, any other investigational agent, other
immunosuppressive therapies corticosteroids with exceptions as described in Section 6.3 and as described in
Section 6.5 for management of CRS or neurologic adverse events
With
Any anti-tumor therapy other than the investigational products are not permitted, including cytotoxic and/or
cytostatic drugs, hormonal therapy (unless treatment for endocrinopathy), immunotherapy or any biological
response modifiers, any other investigational agent, other immunosuppressive therapies. Corticosteroids are
exceptions as described in Section 6.3 and Section 6.5 for management of CRS or neurologic adverse events.
P70, Section 6.8
Excluded
Treatments
Add
Subjects who received AMG 596 as monotherapy are not allowed to participate in the combination therapy
with AMG 404.
P80, Section 7.1,
Schedule of
Assessments,
Table 10
Add
Table 10.  Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 1 (Arm 2, 
Combination Therapy)
P82, Section 7.1,
Schedule of
Assessments
Table 10
Footnote
Replace
Hospitalization at start of cycle 1 will be for a minimum of 7 days from the start of the infusion, and for at least
24 hours following completion of the infusion, and for 72 hours after a dose step at cycle 1 (if applicable)
With
Hospitalization at start of cycle 1 will be for a minimum of 8 days from the start of the AMG 596 infusion, whereby
AMG 404 will be administered on 
 and for at least 24 hours following completion of the AMG 596 infusion.
All subjects will be hospitalized for at least 72 hours after a dose step of AMG 596 at cycle 1 (if applicable).
Subjects should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of
each AMG 404 infusion from cycle 1 
 onwards.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 57 of 86
CONFIDENTIAL
Section
Amended text
P82, Section 7.1,
Schedule of
Assessments
Table 10,
Footnote
Add
k, ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear)
to be done at screening and then if clinically indicated.
P83, Section 7.1,
Schedule of
Assessments,
Table 11
Add
Table 11, Schedule of Assessments Dose Escalation Cohort 
 AMG 596 Cycle 2 (AMG 404 3rd
Infusion), Cycle 4 and all Subsequent Even Number Cycles (Arm 2, Combination Therapy)
P85, Section 7.1,
Schedule of
Assessments
Table 11
Footnote
Replace
Hospitalization at start of cycle 1 will be for a minimum of 7 days from the start of the infusion, and for at least
24 hours following completion of the infusion, and for 72 hours after a dose step at cycle 1 (if applicable)
With
For combination therapy, hospitalization at start of cycle 2 and all subsequent cycles, and after dose step (if
applicable) at cycle 2 and all subsequent cycles, will be for a minimum of 72 hours after start of AMG 596
until cycle 5. Hospitalization will be at a minimum of 48 hours after start of AMG 596 from cycle 6 onwards
(per investigator’s discretion). Subjects should be monitored intensely in hospital or outpatient clinic for at
least 4 hours after start of each AMG 404 infusion from cycle 1 
 onwards.
P85, Section 7.1,
Schedule of
Assessments
Table 11
Footnote
Add
k, ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear)
to be done at screening and then if clinically indicated.
P86, Table 12
Add
Table 12.  Schedule of Assessments Dose Escalation Cohort 
 Infusion Cycle 3, and all 
Subsequent Odd Number Cycles (Arm 2, Combination Therapy)
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 58 of 86
CONFIDENTIAL
Section
Amended text
P85, Section 7.1,
Schedule of
Assessments
Table 11
Footnote
Replace
Hospitalization at start of cycle 1 will be for a minimum of 7 days from the start of the infusion, and for at least
24 hours following completion of the infusion, and for 72 hours after a dose step at cycle 1 (if applicable)
With
For combination therapy, hospitalization at start of cycle 2 and all subsequent cycles, and after dose step (if
applicable) at cycle 2 and all subsequent cycles, will be for a minimum of 72 hours after start of AMG 596
until cycle 5. Hospitalization will be at a minimum of 48 hours after start of AMG 596 from cycle 6 onwards
(per investigator’s discretion). Subjects should be monitored intensely in hospital or outpatient clinic for at
least 4 hours after start of each AMG 404 infusion from cycle 1 
 onwards.
P88, Section 7.1,
Schedule of
Assessments,
Table 12
Footnote
Add
k, ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear)
to be done at screening and then if clinically indicated.
P93, Section 7.1,
Schedule of
Assessments,
Table 15
Add
Table 15. Schedule of Assessment Dose Expansion Cohort 
 Cycle 1 and all Subsequent Odd 
Number Cycles (Arm 2, Combination Therapy)
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 59 of 86
CONFIDENTIAL
Section
Amended text
P95, Section 7.1,
Schedule of
Assessments,
Table 15
Footnote
Add
EOI = End of Infusion; EOT = End of Treatment; LTFU = Long Term Follow Up; SCR = Screening; SFUP = Safety Follow Up
a Hospitalization at start of cycle 1 will be for a minimum of 8 days from the start of the AMG 596 infusion, whereby AMG 404 will be
administered on 
 and for at least 24 hours following completion of the AMG 596 infusion. All subjects will be hospitalized for at
least 72 hours after a dose step of AMG 596 at cycle 1 (if applicable). Subjects should be monitored intensely in hospital or outpatient
clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
 onwards.
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height
will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum
hospitalization period in each cycle. Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect
possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal.
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If
available, data from a prior imaging evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening.
Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW (selected sites only) images of the
brain.  All other known sites of disease should also be recorded and assessed.
g If a subject discontinues after C1 this visit assessments will be considered EOT assessments. After EOT, please perform SFUP
assessments as in Table 16.
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after
meeting all eligibility criteria and treatment and cohort have been assigned. Adverse events occurring during the screening period will
be documented as medical history.
j, ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and
then if clinically indicated.
P96, Section 7.1,
Schedule of
Assessments
Table 16,
Add
Table 16. Schedule of Assessment Dose Expansion cohort 
 Cycle 2 and all Subsequent Even 
Number Cycles (Arm 2, Combination Therapy)
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 60 of 86
CONFIDENTIAL
Section
Amended text
P98, Section 7.1,
Schedule of
Assessments
Table 16
Footnote
Add
a For combination therapy, hospitalization at start of cycle 2 and all subsequent cycles, and after dose step (if applicable) at cycle 2 and all
subsequent cycles, will be for a minimum of 72 hours after start of AMG 596 until cycle 5. Hospitalization will be at a minimum of
48 hours after start of AMG 596 from cycle 6 onwards (per investigator’s discretion)., Subjects should be monitored intensely in hospital
or outpatient clinic for at least 4 hours after start of each AMG 404 infusion from cycle 1 
 onwards
b Clinical evaluations will include physical exam, ECOG, and weight.  Screening only: demographics, medical/surgical history, and height
will also be obtained.
c Vital Signs will be repeated at least every 4 hours during the first 24 hours of infusion and every 6 hours during the minimum
hospitalization period in each cycle. Vital signs will also be assessed prior to subject`s discharge from hospital in order to detect
possible signs and symptoms of infusion reactions.
d Serum pregnancy test will be performed for all females unless surgically sterile or ≥ 2 years postmenopausal
e Radiological Assessment by MRI for tumor staging by modified RANO will be performed at screening (within 14 days of enrollment). If
available, data from a prior imaging evaluation (historical data will be dated within 6 months of enrollment) will be entered at screening.
Scans will include T2-weighted, T2/FLAIR, T1-weighted pre- and post-contrast enhanced and DW (selected sites only) images of the
brain.  All other known sites of disease should also be recorded and assessed.
h Safety Follow Up to be performed 30 days (+/- 7 days) after EOT.
i Adverse events are to be collected for an eligible subject once the subject is enrolled in the study. A subject is considered enrolled after
meeting all eligibility criteria and treatment and cohort have been assigned. Adverse events occurring during the screening period will
be documented as medical history.
j Medications associated with AEs or SAEs occurring between the SFUP visit and End of Study must also be collected.
k, ACTH to be done every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and
then if clinically indicated.
P99, Section 7.2,
General Study
Procedures
Replace
During the study, every effort should be made to perform the study procedures as indicated on the Schedules of
Assessments (Section 7.1, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10).
With
During the study, every effort should be made to perform the study procedures as indicated on the Schedules of
Assessments (Section 7.1, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14,
Table 15, and Table 16).
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 61 of 86
CONFIDENTIAL
Section
Amended text
P99, Section 7.2,
General Study
Procedures
Replace
A dose step can be introduced on 
 of a cycle, and assessments for the first week of the step dose (day 8 to
day 14) must follow assessments for 
 of a cycle except for the pregnancy test.
With
AMG 596 dose step can be introduced on 
 of a cycle, and assessments for the first week of the step dose
(
) must follow assessments for 
 of a cycle except for the pregnancy test. In case of
step dosing, AMG 404 will be administered 
 after the AMG 596 target dose is achieved in cycle 1.
P99, Section 7.2,
General Study
Procedures
Add
AMG 404 will be given every 
 ECG triplicate measurements will be performed during first
AMG 404 infusion at pre-dose, EOI, and 4 hours after end of infusion for cycle 1. In all subsequent
AMG 404 dose, ECG triplicate measurements will only be collected at predose and EOI.
P99, Section 7.2,
General study
procedures
Replace
Blood samples must not be taken/drawn from the catheter port used for AMG 596 infusion
With
Blood samples must not be taken/drawn from the catheter port used for AMG 596 or AMG 404 infusion
P99, Section 7.2,
General Study
Procedures,
Acceptable
Deviation
Windows
Add
After completion of cycle 1 (AMG 596 and AMG 404), +/- 1 day for all visits if logistically necessary
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 62 of 86
CONFIDENTIAL
Section
Amended text
P101, Section
7.2, General
Study
Procedures
Table 17 List of
Analytes
Replace
Chemistry
Hematology
Coagulation
Urinalysis
Other
Sodium
Potassium
Chloride
Bicarbonate
(HCO3) or carbon
dioxide
Total protein
Albumin
Glucose
Blood urea
nitrogen or Urea
Creatinine
Total creatine
kinase
Total bilirubin
(TBL)
Direct bilirubin
Alkaline
phosphatase
(ALP)
Alanine
aminotransferase
(ALT)
Aspartate
aminotransferase
(AST)
Hemoglobin
Hematocrit
Mean corpuscular
volume
Platelets
White blood cell
differential
•
Total
neutrophils
•
Eosinophils
•
Basophils
•
Lymphocytes
•
Monocytes
PT
PTT
INR
Fibrinogen
AT III
Specific gravity
pH
Blood
Protein
Glucose
Bilirubin
Microscopic
exam**
(performed at the
discretion of the
Investigator)
C-reactive
protein (CRP)
IL-6
Serum
Pregnancy
HLA typing
Hepatitis B
surface
antigen
Hepatitis C
antibody
HIV*
 
Approved 
 
 


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Protocol Number:  20160132 
Date:  29 July 2019 
Page 63 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
 
With 
Chemistry 
Hematology 
Coagulation 
 
Urinalysis 
Other  
Sodium 
Potassium 
Chloride 
Bicarbonate (HCO3) 
or carbon dioxide 
Total protein 
Albumin 
Calcium 
Calcium corrected 
Glucose 
Blood urea nitrogen or 
Urea 
Creatinine 
Estimated CrCl 
GFR, MDRD 
calculation 
Total creatine kinase 
Total bilirubin (TBL) 
Direct bilirubin 
Alkaline phosphatase 
(ALP) 
Alanine 
aminotransferase 
(ALT) 
Aspartate 
aminotransferase 
(AST) 
TSH*** 
Free T4*** 
RBC 
Hemoglobin 
Hematocrit 
Mean corpuscular 
volume (MCV) 
Platelets 
White blood cell 
differential 
• 
Total 
neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
PT 
PTT 
INR 
Fibrinogen 
AT III 
 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic 
exam** 
(performed at the 
discretion of the 
Investigator) 
C-reactive 
protein (CRP) 
IL-6 
Serum 
Pregnancy 
HLA typing 
Hepatitis B 
surface 
antigen 
Hepatitis C 
antibody 
HIV* 
ACTH*** 
ANA*** 
ANCA*** 
(cytoplasmic 
and 
perinuclear)  
 
 
 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 64 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P99, P102, 
Section 7.2, 
General Study 
Procedures List 
of analytes， 
Footnote 
Add 
*** Only applicable for AMG 404 infusion 
 
ACTH = Adrenocorticotropic hormone; ANA = Antinuclear Antibodies; ANCA = Antineutrophil cytoplasmic 
antibodies; 
P102, Section 
7.2.1 
Pre-screening 
and Screening 
Delete 
The tissue sample must be obtained after last systemic or radiation therapy. 
 
P102, Section 
7.2.1 
Pre-screening 
and Screening 
Replace 
 
With 
P102, 
Investigational 
In-Vitro 
Diagnostic 
Device (IVD) 
Add 
 
P103, 
Investigational 
In-Vitro 
Diagnostic 
Device (IVD) 
Replace 
Section 7.1, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10).   
 
With 
Section 7.1, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12,Table 13, Table 14,Table 15, and 
Table 16).   
P104, 
Investigational 
In-Vitro 
Diagnostic 
Device (IVD) 
Delete 
AMG 596 PK collection 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 65 of 86
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Section
Amended text
P104, Section
7.2.2 Treatment
Replace
Subjects will be hospitalized for the first 7 days of infusion and for at least 24 hours following completion of infusion
in cycle 1 and for 72 hours after a dose step in cycle 1, and at least for the first 72 hours in any subsequent cycle
and after a dose step in any subsequent cycle.
With
All subjects will be hospitalized for the following periods:
Cycle 1:
•
For the first 
 of AMG 596 monotherapy (Arm 1)
•
For the first 
 of AMG 596 in combination with AMG 404 (Arm 2), hence AMG 404 will be
administered on 
•
For at least 24 hours following completion of AMG 596 cycle 1 for both Arm 1 and Arm 2
•
For additional 72 hours after AMG 596 step dose if necessary
Cycle 2 and all subsequent cycles:
•
For at least the first 72 hours of AMG 596 infusion in both Arm 1 and Arm 2
•
For additional 72 hours after AMG 596 step dose if necessary.
Hospitalization may be shortened to 48 hours from the 6th cycle onwards at the discretion of the
investigator.
AMG 404 can be administered in an outpatient setting starting from cycle 1 
 onwards. Subjects
should be monitored intensely in hospital or outpatient clinic for at least 4 hours after start of each
AMG 404 infusion from cycle 1 
 onwards.
P105, Section
7.2.2 Treatment
Replace
Dosing with AMG 596 can continue unless the subject becomes intolerant to investigational product,
With
Dosing with AMG 596 or AMG 596 in combination with AMG 404 can continue unless the subject becomes
intolerant to investigational product,
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 66 of 86
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Section
Amended text
P106, Section
7.2.2 Treatment
Replace
Biomarker assessments: 
With
Biomarker assessments: 
P106, Section
7.2.2 Treatment
Replace
With
P107, Section
7.2.4, Safety
Follow Up Visit
Replace
The safety follow-up visit (SFUP) is to be performed 30 days (+/- 7 days) after the last dose of AMG 596 or prior to
the initiation of other therapy
With
The safety follow-up visit (SFUP) is to be performed 30 days (+/- 7 days) after the last dose of AMG 596 and
AMG 404 even if the subject begins another therapy.
P107, Section
7.2.4, Safety
Follow Up Visit
Replace
With
P111, Section
7.3.10 Physical
Examination
Add
Table 12, Table 13, Table 14,Table 15, and Table 16
P111, Section
7.3.12, Clinical
Laboratory Test
Add
Table 12, Table 13, Table 14,Table 15, and Table 16
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 67 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P112, Section 
7.4 
Pharmacokinetic 
Blood Sampling 
Replace 
Blood samples will be obtained for determination of serum concentrations of AMG 596 at the time points specified 
in the Schedules of Assessments (section 7.1, Table 5, Table 6, Table 7, Table 8, Table 9 and Table 10).  Blood 
must not be drawn from the port catheter. 
 
With 
Blood samples will be obtained for determination of serum concentrations of AMG 596 in the monotherapy and 
for the determination of serum concentrations of AMG 596 and AMG 404 in the combination therapy at the 
time points specified in the Schedules of Assessments (section 7.1, Table 6, Table 7, Table 8, Table 9, Table 10, 
table 11, table 12 and table 13).   
Replace 
 
With 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 68 of 86
CONFIDENTIAL
Section
Amended text
Add
P114, Section
7.8, Sample
Storage and
Destruction
Replace
the dose response and/or prediction of response to AMG 596
With
the dose response and/or prediction of response to AMG 596 and in combination with AMG 404
P118, Section
9.1.1, Disease
Related Events,
Table 15
Replace
Table 12, Disease-Related Adverse Events by System organ Class
With
Table 18, Disease-Related Adverse Events by System organ Class
P120, Section
9.1.3 Serious
Adverse Events
Delete
•
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
P120, Section
9.2.1 Reporting
Procedures for
Disease Related
Events
Delete
Disease-Related Events assessed by the investigator to be more severe than expected and/or related to the
investigational medicinal product(s)/ study treatment/ protocol-required therapies, and determined to be serious,
must be recorded on the Event eCRF as Serious Adverse Events.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 69 of 86
CONFIDENTIAL
Section
Amended text
P120, Section
9.2.1 Reporting
Procedures for
Disease Related
Events
Add
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.
Disease-related events assessed by the investigator to be more severe than expected
and/or related to the investigational product(s)/study treatment/protocol-required
therapies, and determined to be serious, must be reported on the Event CRF as serious
adverse events and recorded and reported per section 9.2.1 and Appendix J.
Disease-related events pre-defined for this study are listed in Table 18.
P123, Section
9.3 Pregnancy
and Lactation
Reporting
Replace
In addition to reporting any pregnancies occurring during the study, investigators should report pregnancies that
occur through 30 days after the last dose of protocol-required therapies.
With
In addition to reporting any pregnancies occurring during the study, investigators should report pregnancies that
occur through 30 days after the last dose of AMG 596 or through 4 months (120 days) after the last dose of
AMG 404.
P124, Section
10.1.1
Secondary
Endpoint
Add
PK parameters of AMG 404 including, but not limited to, maximum abserved serum concentration (Cmax),
time to achieve Cmax (tmax), and AUC  
PK parameters for AMG 596 dosed in combination with AMG 404 including, but not limited to, average
steady-state concentration (Css), area under the concentration-time curve (AUC), clearance, volume of
distribution and half-life (t1/2) for serum AMG 596.
P124, Section
10.1.1 Study
Endpoints,
Secondary
Endpoint
Replace
Objective response (OR) as per modified RANO, time to response, response duration and time to progression
(TTP); progression free survival (PFS) at 6 and 12 months after treatment initiation.
With
Objective response (OR) as per modified RANO, time to response, response duration and time to progression
(TTP); progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 monotherapy
or AMG 596 in combination with AMG 404.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
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Section
Amended text
P124, Section
10.1.1, Study
Endpoints,
Exploratory
Endpoints
Replace
With
F
P124, Section
10.1.1, Study
Endpoints,
Exploratory
Endpoints
Replace
With
P124, Section
10.1.1, Study
Endpoints,
Exploratory
Endpoints
Replace
With
P124, Section
10.1.2 Analysis
Sets
Add
RANO Evaluable Analysis Set
The RANO Evaluable Analysis Set includes all subjects that are enrolled and receive at least one
administration of AMG 596 with measurable disease at enrollment per RANO.
P124, Section
10.1.2 Analysis
sets
Replace
The DLT Evaluable Analysis Set will be used to summarize incidence of dose limiting toxicity (DLT) (see
Section 3.3. for definition of DLT-evaluable)
With
The DLT Evaluable Analysis Set includes subjects who are DLT-evaluable and will be used to summarize
incidence of dose limiting toxicity (DLT) (see Section 3.3. for definition of DLT-evaluable)
P126, Section
10.2, Sample
Size
Considerations
Delete
It is anticipated that around 82 subjects will be enrolled in the study.  Up to 30 DLT-evaluable subjects will be
enrolled in dose escalation Group 1 (recurrent disease) and up to 12 subjects in dose escalation Group 2
(maintenance setting).  Up to 40 subjects will be enrolled in the dose expansion cohorts (15 subjects in Group 1
and up to 25 subjects in Group 2) at 9 or more sites across US, Australia and Europe.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 71 of 86
CONFIDENTIAL
Section
Amended text
P126, Section
10.2, Sample
Size
Considerations
Add
It is anticipated that up to 190 subjects will be enrolled in the study. It is anticipated that up to 100 subjects
will be enrolled to Arm 1 in this study and up to 90 subjects will be enrolled to Arm 2 in this study.
For Group 1 (recurrent disease), the following are the planned sample sizes.
•
In dose escalation, up to 45 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up
to 30 DLT-evaluable subjects to combination Arm 2
•
In dose expansion, up to 15 subjects will be enrolled to monotherapy Arm 1 and up to 15 subjects to
combination Arm 2
For Group 2 (maintenance setting), the following are the planned sample sizes.
•
In dose escalation, up to 15 DLT-evaluable subjects will be enrolled to monotherapy Arm 1 and up
to 20 DLT-evaluable subjects to combination Arm 2
•
In dose expansion, up to 25 subjects will be enrolled to monotherapy Arm 1 and up to 25 subjects to
combination Arm 2
P126, Section
10.2, Sample
Size
Considerations
Replace
The sample size of dose expansion Group 1 is based on practical considerations.  With 21 subjects treated at the
Group 1RP2D/MTD (6 from dose escalation and 15 from dose expansion)
With
For Group 1 (recurrent disease) in each respective arm (monotherapy and combination), the respective
sample sizes of the dose expansion cohorts are based on practical considerations.  With 21 subjects treated at the
RP2D/MTD (6 from dose escalation and 15 from dose expansion) in an arm
P126, Section
10.2, Sample
Size
Considerations
Replace
The sample size for Group 2 dose expansion is based on a Bayesian predictive probability design (Lee, 2008).  In
Group 2, the ORR of interest is 20% or higher while an ORR of 5% or less is considered insufficient
antitumor-activity.
With
For Group 2 (maintenance setting) in each respective arm (monotherapy and combination), the sample
sizes in the respective dose expansion arm are based on a Bayesian predictive probability design (Lee, 2008).  For
both arms, the ORR of interest is 20% or higher while an ORR of 5% or less is considered insufficient
antitumor-activity.
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 72 of 86
CONFIDENTIAL
Section
Amended text
P126, Section
10.2, Sample
Size
Considerations
Replace
In Group 2, the ORR of interest is 20% or higher while an ORR of 5% or less is considered insufficient
antitumor-activity.  The maximum sample size is 31 subjects (6 from dose escalation and 25 from dose expansion).
With
For both arms, the ORR of interest is 20% or higher while an ORR of 5% or less is considered insufficient
antitumor-activity.  The maximum sample size per arm is 31 subjects (6 from dose escalation and 25 from dose
expansion).
P126, Section
10.2 Sample
Size
Consideration,
Add
During dose expansion and separately for the monotherapy arm (combining data from groups 1 and 2) and
for the combination arm (combining data from groups 1 and 2),
 
Approved 
 
 


Product:  AMG 596 
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Date:  29 July 2019 
Page 73 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P128, Table 19 
Replace 
Table 13a, Stopping Boundary for Dose Expansion with Posterior Probability of 80% and Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20% 
Number of subjects 
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
35 
Study Complete 
 
With 
Table 19.  Stopping Boundary for Dose Expansion with Posterior Probability of 80% and Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20% 
Number of subjects 
Hold enrollment if observing this many grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Study Complete 
 
 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 74 of 86
CONFIDENTIAL
Section
Amended text
P128, Table 20
Replace
True grade 4 or higher treatment-
related adverse event rate
Probability of early stopping of
dose expansion
Average dose expansion
sample size
0.10
2.1%
34.6
0.15
9.7%
33.1
0.20
25.8%
30.2
0.25
47.7%
26.2
0.30
69.2%
21.9
With
Table 20. Operating Characteristics with Batch Size of 10 Subjects
True grade 4 or higher
treatment-related adverse event
rate
Probability of early stopping
of dose expansion
Average dose expansion
sample size
0.10
2.0%
39.5
0.15
9.7%
37.6
0.20
25.8%
33.9
0.25
47.7%
28.8
0.30
69.2%
23.4
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 75 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P128, Section 10.3 
Adaptive Design 
Add 
During dose escalation for both Arm 1 and Arm 2,   
P129, Section 10.3 
Adaptive Design 
Replace 
A bi-variate normal prior distribution (Neuenschwander, Branson and Gsponer; 2008) is used to select for  
θ = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest planned dose (
 μg/day) 
is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference dose (
 μg/day) is 0.05. 
 
With 
For both Arm 1 and Arm 2 , a bi-variate normal prior distribution (Neuenschwander, Branson and Gsponer; 
2008) is used to select for θ = (log a, log b) where the probability that the true DLT rate is ≤ 0.40 at the lowest 
monotherapy planned dose  
(
 μg/day) is 0.90 and the probability the true DLT rate is ≤ 0.05 at the reference dose (
 μg/day) is 0.05. 
P129, Section 10.4.1 
Interim Analysis 
Add 
Arm 1 
P129, Section 10.4.1 
Interim Analysis 
Add 
Arm 2 
In dose escalation, the DLRT will review the safety data after each cohort and make a decision on the 
next dose level to be explored for the estimate of RP2D/MTD based on a BLRM design.  The RP2D/MTD 
will be established separately for Group 1 (recurrent disease) and Group 2 (maintenance setting) 
subjects.   
Interim safety analyses during dose expansion will occur once 1) 5 subjects with recurrent disease 
have been enrolled and 2) after enrollment of 10 subjects with maintenance setting.  The BLRM will 
estimate the RP2D/MTD using available data from dose escalation and dose expansion.  Based on this 
revised RP2D/MTD estimate and reviewing all available safety data, the dose level for dose expansion 
may be revised.  In Part 2 dose expansion, the ORR will be evaluated after treating n=10 Group 
2 subjects for at least 6 months.  The futility will be assessed initially for N=10 and continuously 
afterwards using a Bayesian predictive probability design.  Enrollment may be terminated if 
insufficient antitumor-activity is observed. 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 76 of 86
CONFIDENTIAL
Section
Amended text
P131, Section 10.5.1
General
Considerations
Add:
The analyses described below will be reported separately for subjects enrolled to Arm 1 and for
subjects enrolled to Arm 2. Unless otherwise specified, the analyses will be done using the Safety
Analysis Set.
P131, Section 10.5.1
General
Considerations
Replace
ORR will be presented with 80% Clopper-Pearson exact CI.
With
ORR will be presented with 80% Clopper-Pearson exact CI using the RANO Evaluable Analysis Set.
P131, Section 10.5.2
Dose Limiting
Toxicities (DLT)
Add
The DLT endpoint will be analyzed using the DLT Evaluable Analysis Set.
P132, Section 10.5.3
Secondary Endpoint
Replace
An exact 80% CI will be estimated for the OR rate for all subjects in part 2 and those in part 1 treated at
RP2D/MTD for each group.
With
Using the RANO Evaluable Analysis Set, an exact 80% CI will be estimated for the OR rate for all subjects
in part 2 and those in part 1 treated at RP2D/MTD for each group.
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 77 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P131, Section 10.5, 
Planned Method of 
Analysis, Secondary 
Endpoints, 
Pharmacokinetic 
Analyses 
Replace 
The serum PK parameters of AMG 596 including, but not limited to, average Css, area under the 
concentration-time curve (AUC), clearance, volume of distribution and half-life (t1/2), 
 
 CSF will be estimated using non-compartmental methods and summarized by dose level using 
means, standard deviations, medians, minimums, and maximums.   
 
With 
The serum PK parameters of AMG 596 as monotherapy or in combination therapy with AMG 404 
including, but not limited to, average Css, area under the concentration-time curve (AUC), clearance, volume of 
distribution,  
half-life (t1/2), and 
 and serum PK parameters of AMG 404 including, but 
not limited to, Cmax, tmax, and AUC  will be estimated using non-compartmental methods and summarized by 
dose level using means, standard deviations, medians, minimums, and maximums.   
P131, Section 10.5. 
Planned Method of 
Analysis Exploratory 
Endpoint 
Replace 
 
 
  
 
With 
 
  
P131, Section 10.5, 
Planned Method of 
Analysis, Exploratory 
Endpoint 
Delete 
. 
P140, Reference 
Add 
AMG 404 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 78 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P140, Reference 
Add 
Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, Dieckmann K, Filipits M, Brandstetter 
A, Weller M, Kurscheid S, Hegi ME, Zielinski CC, Marosi C, Hainfellner JA, Preusser M, Wick W. 
Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro 
Oncology. 2015 Aug;17(8):1064-75.  
P140, Reference 
Add 
Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson 
BM, Rytlewski JA, Sanders CM, Kawaguchi ES, Du L, Li G, Yong WH Gaffey SC, Cohen AL, Mellinghoff 
IK, Lee EQ, Reardon DA, O'Brien BJ, Butowski NA, Nghiemphu PL, Clarke JL, Arrillaga-Romany 
IC, Colman H, Kaley TJ, de Groot JF, Liau LM, Wen PY, Prins RM. Neoadjuvant anti-PD-1 
immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in 
recurrent glioblastoma. Nat Med. 2019 Mar;25(3):477-486.  
P141, Reference 
Add 
Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Kohnke T, Vick B, Jeremias I, Metzeler KH, Altmann 
T, Schneider S, Fiegl M, Spiekermann K, Bauerle PA, Hiddemann W, Riethmüller G, Subklewe M. 
Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody 
construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia (2016) 30:484–
91. 
P141, Reference 
Add 
Omuro, A. , Vlahovic, G., Lim,M., Sahebjam,S., Baehring, J.,, Cloughesy, T.,, Voloschin, A., 
Ramkissoon, S.H., Ligon, K.L.,Latek,R. ,Zwirtes, R. Strauss,L., Paliwal, P., Harbison, C.T., Reardon, 
D.A.,Sampson, J.H.,Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: 
results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol. 2018;20(5):674-686 
P142, Reference 
Add 
Osada T, Patel SP, Hammond SA, Osada K, Morse MA, Lyerly HK.CEA/CD3-bispecific T cell-engaging 
(BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. 
Cancer Immunol Immunother. (2015) 64:677–88. 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  29 July 2019
Page 79 of 86
CONFIDENTIAL
Section
Amended text
P142, Reference
Add
Reardon, D.A., Omuro, A., Brandes, A.A., Rieger, J., Wick,A., Sepulveda,J., Phuphanich,S., de Souza,
P., Ahluwalia, M.S., Lim,M., Vlahovic, G., Sampson, J., et al., 2017a. OS10.3: randomized phase 3 study
evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent
glioblastoma: CheckMate 143. Neuro Oncol. 2017 V19 Page iii21
P142, Reference
Add
Reardon, D.A, Kim, T.,Frenel, J.S.,Santoro, A., Lopez, J., Subramaniam, D.S., Siu, L.L.,Rodon,J.,
Tamura, K.,Saraf, S., Morosky, A., Stein, K., Soria, J.C., ATIM-35. Results of the phase Ib Keynote-028
multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1 positive
Glioblastoma Multiforme (GBM), Neuro Oncology. 2016 V18, P25-26
P142, Reference
Add
Reardon, D. A., Nayak, L., Peters, K.B., Clarke, J.L., Jordan, J. T., Groot, J. F., Nghiemphe, P. L., Kaley,
T. J., Colman,H., Gaffey, S.C., Caruso, V., Debruyne, M. B., Bahavsar, C., Molinaro, A. M., Smith, T.,
Severgnini, M., Wen, P. Y., Phase II study of pembrolizumab or pembrolizumab plus bevacizumab for
recurrent glioblastoma (rGBM) patients. Journal of Clinical Oncology, 2018, 36, no. 15_suppl (May 20
2018) 2006-2006
P142, Reference
Add
Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, Inogés
S, de Andrea C, López-Diaz de Cerio A, Tejada S, Berraondo P, Villarroel-Espindola F, Choi J, Gúrpide
A, Giraldez M, Goicoechea I Gallego Perez-Larraya J, Sanmamed MF, Perez-Gracia JL, Melero I.
Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma.Nat 
Med. 2019 Mar;25(3):470-476
P142, Reference
Add
Wang, X.,Guo, G.,Guan, H.,Yu, Y.,Lu, J., and Yu, J. Challenges and potential of PD-1/PD-L1 checkpoint
blockade immunotherapy for glioblastoma.J Exp Clin Cancer Res. 2019;38(1) 87. doi: 10.1186/s13046-
019-1085-3.
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 80 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P143, Reference 
Add 
Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, Bordbar D, Shan D, Samanamud 
J, Mahajan A, Filip I, Orenbuch R, Goetz M, Yamaguchi JT, Cloney M, Horbinski C, Lukas RV, Raizer 
J, Rae AI, Yuan J, Canoll P, Bruce JN, Saenger YM, Sims P, Iwamoto FM, Sonabend AM, Rabadan R 
“Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat 
Med. 2019; 25(3):462-469.  
P144, Section 14, 
Appendices 
Replace 
specified in Section 6.4.2. and Section 6.4.3. 
 
With 
specified in Section 6.3.3, Section 6.3.4, Section 6.3.5 and Section 6.3.6 
P155, Table 18 
Replace 
Table 13. Measurement Summary 
 
With 
Table 21. Measurement Summary 
P155, Table 19 
Replace 
Table 14. Response Assessment 
 
With 
Table 22. Response Assessment 
P157, Appendix E 
Delete 
Table 15. Grading and Management of Cytokine Release Syndrome (CRS) 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 81 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P157, Appendix E 
Replace 
CRS 
Grade 
Description of Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of AMG 596 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
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 earlier. 
N/A 
2 
Symptoms require and 
respond to moderate 
intervention 
Oxygen requirement 
< 40%, OR 
Hypotension responsive to 
fluids or low dose of one 
vasopressor, OR 
Grade 2 organ toxicity 
or grade 3 transaminitis 
per 
CTCAE criteria 
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. 
For subjects with extensive 
co-morbidities or poor performance 
status, manage per grade 3 CRS 
guidance below. 
Immediately interrupt 
AMG 596 until event 
resolves to CRS grade  
≤ 1 but for no less than  
72 hours. 
Permanently discontinue 
AMG 596 if there is no 
improvement to CRS 
≤ grade 1 within 7 days. 
 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 82 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
 
With 
CRS 
Grade 
Description of Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of Dosing 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
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 earlier. 
N/A 
2 
Symptoms require and 
respond to moderate 
intervention 
Oxygen requirement 
< 40%, OR 
Hypotension responsive to 
fluids or low dose of one 
vasopressor, OR 
Grade 2 organ toxicity 
or grade 3 transaminitis 
per 
CTCAE criteria 
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. 
For subjects with extensive 
co-morbidities or poor performance 
status, manage per grade 3 CRS 
guidance below. 
Immediately interrupt 
dosing until event 
resolves to CRS grade ≤ 
1 but for no less than 
72 hours. 
Permanently discontinue 
AMG 596 and AMG 404 if 
there is no improvement 
to CRS ≤ grade 1 within 7 
days. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 83 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P164, Appendix E 
 
Replace 
CRS 
Grade 
Description of 
Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of AMG 
596 
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 
Admit to intensive care unit for close 
clinical and vital sign monitoring per 
institutional guidelines. 
Administer dexamethasone (or 
equivalent) IV at a dose maximum of 3 
doses of 8 mg (24 mg/day).  The dose 
should then be reduced step-wise. 
 
Investigators may also consider use of 
Tocilizumab as an additional therapy in 
this setting at a dose of 4-8 mg/kg as a 
single dose. 
Immediately interrupt 
AMG 596 until event 
resolves 
to CRS grade ≤ 1 but 
for no less than 72 
hours. 
Permanently 
discontinue 
AMG 596 if there is no 
improvement to CRS 
≤ grade 2 within 5 days 
or CRS ≤ grade 1 
within 7 days. 
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 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, Tocilizumab can be 
considered administered at a dose of  
4-8 mg/kg as a single dose and may be 
repeated once within 24 to 48 hours 
based on clinical assessment. 
Immediately stop the 
infusion and 
permanently 
discontinue 
AMG 596 therapy. 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 84 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
 
With 
CRS 
Grade 
Description of 
Severitya 
Minimum Expected Intervention 
Instructions for 
Interruption of 
Dosing 
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 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer dexamethasone (or equivalent) IV 
at a dose maximum of  
3 doses of 8 mg (24 mg/day).  The dose 
should then be reduced step-wise. 
 
Investigators may also consider use of 
Tocilizumab as an additional therapy in this 
setting at a dose of 4-8 mg/kg as a single 
dose. 
Immediately interrupt 
dosing until event 
resolves 
to CRS grade ≤ 1 but 
for no less than 
72 hours. 
Permanently 
discontinue 
AMG 596 if there is 
no improvement to 
CRS ≤ grade 2 within 
5 days or CRS ≤ 
grade 1 within 
7 days. 
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 
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, Tocilizumab can be considered 
administered at a dose of 4-8 mg/kg as a 
single dose and may be repeated once within 
24 to 48 hours based on clinical assessment. 
Immediately stop the 
infusion and 
permanently 
discontinue 
AMG 596 and 
AMG 404 therapy. 
 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 85 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
160-167, 
Appendix G 
Add 
Appendix H. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions 
Associated with AMG 404* 
P168, 
Appendix H 
Add 
Appendix I. Management of Infusion Related Reactions with AMG 404 
Severity (CTCAE Grade 
Version 5.0) 
AMG 404 Dose 
Modification 
Management 
Premedication at 
Subsequent Dosing 
Grade 1 (mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated) 
Interrupt or slow the 
rate of the infusion. 
• Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable.  
• Treat per institutional guidelines. 
None 
Grade 2 (therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS,  
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours) 
Interrupt or slow the 
rate of the infusion.  
For subjects who 
develop grade 2 
infusion-related 
reaction despite 
adequate 
premedication, 
permanently 
discontinue 
AMG 404. 
• Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable.  
• Treat per institutional guidelines. Additional 
appropriate medical therapy may include 
but is not limited to IV fluids, antihistamines, 
NSAIDs, acetaminophen, and narcotics. 
Subject may be 
premedicated 1.5 hours  
(± 30 minutes) prior to 
infusion of  
AMG 404 with:  
• Diphenhydramine 50 mg 
orally (or equivalent dose 
of antihistamine). 
• Acetaminophen 
500-1000 mg orally (or 
equivalent dose of 
antipyretic). 
Grade 3 (prolonged [e.g., not 
rapidly responsive to 
symptomatic medication and/or 
brief interruption of infusion]; 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
clinical sequelae) 
OR 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue study 
drug. 
• Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable.  
• Hospitalization may be indicated. 
• Treat per institutional guidelines. Additional 
appropriate medical therapy may include 
but is not limited to IV fluids, antihistamines, 
NSAIDs, acetaminophen, narcotics, 
oxygen, vasopressors, corticosteroids, and 
epinephrine. In cases of anaphylaxis, 
epinephrine should be used immediately. 
No subsequent dosing 
 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  29 July 2019 
Page 86 of 86 
CONFIDENTIAL 
 
 
Section 
Amended text 
P169, 
Appendix I 
Add 
Appendix J, Safety Events: Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting 
Disease-related Event Definition 
• 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease. See [Section 9.2.3.1.1.1 / Section 12.8] for 
the list of disease-related events.  All serious disease-related events will be recorded and 
reported to the sponsor or designee within 24 hours. 
• 
Disease-related events that would qualify as an adverse event or serious adverse event: 
o 
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 reported as 
an adverse event or serious adverse event. 
• 
Disease-related events that do not qualify as adverse events or serious adverse events: 
o 
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 reported 
as a disease-related event.    
 
 
 
Approved 
 
 


Product:  AMG 596
Protocol Number:  20160132
Date:  11 March 2019
Page 1 of 11
CONFIDENTIAL
Amendment 4
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 596 in Subjects With Glioblastoma Expressing 
Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII)
Amgen Protocol Number 20160132
IND Number 134352 
EudraCT number 2017-001658-32
Amendment Date:
11 March 2019
Rationale:
Protocol Amendment 4 includes changes to allow enrollment of a broader patient 
population and allow treatment with potentially efficacious doses as early as possible. 
Revisions to Protocol Amendment 4 include:

Update the treatment schema to reflect the switch in Cohort 2 to a 
 
continuous infusion treatment cycle and multiple subject cohorts

Allow intrasubject dose escalation to minimize the number of subjects receiving 
sub-therapeutic doses

Allow for up to 5 subjects to be enrolled into a cohort. On a limited basis, one 
additional subject may be allowed to be enrolled if the subject has been 
determined to be eligible and the cohort has been filled.

Allow subjects with lower grade malignant gliomas that are EGFRvIII positive to 
be enrolled

Align treatment discontinuation with Dose Limiting Toxicities

Add stopping rules for dose expansion.
In addition, clarifications and corrections of inconsistencies, and administrative and 
typographical changes were made throughout the protocol.
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  17 May 2018 
Page 1 of 8 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 596 in Subjects With Glioblastoma Expressing 
Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) 
 
Amgen Protocol Number 20160132 
IND Number 134352 
EudraCT number 2017-001658-32 
 
Amendment Date: 
17 May 2018 
 
Rationale: 
The protocol amendment #3 is amended to provide additional information on 
 
. The 
plasma test is due to be available in the second half of 2018 and will be used in place of 
having subjects undergo a repeat surgery or biopsy to confirm EGFRvIII positivity. The 
current biopsy requirement is not feasible in patients with advanced glioblastoma and 
rapid deterioration, as there is too much time required for the procedure and obtaining 
results using the biopsy confirmation. Therefore, the protocol is being revised to allow:  
− 
Enrollment of subjects based on testing of available tumor tissue until availability 
of the plasma-based test. Testing prior to enrollment is required for subjects who 
received an EGFRvIII or amplified EGFR targeting therapy. Plasma will be 
collected from all subjects prior to treatment start allowing retrospective testing 
for EGFRvIII. 
− 
A short description of the plasma-based test will be added 
− 
Validated local tests for EGFRvIII detection will be allowed for pre-screening 
This revised approach for EGFRvIII positive glioblastoma identification can be justified 
as it is known that EGFRvIII expression is very heterogeneous. In particular, tests based 
on a small tissue sample derived from a biopsy may not reflect the expression status in 
other tumor areas. Quantitative differences for EGFRvIII detection between primary and 
recurrent glioblastomas are reported in up to 50% of cases though, qualitative 
differences were much lower with EGFRvIII expression remaining similar in 79% 
(Bent et al, 2015) and 87.5% (Felsberg et al, 2017) of glioblastomas. Loss of EGFRvIII 
expression was described as a potential resistance mechanism in glioblastomas treated 
with an EGFRvIII targeting vaccine, rindopepimut. In consequence, the request for 
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  17 May 2018 
Page 2 of 8 
CONFIDENTIAL 
 
 
EGFRvIII testing on tissue obtained shortly before or during screening remains in the 
protocol for subjects treated with EGFRvIII- or the amplified EGF receptor targeting 
agents (Schuster et al, 2015). 
Van den Bent et al: Neuro Oncol. 2015 Jul;17(7):935-41.  
Schuster et al, Neuro Oncol. 2015 Jun;17(6):854-61. 
Felsberg et al. Clin Cancer Res, 23(22), 6846-6855. 
In addition, few clarifications or corrections of inconsistencies, administrative and 
typographical changes were made throughout the protocol. 
Approved 
 
 


CONFIDENTIAL
Product:  AMG 596
Protocol Number:  20160132
Date:  30 January 2018
Page 1 of 17
Amendment 2
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 596 in Subjects With Glioblastoma Expressing 
Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII)
Amgen Protocol Number 20160132
IND Number 134352 
EudraCT number 2017-001658-32
Amendment Date:
30 January 2018
Rationale:
The protocol amendment #2 addresses several comments and changes requested by 
either European Ethics Committees or Regulatory Authorities based on Protocol 
Amendment #1.
In addition to clarifications or corrections of inconsistencies, administrative and 
typographical changes were made throughout the protocol.
Approved 
 
 


Product:  AMG 596 
Protocol Number:  20160132 
Date:  05 July 2017 
Page 1 of 19 
Amendment 1 
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 596 in Subjects With Glioblastoma Expressing 
Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII) 
 
Amgen Protocol Number 20160132 
IND Number 134352 
EudraCT number 2017-001658-32 
 
Amendment Date: 
Draft 05 July 2017 
Rationale: 
Protocol is amended to incorporate FDA recommendations based on review of the IND 
and recommendations of the Melbourne Health Human Research Ethics Committee 
from the meeting on 14/06/2017. 
Also administrative, typographical and formatting changes were made throughout the 
protocol. 
CONFIDENTIAL 
 
 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 1 of 49 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of 
AMG 596 in Subjects With Glioblastoma 
Expressing Mutant Epidermal Growth Factor 
Receptor Variant III (EGFRvIII) 
Short Protocol Title: 
AMG596 
Protocol Number: 
20160132 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: +1 805-447-1000 
SAP Date: 
Document Version 
Date 
Amendment 1 (v 2.0) 
20 May 2019 
NCT Number: NCT03296696
This NCT number has been applied to the document
for the purposes of posting on clinicaltrials.gov


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 2 of 49 
 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
06SEP2017 
Not Applicable 
[Amendment 1 (v2.0)] 
23APR2019 
1. Updated the definition of Baseline 
as the definition did not consider 
the assessments on the same day 
of first dose of IP administration 
when available. 
2. Updated the definition of 
Treatment Emergent Adverse 
Events to consider 37 days after 
the last dose of IP. 
3. Included RANO Evaluable 
Analysis Set as the study inclusion 
criteria allows Inevaluable scans 
as well and RANO Criteria doesn’t 
include Inevaluable and not 
applicable responses 
4. Updated section 9.5.1 Analysis of 
Efficacy Endpoint(s) to use RANO 
Evaluable Analysis Set for the 
analysis. 
5. Added censoring rules for time to 
response, duration of response 
and time to progression 
 
 
6. Added references for  
 
• 
Estimation of the median and CI 
will use the Brookmeyer and 
Crowley (1982) method 
 
• 
Landmark estimates (eg, 6 month 
PFS) will be estimated using the 
Kaplan-Meier curve and CI using 
Greenwood’s formula to estimate 
the standard error (see Kalbfleisch 
J.D. and Prentice R.L. (1980) 
• 
Clopper-Pearson method to 
present exact confidence 
intervals. 
 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 3 of 49 
 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ..................................................................................................... 3 
1. 
Introduction .............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses .................................................................... 9 
2.1 
Objectives and Endpoints ............................................................................. 9 
2.2 
Hypotheses and/or Estimations .................................................................. 10 
3. 
Study Overview ...................................................................................................... 10 
3.1 
Study Design .............................................................................................. 10 
3.2 
Sample Size ............................................................................................... 13 
3.3 
Estimated Study Duration ........................................................................... 14 
3.4 
Study Duration for Subjects ........................................................................ 14 
3.5 
Treatment Schema ..................................................................................... 15 
4. 
Covariates and Subgroups ..................................................................................... 15 
5. 
Definitions .............................................................................................................. 15 
6. 
Analysis Sets .......................................................................................................... 22 
7. 
Planned Analyses .................................................................................................. 22 
7.1 
Interim Analysis and Early Stopping Guidelines ......................................... 22 
7.2 
Primary Analysis ......................................................................................... 23 
7.3 
Final Analysis ............................................................................................. 23 
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 .................................................. 24 
8.4 
Detection of Bias ........................................................................................ 24 
8.5 
Outliers ....................................................................................................... 24 
8.6 
Distributional Characteristics ...................................................................... 24 
8.7 
Validation of Statistical Analyses ................................................................ 24 
9. 
Statistical Methods of Analysis ............................................................................... 24 
9.1 
General Considerations .............................................................................. 24 
9.2 
Subject Accountability ................................................................................ 25 
9.3 
Important Protocol Deviations .................................................................... 25 
9.4 
Demographic and Baseline Characteristics ................................................ 25 
9.5 
Efficacy Analyses ....................................................................................... 25 
9.5.1 
Analyses of Efficacy Endpoint(s) ................................................ 26 
9.6 
Safety Analyses .......................................................................................... 27 
9.6.1 
Adverse Events and Disease-related Events ............................. 27 
9.6.2 
Laboratory Test Results ............................................................. 28 
9.6.3 
Vital Signs ................................................................................... 29 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 4 of 49 
 
CONFIDENTIAL 
 
 
9.6.4 
Performance Status Score ......................................................... 29 
9.6.5 
Electrocardiogram ...................................................................... 29 
9.6.7 
Exposure to Investigational Product ........................................... 29 
9.6.8 
Exposure to Concomitant Medication ......................................... 30 
9.7 
Other Analyses ........................................................................................... 30 
9.7.1 
Analyses of Pharmacokinetic Endpoints .................................... 30 
9.7.2 
Analyses of Biomarker Endpoints ............................................... 30 
9.7.3 
Immunogenicity .......................................................................... 31 
10. 
Changes From Protocol-specified Analyses .......................................................... 31 
11. 
Literature Citations / References ............................................................................ 32 
12. 
Prioritization of Analyses ........................................................................................ 33 
13. 
Data not Covered by This Plan .............................................................................. 33 
14. 
Appendices ............................................................................................................ 34 
Appendix A.  Handling of Missing or Incomplete Dates for Adverse 
Events and Concomitant Medications ........................................................ 35 
Appendix C.  Reference Values/Toxicity Grades ................................................... 43 
Appendix D.  Modified Response Assessment In Neuro-Oncology 
(RANO) ....................................................................................................... 44 
Appendix E.  Grading and Management of Cytokine Release Syndrome 
(CRS)  ......................................................................................................... 47 
Appendix F.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale ................................................................. 49 
 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 5 of 49 
 
CONFIDENTIAL 
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
ALP 
Adverse event 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMG 596 
Anti EGFRvIII Bispecific T-cell Engager 
ANA 
Anti-nuclear antibody 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BiTE® 
BLRM 
Bispecific T-cell engager 
Bayesian logistic regression model 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CEA 
Carcinoembryonic antigen 
CI 
Confidence interval 
cIV 
Continuous intravenous 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRS 
Cytokine-Release Syndrome 
CSF 
Cerebrospinal fluid 
Css 
Steady-state drug concentration in plasma during constant-rate infusion 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
DILI 
drug induced liver injury 
DLRM 
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DLT 
Dose-limiting toxicity 
DWI 
Diffusion-weighted MRI 
EC50 
50% of the maximal effective concentration level 
EC90 
90% of the maximal effective concentration level 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 6 of 49 
 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Epidermal Growth Factor 
EGFRvIII 
Epidermal Growth Factor Receptor Variant III 
eCRF 
Electronic Case Report Form 
Electronic Source 
Data (eSource)  
source data captured initially into a permanent electronic record used 
for the reconstruction and evaluation of a study 
End of Study (EOS) 
Defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, long-term follow-up), as 
applicable  
End of Treatment 
(EOT) 
Defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject 
EOI 
End of infusion 
EOIP 
End of Investigational Product.  Defined as the last assessment for the 
protocol specified treatment phase of the study for an individual subject 
EudraCT 
European Clinical Trials Database 
eSAE 
Electronic serious adverse event (form) 
FDA 
Food and drug administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FIH 
First in human 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
Heart rate 
Number of cardiac cycles per unit of time 
HepBsAg 
Hepatitis B surface antigen 
HepCAb 
Hepatitis C virus antibody 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
hr 
Hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDH 
Isocitrate dehydrogenase 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 7 of 49 
 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
IVSS 
Intravenous solution stabilizer 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
LKM 1 
Liver Kidney Microsomal antibody 1 
MABEL 
Minimal anticipated biological effective level 
MHC 
Major histocompatibility complex 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
NA 
Not available 
NASH 
Nonalcoholic fatty liver disease including steatohepatitis 
ng 
Nanogram 
nM 
Nanomolar 
NYHA 
New York Heart Association 
OR 
Overall response 
ORR 
Objective response rate 
PBMCs 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PFS 
Prefilled syringe 
POR 
Proof of Receipts 
pg 
Picogram 
Primary Completion 
Defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), for 
the purposes of conducting the primary analysis, whether the study 
concluded as planned in the protocol or was terminated early  
RANO 
Response Assessment in Neuro-Oncology 
RP2D 
Recommended Phase 2 Dose 
PR 
Partial response 
SAP 
SCR 
Statistical analysis plan 
Screening 
SD 
Stable disease 


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Abbreviation or Term 
Definition/Explanation 
SEC 
Self-Evident Corrections 
SoC 
Source Data 
Standard of Care 
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 
product(s)/protocol-required therapies is/are administered to the subject 
t1/2 
Terminal-phase elimination half-life 
TBL 
Total bilirubin 
TMZ 
Temozolomide 
TPI 
Toxicity probability interval 
TTP 
Time to progression 
T2/FLAIR 
T2-weighted fluid-attenuated inversion recovery 
ULN 
Upper limit of normal 
Vss 
Apparent volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 
w/v 
Weight/volume 
µg 
Microgram 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20160132, AMG 596 
dated 05 July 2017.  The scope of this plan includes the interim analysis, the primary 
analysis and the final analysis that are planned and will be executed by the Amgen 
Global Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate the safety and tolerability of 
AMG 596 administered by continuous 
intravenous (cIV) infusion in subjects with 
EGFRvIII-positive glioblastoma in the 
recurrent setting (Group 1) and afterwards in 
the maintenance treatment phase of newly 
diagnosed glioblastoma (maintenance 
setting) (Group 2). 
• 
Dose limiting toxicities (DLT), 
treatment-emergent adverse events, 
treatment-related adverse events and 
clinically significant changes in vital signs, 
physical examinations, and clinical 
laboratory tests. 
Secondary 
• 
Evaluate the pharmacokinetics (PK) of 
AMG 596 in serum when administered by cIV 
infusion. 
• 
PK parameters for AMG 596 including, but 
not limited to, average steady-state 
concentration (Css), area under the 
concentration-time curve (AUC), 
clearance, volume of distribution and 
half-life (t1/2) for serum AMG 596. 
• 
Evaluate the clinical benefit of AMG 596 as 
determined by objective response rate (ORR) 
per modified Response Assessment in 
Neuro-Oncology Criteria (RANO) in subjects 
with EGFRvIII-positive glioblastoma in the 
recurrent and in the maintenance setting. 
• 
Objective response (OR) as per modified 
RANO, time to response, response 
duration and time to progression (TTP). 
• 
Evaluate progression free survival (PFS) at 
6 and 12 months after initiation of treatment. 
• 
Progression free survival (PFS) at 6 and 
12 months after treatment initiation. 
 
Exploratory 


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2.2 
Hypotheses and/or Estimations 
• 
AMG 596 is safe and well tolerated in at least one dose level when administered 
in subjects with EGFRvIII-positive glioblastoma in the recurrent (Group 1) and 
thereafter in the maintenance setting (Group 2). 
• 
AMG 596 can induce objective tumor shrinkage and/or overcome lack of 
response to SoC in subjects with EGFRvIII-positive glioblastoma in either 
recurrent or in the maintenance setting at a tolerable dose. 
3. 
Study Overview 
3.1 
Study Design 
This is a first in human (FIH), open-label sequential dose exploration study evaluating 
AMG596 in subjects with EGFRvIII-positive glioblastoma.  The study will be conducted in 
two parts: Part 1 - Dose escalation and Part 2 – Dose Expansion.  Study will enroll 
2 groups of subjects according to disease stage, recurrent disease (Group 1) and 
maintenance treatment after SoC in newly diagnosed disease (Group 2).  Subjects will 
be assigned to a treatment cohort based upon the order in which they qualify for the 
study.  For the schedule of assessment, please refer to Tables 5, 6, 7, 8, 9 & 10 in the 
protocol. 
 
The adaptive dose escalation part of the study using Bayesian logistic regression model is 
aimed at determining the recommended Phase 2 Dose (RP2D)/ the maximum tolerated 
dose (MTD), if feasible.  Treatment is divided into 2 periods: (1) DLT period 1 for 
 
of AMG 596 infusion and (2) DLT period 2 for 
 of infusion.  This distinction 
between DLT period 1 and DLT period 2 is maintained throughout dose escalation until the end of 
the dose escalation phase. 
The start dose based on preclinical evaluations for the estimation of the Minimum 
Anticipated Biological Effective Level (MABEL) is
µg/day.  Further pre-specified 
nominal doses for use in the dose escalation are
 
µg/day.  The dose level review team (DLRT) may consider treating at 
intermediate doses if required.  If the MTD or a biological active dose considered the 
RP2D is not reached within the pre-planned nominal dose range, the DLRT may decide 
to expand the nominal dose range to dose levels 
 µg/day after careful 
consideration of all available safety, laboratory, and PK information.  The preliminary 
estimate of the RP2D/MTD of AMG 596 will be done initially in subjects with recurrent 
disease (Group 1) and subsequently in subjects with maintenance treatment after SoC in 
newly diagnosed disease (Group 2). 


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Dose Escalation rules for Group 1: Recurrent Disease 
Dose escalation decisions will be made in accordance with the rules below:  
Phase 1, Single subject cohorts:  
o In first cohorts AMG 596 will be administered as a cIV infusion for
at escalating doses with N = 1 per cohort.  In the single 
subject cohorts, only a limited number of subjects will be enrolled at dose 
levels anticipated to be lower than those at which visible 
pharmacodynamics activity including adverse events related to AMG 596 
therapy will be expected.  In addition, the investigator together with the 
subject will decide on subsequent treatment duration carefully.  Subjects 
are allowed to stay on study in
cycles until 
discontinuation criteria apply. 
o The DLT period is 
 DLT period 1 is from day 
of 
AMG 596 infusion, and DLT period 2 is from day 
of infusion 
(includes cycle 2). 
o The cohort size will be increased to N = 2-4 subjects (ie, Start of Dose 
Escalation Phase 2, multiple subject cohorts) after observation of  
 
Treatment-related adverse events of common terminology criteria 
for adverse events (CTCAE) grade 2 or higher and/or 
 
Quantifiable cytokine levels in blood or CSF above baseline 
Phase 2, Multiple subject cohorts: 
o Subjects in the first multiple subject cohort receive the same dose as the 
last single subject cohort. 
o All subjects receive
infusion cycles with
treatment break 
until treatment discontinuation criteria apply.  
o In the first cycle, DLT period 1 is from day 
of AMG 596 infusion 
and DLT period 2 is from day
of infusion. 
It is anticipated that dose-escalation will proceed according to the pre-planned nominal 
doses though intermediate dose levels may be used if required after reviewing all 
available safety data. 
When a first DLT is observed, the Bayesian logistic regression model (BLRM) will be 
used to guide dose level selection (Neuenschwander et al., 2008).  The cohort size will 
be N = 2-4 subjects.  After each cohort, the model’s recommended MTD dose level for 
evaluation is the dose level with the highest probability of the target toxicity probability 
interval (TPI), but with a less than 0.25 probability of an excessive or unacceptable TPI.  
The target TPI 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 actual dose selected at each dose 


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decision may be at or below the model’s recommended dose as determined by the 
DLRT after considering all information. 
Stopping rules for Group 1: Recurrent Disease 
Dose escalation will be completed when any of the following occurs: 
• 
The maximum total sample size of N = 30 DLT evaluable subjects (including 
single subject cohorts) is reached 
• 
The BLRM model recommends the same dose level at least 2 times and at 
least 6 subjects have been treated at the recommended RP2D/MTD dose 
level.  If step-dosing is required, this stopping criteria applies separately to 
each period. 
• 
The highest planned dose level is reached without any DLTs being observed 
Dose Escalation rules for Group 2: Maintenance Treatment after SoC in Newly 
Diagnosed Disease 
• 
A first cohort will start after RP2D/MTD has been established in Group 1 
subjects with recurrent EGFRvIII-positive glioblastoma.  The starting dose in 
Group 2 will be decided by the DLRT and will be the MTD of Group 1, or will be 
no higher than a 2-fold increase of the Group 1 RP2D if no MTD was reached 
and no DLT was observed at the highest dose administered in Group 1 dose 
escalation.  Treatment may consist either of 
dose AMG 596 cIV 
infusion or step-dosing as established for recurrent disease.  Further treatment 
cycles with
between cIV infusions will be provided until any of the 
treatment discontinuation criteria applies.  
• 
The BLRM will be used to guide dose level selection.  The cohort size will be 
N = 4-6 subjects.  The actual dose selected at each dose decision may be at or 
below the model’s recommended dose as determined by the DLRT after 
considering all information.  
Stopping rules for Group 2: Maintenance Treatment after SoC in Newly 
Diagnosed Disease 
Dose escalation in Group 2 will be completed when any of the following occurs. 
 
The maximum sample size of N = 12 DLT evaluable subjects is 
reached 
 
At least 6 subjects have been treated at the recommended 
RP2D/MTD dose level 
 
The highest pre-specified nominal dose level is reached without 
any DLTs being observed. 
Dose expansion for Group 1 (Recurrent disease) & for Group 2 (Maintenance Treatment 
after SoC in Newly Diagnosed Disease):  
The purpose of dose expansion will be to further explore safety and to evaluate 
preliminary antitumor-activity in subjects with recurrent disease (Group 1) and in 


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subjects in the maintenance setting (Group 2).  It is anticipated that 15 subjects will be 
enrolled to Group 1 and up to 25 subjects will be enrolled to Group 2.  
In Group 2 (maintenance setting), the objective response rate (ORR) of interest is 20% 
or higher while an ORR of 5% or less is considered insufficient antitumor-activity.  The 
ORR in Group 2 will be evaluated after 10 subjects are treated and have been evaluated 
at the first on study imaging scan or have discontinued the study before that.  If ORR is 
lower than 5%, enrollment may be terminated due to futility.  Otherwise, the ORR will be 
evaluated for additional new subjects and the futility stopping rules are calculated using 
a Bayesian predictive probability design.  
A BLRM design may be used to update the estimate of the RP2D/MTD using data from 
subjects enrolled to dose escalation and dose expansion.  Based on this revised 
RP2D/MTD estimate and reviewing all available safety data, the dose level for dose 
expansion may be revised. 
The subjects enrolled in Part 2 dose expansion will be followed for imaging evaluation 
until the earliest of: clinically significant disease progression, death, consent withdrawal, 
start of new anti-tumor therapies or 12 months after treatment initiation.  Subjects who 
stopped treatment will be contacted for long term follow up for up to 12 months after 
treatment initiation. 
3.2 
Sample Size 
It is anticipated that around 82 subjects will be enrolled in the study.  Up to 
30 DLT-evaluable subjects will be enrolled in dose escalation Group 1 (recurrent 
disease) and up to 12 subjects in dose escalation Group 2 (maintenance setting).  Up to 
40 subjects will be enrolled in the dose expansion cohorts (15 subjects in Group 1 and 
up to 25 subjects in Group 2) at 9 or more sites across US, Australia and Europe. 
The sample size in dose escalation is based on practical considerations and it is 
consistent with conventional oncology studies with the objective to identify the 
RP2D/MTD.  With 2 subjects per cohort, there is a 19-56% probability of observing at 
least one DLT for a cohort if the true DLT rate is 10-33% and with 6 subjects per cohort, 
the probability is 47-91%.  
The sample size of dose expansion Group 1 is based on practical considerations.  With 
21 subjects treated at the Group 1 RP2D/MTD (6 from dose escalation and 15 from dose 
expansion), there is a 66% probability of observing an adverse event with 5% incidence 
rate.  For an ORR of 20%, the probability of observing the OR in at least 4 subjects 


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would be 63%.  The estimated ORR and exact 80% CI for 4 responses is 19% and 
9%-35% respectively. 
The sample size for Group 2 dose expansion is based on a Bayesian predictive 
probability design (Lee, 2008).  In Group 2, the ORR of interest is 20% or higher while 
an ORR of 5% or less is considered insufficient antitumor-activity.  The maximum 
sample size is 31 subjects (6 from dose escalation and 25 from dose expansion).  Futility 
will be assessed initially after treating 10 subjects for at least 6 months and continuously 
for each additional subject afterwards.  If ORR is lower than 5%, enrollment may be 
terminated due to futility.  The guidelines for early termination due to futility are as 
follows: 
Number of Treated Subjects 
Futility Termination Guideline 
10  
0 responders 
19  
1 or fewer responders 
26  
2 or fewer responders 
31 
3 or fewer responders 
With this design, the probability of accepting the treatment is 0.05 (type I error) when 
ORR = 5% and 0.8 (power) when ORR = 20%.  If the ORR is 5%, the probability of 
stopping the trial early at the interim with 10 evaluable subjects for futility is 60% and the 
expected additional subjects to be assessed in dose expansion is 9.6. 
3.3 
Estimated Study Duration 
The duration of this study will be approximately 3.5 years, with about 36 months for 
enrollment (a maximum of 24 months for the dose escalation cohorts, and 12 months for 
the dose expansion cohort) and 6 months protocol treatment period. 
3.4 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for approximately 
8 months including a screening period lasting 14 days, a treatment period lasting 
approximately 4 to 6 months, and a safety follow up period lasting 30 days (+/- 7 days).  
Additionally, there is a long term follow up for up to 12 months from treatment initiation.  
The actual duration for individual subjects will vary depending upon tolerability of 
AMG 596, evidence of clinical progression, and willingness to participate in the study. 
In the event that a subject demonstrates clinical benefit from therapy, he or she may 
continue treatment with AMG 596 until he or she experiences an unacceptable adverse 


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event, clinically significant disease progression, or he or she wishes to withdraw 
consent. 
The safety follow up study visit (SFUP) should occur 30 days (+/- 7 days) after the last 
dose of AMG 596 or prior to the initiation of other therapy, whichever occurs first.  End of 
study for an individual subject is defined as the date of the final long-term follow up study 
visit (LTFU) when assessments and procedures are performed. 
3.5 
Treatment Schema 
For treatment schema, pls. refer Figure 1 & Figure 2 from the protocol. 
4. 
Covariates and Subgroups 
  
Due to the small sample size, the impact of baseline characteristics on study outcomes 
will not be explored, and no subgroup analyses will be performed. 
  
  
5. 
Definitions 
Adverse Event (AE): 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject. 
Dose Limiting Toxicity: 
The grading of adverse events will be based on the guidelines provided in the common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 available online at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  
Also, the grading for Cytokine Release Syndrome (CRS) will be performed according to 
the recommendations provided by Lee et al, 2014 (Appendix E of the protocol). 
A Dose Limiting Toxicity (DLT) is defined as any adverse event meeting the criteria listed 
below occurring during the first 
 days in each dose exploration cohort and attributable 
to AMG 596: 
Hematological DLTs 
• 
ANC < 0.5 × 109/L for ≥ 7 days 
• 
Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection) with ANC < 0.5 × 109/L and fever ≥ 38.5°C 
• 
Platelets < 50 × 109/L > 7 days or clinically significant bleeding 


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Non-hematological DLTs 
• 
Any grade 4 non-hematological toxicity 
• 
Any grade 3 or higher non-hematological toxicity if: 
− 
Nausea and vomiting, which is refractory to anti-emetics 
− 
Flare-up of pain because of potential increase in tumor volume is not 
regarded as a DLT 
− 
Grade 3 non-hematologic toxicity lasting > 3 days despite appropriate 
treatment 
− 
Grade 3 fatigue will not be classified as DLT, irrespective of duration 
− 
Grade 3 acute kidney injury 
− 
Any grade 3 seizure, ataxia or encephalopathy 
− 
Other grade 3 neurologic-related adverse events lasting > 3 days despite 
appropriate treatment 
− 
Neurologic-related adverse event leading to treatment interruption that 
needed more than 1 week to resolve to CTCAE grade ≤ 1 
Any adverse event occurring outside the DLT window that is determined by the 
investigator to be possibly related to the investigational product, which is seen more 
frequently or 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.   
Subjects are classified as DLT-evaluable if they have had the opportunity to complete 
the DLT period and:  
• 
Subject in the
cycle receiving a complete first cycle with 
100% of the planned doses of investigational product, or 
• 
Subject in the
cycle receiving at least 90% of the planned 
doses of investigational product  or 
• 
Subject that has experienced a DLT  
Serious Adverse Event: 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal, 
• 
life-threatening (places the subject at immediate risk of death), 
• 
requires in-patient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
congenital anomaly/birth defect, and/or 
• 
other medically important serious event. 


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Treatment-Emergent AE: 
A treatment-emergent adverse event is any adverse event that begins or worsens after 
the initial dose of investigational product and before the end of study or   37 days after 
the last dose of investigational product (whichever occurs later).  The severity of each 
adverse event will be graded using the CTCAE version 4.0 criteria.  
Grading for Cytokine Release Syndrome (CRS) will be performed according to the 
recommendations provided by Lee et al, 2014 (Appendix E of the protocol). 
Adverse events will be coded using MedDRA. 
Treatment-Related AE: 
A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by the investigational product. 
For any variable, unless otherwise defined, baseline is the last assessment taken prior to 
the first investigational product administration. 
Baseline: 
For any variable, unless otherwise specified, the baseline value for 
parameters/assessments scheduled to be performed on the same day as the first 
administration of protocol specified therapy, is the last value measured before the first 
administration of protocol specified therapy 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 protocol specified therapy, the baseline value is the value from the 
screening period measured closest to the day of first administration of protocol specified 
therapy. In the event that multiple assessments are done on the same day as the first 
administration of protocol specified therapy and there is no time associated with the 
assessments, the value associated with the last clinically planned event before the first 
administration of protocol specified therapy will be used as the baseline value. 
Change from Baseline: 
Change from Baseline is the arithmetic difference between post-Baseline and 
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Change (percentage) from Baseline = [(Post-baseline Value – Baseline Value) / 
Baseline Value] x 100 
Cmax: 
Maximum concentration of AMG 596 


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Css: 
Steady-state drug concentration in serum during constant-rate infusion 
AUC0-t: 
It is defined as the area under the concentration-time curve from time 0 to t hours. 
Half-life (t1/2): 
The time required for the observed concentration of a drug to be reduced by one-half. 
Duration of Response: 
The number of days between the first tumor response assessment of an objective 
response (PR or CR) which is subsequently confirmed to the time of the first tumor 
response assessment of progressive disease or death if due to disease progression 
[date of first progressive disease assessment or death – date of first  objective response 
assessment +1].  This will be calculated only for those subjects who have a confirmed 
disease response based on a review of MRI scans. 
The following censoring strategies for missing assessment dates will be used for the 
duration of response: 
Subjects who respond (PR or better) and have not progressed while on study or not died 
will be censored at the date of assessment of the last evaluable response. 
Subjects who do not achieve an objective response will be excluded from analysis. 
Subjects who withdraw consent to participate in the study prior to achieving objective 
response will be censored at their last evaluable radiological assessment date. 
End of study: 
Primary Completion: 
The primary completion of study will occur when the last subject is assessed or receives 
an intervention for the purposes of final collection of data for the primary analysis.  (The 
primary analysis will occur when target enrollment in Part 1 and Part 2 is complete and 
each subject either completes 6 months on study or withdraws from the study.) 
End of Study: 
The time when the last subject is assessed or receives an intervention for evaluation in 
the study.  (The final analysis will occur at this time.) 


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Enrollment: 
A subject is considered enrolled after meeting all eligibility criteria and treatment and 
cohort have been assigned for the study. 
See protocol section 5.0 for further details. 
Investigational Product: 
The term investigational product is used in reference to AMG 596. 
Maximum Tolerated Dose (MTD): 
The MTD is defined as the maximum dose with the highest probability of the target 
toxicity probability interval (TPI), but with a less than 0.25 probability of an excessive or 
unacceptable TPI.  
The target TPI is (0.20, 0.33] and TPIs of (0.33, 0.60] and (0.60, 1.00] are defined as 
excessive and unacceptable, respectively. 
Overall Survival (OS): 
The number of days from the date of first administration of AMG 596 to the date of 
death, regardless of cause. 
Subjects who withdraw from treatment without withdrawing consent will be followed for 
survival status whenever possible.  Subjects who are alive (no record of death) and are 
lost to follow-up will be censored at the date of last contact. 
Objective Response (OR): 
Tumor response assessment of either complete response or partial response (CR or 
PR) per modified RANO criteria. 
Progression Free Survival (PFS): 
The number of days from the date of first administration of AMG 596 to the date of 
radiological evidence of disease progression (date of MRI scan) or death, regardless of 
cause. 
The following censoring strategies for missing assessment dates will be used for the 
progression free survival analysis: 
If a subject’s disease has not progressed and the subject is alive, progression-free 
survival time will be censored at the last date they are known to be progression-free (ie, 
the last evaluable radiological assessment date). 
If a subject has no tumor evaluation in the study, progression-free survival time will be 
censored at the date of the first administration of AMG 596. 


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Subjects who withdraw consent to participate in the study prior to disease progression 
will be censored at their last evaluable radiological assessment date. 
Response Criteria (per modified RANO): 
Complete Response (CR): 
• 
Disappearance of all enhancing disease  
• 
No new lesions  
• 
Stable or improved T2/FLAIR 
• 
No more than physiological steroids 
• 
Clinically stable or improved 
• 
Disappearance confirmed with follow-up scan after ≥4 weeks 
Partial Response (PR): 
• 
≥50% decrease in the sum of perpendicular diameters of enhancing disease from 
baseline 
• 
Stable or improved T2/FLAIR 
• 
Stable or decreased steroid dose 
• 
Clinically stable or improved 
• 
Decrease confirmed with follow-up scan after ≥ 4 weeks 
Stable Disease (SD): 
• 
Changes do not qualify for CR, PR or PD  
• 
Stable or improved T2/FLAIR 
• 
Stable or decreased steroid dose 
• 
Clinically stable or improved 
Progressive Disease (PD): 
Any of the below 
• 
≥ 25% increase in the sum of perpendicular diameters of enhancing disease from 
the lesser of baseline or nadir 
• 
Or substantially worsened T2/FLAIR  
• 
Or unequivocal progression in new lesions 
• 
Or substantial clinical decline  
• 
Increase confirmed with follow-up scan ≥ 4 weeks after initial observation. 
Screening Date: 
Screening date is defined as the date the informed consent was signed. 


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Study Day 1: 
Day 1 is defined as the first day that investigational product is administered to the 
subject.  The day before Day 1 is referenced as Day-1. 
Study Day: 
Post day of dose: study day = (study date - date of Study Day 1) + 1 
Pre day of dose: study day = (study date – date of Study Day 1) 
Time to Response: 
Time to response is calculated as the number of days from the date of first 
administration of AMG 596 to the date of confirmation of first objective response per MRI 
scan (date of confirmation of first objective response – date of first dose of AMG 596+1).   
If a subject did not respond, time to response will be censored at the date of the last 
evaluable response assessment. 
If a subject has no tumor evaluation related to response assessment as per modified 
RANO criteria, time to response will be censored at the date of the first administration of 
AMG 596. 
Time to Progression: 
Time to progression is calculated as the number of days from the date of first 
administration of AMG 596 to the initial date of radiographic progressive disease (PD) 
per MRI scan (Initial date of first PD – date of first dose of AMG 596+1).  
The following censoring strategies for missing assessment dates will be used for the 
time to progression: 
If a subject’s disease has not progressed , time to progression will be censored at the 
last date they are known to be progression-free (ie, the last evaluable radiological 
assessment date). 
If a subject has no tumor evaluation in the study, time to progression will be censored at 
the date of the first administration of AMG 596. 
Subjects who withdraw consent to participate in the study prior to disease progression 
will be censored at their last evaluable radiological assessment date. 
 


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6. 
Analysis Sets 
For all analyses, subjects will be analyzed according to the dose and treatment they 
received, not the dose and treatment to which they were assigned. 
Safety Analysis Set 
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 one 
administration of AMG 596. 
DLT Evaluable Analysis Set 
The DLT Evaluable Analysis Set will be used to summarize incidence of dose limiting 
toxicity (DLT).  Subjects are classified as DLT-evaluable if they have had the opportunity 
to complete the DLT period and:  
• 
Subject in the
cycle receiving a complete first cycle with 
100% of the planned doses of investigational product, or 
• 
Subject in the
cycle receiving at least 90% of the planned 
doses of investigational product  or 
• 
Subject that has experienced a DLT  
Pharmacokinetic Analysis Set 
The pharmacokinetic (PK) analysis set will contain all subjects for whom at least one PK 
parameter or endpoint can be adequately estimated. 
Efficacy Analysis Set 
All subjects that are enrolled and receive at least one administration of AMG 596 at the 
MTD will be included in the analysis of the secondary efficacy endpoints. 
RANO Evaluable Analysis Set 
All subjects that are enrolled and receive at least one administration of AMG 596 and 
who have at least one measurable lesion at baseline will be part of this analysis set. 
  
7. 
Planned Analyses 
There are 3 analyses (interim, primary and final) which are planned in the study. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Part 1 Dose Escalation:  
The DLRT will review the safety data after each cohort and make a decision on the next 
dose level to be explored for the estimate of RP2D/MTD based on a BLRM design.  The 
RP2D/MTD will be established separately for Group 1 (recurrent disease) and Group 2 


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(maintenance setting) subjects.  The interim analysis will include the establishment of 
RP2D/MTD and the estimate of ORR. 
• 
The first interim of safety data analysis in Part 1 dose escalation will happen at 
the earlier of  
− 
When 15 subjects enrolled and completed DLT observation or 
− 
Completion of dose escalation of Group 1.  Efficacy data will also be 
analyzed for subjects who have had at least one imaging evaluation after 
start of treatment or have dropped out before that. 
Part 2 Dose Expansion: 
Interim safety analyses during dose expansion will occur once 1) 5 subjects with 
recurrent disease have been enrolled and 2) after enrollment of 10 subjects with 
maintenance setting.  The BLRM will estimate the RP2D/MTD using available data from 
dose escalation and dose expansion.  Based on this revised RP2D/MTD estimate and 
reviewing all available safety data, the dose level for dose expansion may be revised. 
In Part 2 dose expansion, the ORR will be evaluated after treating n = 10 Group 2 
subjects for at least 6 months.  The futility will be assessed initially for N = 10 and 
continuously afterwards using a Bayesian predictive probability design.  Enrollment may 
be terminated if insufficient antitumor-activity is observed. 
For stopping rules, please. refer section 3.1 Study Design in the SAP. 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment in Part 1 and Part 2 is complete 
and each subject either completes 6 months on study or withdraws from the study. 
7.3 
Final Analysis 
A final analysis for each group is planned after all subjects in each group have ended the 
study (parts 1 and 2). 
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. 


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8.3 
Handling of Missing and Incomplete Data 
The following imputation of missing values will be done: 
• 
Incomplete adverse event and concomitant medication dates will be imputed as 
per Appendix A.  If imputed dates are used, then they will be identified as such in 
the final study report. 
• 
Non-pharmacokinetic measurements that are below the quantification limits will 
be considered equal to the lower limit of quantification for all analyses unless 
explicitly noted otherwise. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by listing important protocol violations by cohort and site. 
8.5 
Outliers 
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed.  If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version [9.3] or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, PD, efficacy 
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. 


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ORR will be presented with 80% Clopper-Pearson exact CI.  PFS will be summarized 
using Kaplan-Meier method.  Graphical summaries of the data may also be presented, 
eg. duration on study, changes in tumor load per time. 
9.2 
Subject Accountability 
A summary of subject disposition and investigational product disposition will be provided 
for all subjects enrolled in the study.  A subject disposition listing, noting inclusion in 
each analysis subset, will be provided for all subjects enrolled.  
A subject listing noting duration of investigational product administration, reason for 
discontinuation of treatment, and reason for discontinuing study will be provided.  A list 
of subjects screened but not enrolled (screen failures) will be provided.  
In addition, significant known protocol deviations will be noted for individual subjects; a 
summary table may also be provided. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
Descriptive statistics will be presented for age, height, weight. 
Frequency counts and percentage will be presented for gender, ethnic group, baseline 
disease stage, lines of prior oncology therapeutics, and primary tumor type. 
A listing of the demographic and baseline characteristics will be provided.  
Lists of medical/surgical history, including prior chemotherapy, will be provided. 
9.5 
Efficacy Analyses 
Unless otherwise specified, all subjects that are enrolled and receive at least one 
administration of AMG 596 at the MTD (the efficacy analysis set) will be included in the 
analysis of the secondary efficacy endpoints.  


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 The following methods will be used with Kaplan-Meier analyses of efficacy endpoints. 
• 
Estimation of the median and CI will use the Brookmeyer and Crowley (1982) 
method 
• 
Landmark estimates (eg, 6 month PFS) will be estimated using the Kaplan-Meier 
curve and CI using Greenwood’s formula to estimate the standard error (see 
Kalbfleisch J.D. and Prentice R.L. (1980) 
9.5.1 
Analyses of Efficacy Endpoint(s) 
Duration of Response: 
Descriptive statistics will be provided. As appropriate, duration of response will be 
analyzed using the Kaplan-Meier method.  Kaplan-Meier curves and estimates will be 
presented.  Subjects without an objective response are excluded from the analyses of 
this endpoint.  The median duration of response and other percentiles, as appropriate, 
and 80% CI will be presented. The percent of subjects with durable response at 6 and 
12 months along with 80% CI will be presented. 
Time to Response: 
Descriptive statistics will be provided. As appropriate, time to response will be analyzed 
using the Kaplan-Meier method.  Kaplan-Meier curves and estimates will be presented.  
The median time to response and other percentiles, as appropriate, and 80% CI will be 
presented.  
Time to progression: 
Time to progression will be analyzed using the Kaplan-Meier method.  Kaplan-Meier 
curves and estimates will be presented.  The median time to progression and other 
percentiles, as appropriate, and 80% CI will be presented. The percent of subjects who 
are progression-free at 6 and 12 months along with 80% CI will be presented. 
Objective Response Rate: 
Objective Response Rate will be analyzed using RANO Evaluable Analysis Set.  
The number and proportion of patients with an objective response will be tabulated by 
AMG 596 dose received (MTD or other doses).  An exact 80% confidence interval will be 
calculated using Clopper-Pearson method (Clopper and Pearson, 1934. See Appendix B 
for code fragment) for the OR rate for all subjects in part 2 and those in part 1 treated at 
RP2D/MTD for each group.   


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Progression Free Survival: 
Progression free survival (PFS) will be analyzed using the Kaplan-Meier method.  
Kaplan-Meier progression free survival curves and estimates will be presented.  The 
median PFS and other percentiles, as appropriate, and 80% CI will be presented. The 
percentage of subjects alive and progression-free at 6 and 12 months along with 80% CI 
will be presented. 
Response Criteria: 
Response criteria will be analyzed using RANO Evaluable Analysis Set.  
The number and percentage of subjects in each response category (CR, PR, SD and 
PD) will be tabulated by AMG 596 dose received (MTD or other doses). 
    
9.6 
Safety Analyses 
   
9.6.1 
Adverse Events and Disease-related Events 
  
The Medical Dictionary for Regulatory Activities (MedDRA) version [21.1] or later will be 
used to code all events categorized as adverse events, disease-related events, to a 
system organ class and a preferred term. 
Treatment-emergent adverse events are events with an onset after the administration of 
the first dose of investigational product.  
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, disease related adverse events, adverse 
events leading to withdrawal of investigational product , and fatal adverse events, 
adverse events of interest (if applicable).  The identification of adverse events of special 
interest is a continuous process.  Events may be identified and documented as the 
safety profile of the drug is characterized.  The severity of each adverse event will be 
graded using CTCAE version 4.0 criteria.  Grading for Cytokine Release Syndrome 
(CRS) will be performed according to the recommendations provided by Lee et al, 2014 
(Appendix E of the protocol). 
Subject incidence of all treatment-emergent, serious, treatment-related, serious 
treatment-related, those leading to withdrawal of investigational product, and fatal 
adverse events will be tabulated by system organ class and preferred term in 
descending order of frequency.  
Where appropriate the tables will also be presented by worst grade. 


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The above adverse event tables will not be created if two or fewer subjects experience 
the adverse event. 
Details of each adverse event will be listed.  Listings and/or narratives of any on-study 
deaths, serious and significant treatment-emergent adverse events, including early 
withdrawals due to adverse events, also will be provided should they occur. 
Dose Limiting Toxicities (DLT) 
The probability of each TPI and of a DLT from the BLRM will be summarized by dose 
and group along with the estimated dose-toxicity curve.  Subject incidence of DLT by 
dose level and group will be summarized. 
As a sensitivity analysis, a one-parameter Continual Reassessment Method (CRM) 
model may be used to estimate the dose-toxicity relationship to help making dose 
escalation decisions. 
Disease-Related Event (DREs) 
Safety endpoints (eg, mortality and morbidity) that are study endpoints are reported on 
an eCRF.  A negatively adjudicated safety endpoint will be reported to the investigator 
and treated by Amgen as appropriate.  This could include no action, or a report on the 
eCRF as a Disease-Related event, an adverse event, or a serious adverse event. 
9.6.2 
Laboratory Test Results 
The number and percentage of subjects experiencing clinically significant worsening in 
serum chemistry, serum hematology, and coagulation labs will be presented overall for 
all subjects receiving investigational product.  Clinically significant worsening is based on 
grade shifts using CTCAE version 4.0.  Two tables will present these overall summaries. 
1. For each laboratory toxicity with a worst grade of 3 or 4 in at least one subject, 
the number and percentage of subjects experiencing this laboratory toxicity at 
any grade, worst grade 3, and worst grade 4 will be presented.  The direction of 
the laboratory worsening will be denoted (eg, decrease in platelets, increase or 
decrease in magnesium). 
2. If required, laboratory parameters with a post-dose shift in at least one subject, 
the number and percentage of subjects experiencing a one grade shift, two grade 
shift, three grade shift, and four grade shift post-dose will be presented.  The 
direction of the laboratory worsening will be denoted.  
All laboratory data will be listed for the subject and laboratory of interest in order to 
provide proper context.  Values outside the normal laboratory reference ranges will be 
flagged as high or low on the listings. 
  


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9.6.3 
Vital Signs 
Vital signs data will be listed and reviewed for each subject.  Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline 
over time may be provided. 
9.6.4 
Performance Status Score 
Shifts in scores for ECOG scores between baseline and each assessed time point will 
be tabulated and ECOG performance status scores will also be summarized at each 
assessed time point. 
9.6.5 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. 
Subjects’ maximum change from baseline in QTc will be categorized and the number 
and percentage of subjects in each group will be summarized. 
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized. 
All on-study ECG data will be listed, and select parameters of interest may be plotted.  
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 
provided, and these data would not be expected to be useful for meta-analysis with data 
from other trials.  
  
9.6.7 
Exposure to Investigational Product 
Descriptive statistics will be presented summarizing the following: the number of doses 
of investigational product, the total (cumulative dose) and total dose per cycle.  


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The duration of
of infusion and the maximum/minimum/average 
infusion duration post
of infusion will also be summarized in 
hours and days separately. 
Details for each AMG 596 administration including dose interruption and dose delay will 
be listed for every subject. 
  
  
  
9.6.8 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary.  A subject listing of all prior 
and concomitant medications ((including total dexamethasone and total dexamethasone 
per cycle) will be presented. 
  
9.7 
Other Analyses 
   
9.7.1 
Analyses of Pharmacokinetic Endpoints 
The PK parameters of AMG 596 including, but not limited to, 
 
 
 will be estimated using 
non-compartmental methods and summarized by dose level using means, standard 
deviations, medians, minimums, and maximums.  
 
  Summary statistics will be computed for each 
sampling time and parameter as appropriate. 
9.7.2 
Analyses of Biomarker Endpoints 


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9.7.3 
Immunogenicity 
The impact of immunogenicity on safety will also be reviewed by assessing adverse 
events and serious adverse events. 
  
  
  
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


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11. 
Literature Citations / References 
SAS Institute Inc. SAS Language: version 8 first edition. SAS Institute, Inc, Cary, 
NC,USA, 1990. 
Zhou, Y and Whitehead, J. Bayesian ADEPT: Operating manual. The University of 
reading (2002). 
Collett, D. Modeling Survival Data In Medical Research, London: Chapman and Hall 
1994.Neuenschwander, B., M. Branson and T. Gsponer. "Critical aspects of the 
Bayesian approach to phase I cancer trials." Stat Med 2008;27(13): 2420-2439. 
Lee, Bioinformatics. 2008 Nov 1;24(21):2542-3. 
Lee, D. W., R. Gardner, D. L. Porter, C. U. Louis, N. Ahmed, M. Jensen, S. A. Grupp 
and C. L. Mackall. "Current concepts in the diagnosis and management of cytokine 
release syndrome." Blood 2014;124(2): 188-195. 
Okada, H., M. Weller, R. Huang, G. Finocchiaro, M. R. Gilbert, W. Wick, B. M. Ellingson, 
N. Hashimoto, I. F. Pollack, A. A. Brandes, E. Franceschi, C. Herold-Mende, L. Nayak, 
A. Panigrahy, W. B. Pope, R. Prins, J. H. Sampson, P. Y. Wen and D. A. Reardon. 
"Immunotherapy response assessment in neuro-oncology: a report of the RANO working  
group." Lancet Oncol 2015;16(15): e534-542. 
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., & 
Carbone, P. P. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol, 1982;5(6), 649-655. 
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometricka. 1934;26:404-413. 
Brookmeyer, R. and Crowley, J. (1982) A Confidence Interval for the Median Survival 
Time, Biometrics, 38, 29 - 41. 
Kalbfleisch, J.D. and Prentice, R.L. (1980) The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons. 
 


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12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data not Covered by This Plan 
Exploratory data not included in this plan may be analyzed at a later date or may be 
analyzed by a different Amgen Department. 


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14. 
Appendices 


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Appendix A.  Handling of Missing or Incomplete Dates for Adverse Events and 
Concomitant Medications 
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 
Equal to 1st 
Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
Not equal 
to 1st Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
Equal to 1st 
Dose 
yyyymm 
3 
1 
3 
1 
N/A 
1 
1 
Not equal 
to 1st Dose 
yyyymm 
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. 


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


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Appendix D.  Modified Response Assessment In Neuro-Oncology (RANO) 
The RANO criteria are extentions to the Macdonald criteria that incorporate T2/ FLAIR 
images to better capture lesion response.  Here, the RANO criteria are further modified 
to capture pseudoprogression and delayed responses which may be observed in 
response to immunotherapies (Okada et al, 2015).   
Patients require at least 1 bi-dimensionally measurable contrast-enhancing lesion that 
can be accurately assessed at baseline by magnetic resonance imaging (MRI) to be 
included in this a study.  
Definitions: 
• 
Measurable lesions contrast-enhancing lesions that can accurately be measured 
bidimensionally with ≥10mm longest diameter and ≥ 10mm perpendicular 
diameter and noted on more than one imaging slice. 
• 
Non-measurable lesions – all other lesions, including small lesions, ie, bone 
lesions, leptomeningeal disease and cystic lesions that are not confirmed and 
followed by imaging techniques. 
Documentation of index and non-index lesions: 
• 
Index Lesions 
− 
All measureable lesions (up to 5) should be identified as index lesions, 
measured and recorded during screening. 
− 
Enhancing lesions should be selected based on size (largest cross sectional 
area) and suitability for accurate repeat measure (clearly defined borders) 
− 
The sum of bidimensional products (total cross-sectional area of measurable 
lesions) for all enhancing measurable lesions at screening will be calculated 
and reported as the baseline disease burden.   
− 
Baseline disease burden will be the reference used to characterize 
radiographic objective tumor response.  
− 
Baseline or nadir, whichever is smaller, is used to calculate PD. 
• 
Non-Index Lesions 
− 
All other lesions (or sites of disease) should be identified and recorded as 
non-index lesions during screening.   
− 
Measurable lesions located in previously irradiated sites that have not since 
shown documented progression are non-index lesions. 
− 
Incidental new lesions will be recorded and tracked as non-index lesions. 
− 
Measurement of non-index lesions is not required, but absence or presence 
and qualitative changes (unequivocal response, stable, unequivocal 
progression) should be recorded throughout the study. 


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Table of Measurement Summary 
Imaging modality 
MRI  
Sequences for this protocol 
- 
Axial Pre Contrast (2D) T1 
- 
Axial T2/FLAIR 
- 
Axial T2 
- 
Axial Post Contrast (2D) T1 
- 
Axial DWI (at selected sites) 
- 
Sagittal Post Contrast (3D) T1 (at selected sites) 
Measurement technique 
Bidimensional; sum of products of perpendicular diameters 
Imaging intervals 
Screening, every 10-12 weeks, SFUP, LTFU 
Measurable lesions  
Contrast-enhancing lesions with ≥ 10mm longest diameter 
and ≥ 10mm perpendicular diameter 
Measurable disease 
One to five index lesions 
Table of Response Assessment 
All % changes are calculated as change from baseline burden, except PD which is 
baseline or nadir. 
Complete response (CR) 
• 
Disappearance of all enhancing disease  
• 
no new lesions  
• 
stable or improved T2/FLAIR 
• 
no more than physiological steroids 
• 
clinically stable or improved 
• 
Disappearance confirmed with follow-up scan after 
≥ 4 weeks 
Partial response (PR) 
• 
≥ 50% decrease in the sum of perpendicular 
diameters of enhancing disease from baseline 
• 
stable or improved T2/FLAIR 
• 
stable or decreased steroid dose 
• 
clinically stable or improved 
• 
Decrease confirmed with follow-up scan after 
≥ 4 weeks 
Stable disease (SD) 
• 
Changes do not qualify for CR, PR or PD  
• 
stable or improved T2/FLAIR 
• 
stable or decreased steroid dose 
• 
clinically stable or improved 
Progressive disease (PD) 
• 
Any of the below 
• 
≥ 25% increase in the sum of perpendicular 
diameters of enhancing disease from the lesser of 
baseline or nadir 
• 
or substantially worsened T2/FLAIR  
• 
or unequivocal progression in new lesions 
• 
or substantial clinical decline  
• 
Increase confirmed with follow-up scan ≥ 4 weeks 
after initial observation.   


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Reponses (CR and PR) are dated at time of confirmation scan. 
Progression (PD) is backdated to initial observation, if confirmed. 
Patients with a neurological decline attributable to their underlying tumor requiring 
discontinuation of treatment without objective evidence of measurable radiographic 
disease progression at that time should be classifies as having “clinical deterioration.” 
Every effort should be made to document the radiographic progression even after 
discontinuation of treatment. 


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Appendix E.  Grading and Management of Cytokine Release Syndrome (CRS)  
  
CRS 
Grade 
Description of Severitya 
Minimum Expected  
Intervention 
Instructions for 
Interruption of AMG 596 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
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 
earlier. 
N/A 
2 
Symptoms require and 
respond to moderate 
intervention 
Oxygen requirement 
< 40%, OR 
Hypotension responsive to 
fluids or low dose of one 
vasopressor, OR  
Grade 2 organ toxicity or 
grade 3 transaminitis per 
CTCAE criteria 
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. 
For subjects with extensive 
co-morbidities or poor 
performance status, 
manage per grade 3 CRS 
guidance below. 
Immediately interrupt 
AMG 596 until event 
resolves to CRS grade ≤ 1 
but for no less than 
72 hours. 
Permanently discontinue 
AMG 596 if there is no 
improvement to CRS 
≤ grade 1 within 7 days. 
Page 1 of 2 
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 
 


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CRS 
Grade 
Description of Severitya 
Minimum Expected  
Intervention 
Instructions for 
Interruption of AMG 596 
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 
Admit to intensive care unit 
for close clinical and vital 
sign monitoring per 
institutional guidelines. 
Administer 
dexamethasone (or 
equivalent) IV at a dose  
maximum of 3 doses of 
8 mg (24 mg/day).  The 
dose should then be 
reduced step-wise. 
Investigators may also 
consider use of 
Tocilizumab as an 
additional therapy in this 
setting at a dose of 
4-8 mg/kg as a single 
dose. 
Immediately interrupt 
AMG 596 until event 
resolves to CRS grade ≤ 1 
but for no less than 
72 hours. 
Permanently discontinue 
AMG 596 if there is no 
improvement to CRS 
≤ grade 2 within 5 days or 
CRS ≤ grade 1 within 
7 days. 
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 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, Tocilizumab 
can be considered 
administered at a dose of 
4-8 mg/kg as a single dose 
and may be repeated once 
within 24 to 48 hours 
based on clinical 
assessment. 
Immediately stop the 
infusion and permanently 
discontinue AMG 596 
therapy. 
Page 2 of 2 
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 


Product:  AMG 596  
Protocol Number:  20160132 
Date:  20 May 2019 
Page 49 of 49 
 
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)