Phase 1/1b 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)

Glioblastomas or malignant gliomas 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. Furthermore,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 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 Moreover, no survival benefit has
since been demonstrated for any new agent in a randomized trial. With the
current study, a new immunotherapeutic option will be explored. After
establishing the maximum tolerated dose (MTD) or recommended phase 2 dose
(RP2D) in the recurrent setting, the safety and tolerability of AMG 596 will be
further explored as a maintenance therapy following adjuvant radiochemotherapy
after initial surgery assuming that subjects with lower disease burden may
better tolerate treatment.

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):
*
* Evaluate the pharmacokinetics (PK) of AMG 596 and AMG 404 in cerebrospinal
fluid (CSF)
* Evaluate pharmacodynamic evidence and biological impact of AMG 596 in
monotherapy and in combination with AMG 404 by characterization of eg, changes
in cytokine levels and other soluble factors as a result of T-cell activation
in peripheral blood and CSF, cellular changes in tumor tissue, changes in
expression of EGFRvIII and related markers
* Evaluate the formation and incidence of anti-AMG 596 and anti-AMG 404
antibodies

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 595 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 day 1 to day 7 of AMG 596
infusion and (2) DLT period 2 for day 8 to day 28 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
(e.g., 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 4.5 µg/day. Further pre-specified nominal AMG 596 doses for
potential use in any dose escalation Arms are 15, 45, 150, 500, 1000, 1500,
3000, 6000, 12000 *g/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 >
12000 *g/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.

Group 1, Recurrent Disease
AMG596 monotherapy (Arm 1)
* Dose Escalation in single subject cohorts:
o In first cohorts AMG 596 will be administered as a cIV infusion for 7-day
on/7-day off 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 7-day
on/7-day off cycles until discontinuation criteria apply.
o Combination of AMG 596 and AMG 404: The starting dose of AMG 596 is 15
ug/day administered in 28 days on, 14 days off cycles
and the defined AMG 404 dose is 480 mg every 4 weeks.
o 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:
o Subjects in the first multiple subject cohort receive the same dose as
the last single subject cohort
o All subjects receive AMG 596 in 28 days on, 14 days offinfusion 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

AMG 596 and AMG 404 Combination Therapy (Arm 2)
The starting dose of AMG 596 is 15 ug/day administered in 28 days on, 14 days
off cycles and
the defined AMG 404 dose is 480 mg every 4 weeks. Combination therapy will
start with multiple
subject cohorts N=2-4. BLRM will be used to guide dose selection with the same
model described
previously in the section for Arm 1.
Dose escalation to Arm 2 will be completed when any of the following occurs:
* -The maximum total sample size of N=40 DLT evaluable subjects is reached
* -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

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 28-day
flat dose AMG 596 cIV infusion or step-dosing as established
for recurrent disease. Further treatment cycles with 14-day breaks 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 480 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).

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: *4 grade 4 or higher treatment-related adverse events for 10
enrolled subjects, *6 grade 4 or higher treatment-related adverse events for 20
enrolled subjects, *9 grade 4 or higher treatment-related adverse events for 30
enrolled subjects and study is complete at 35 enrolled subjects. 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 (e.g.
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.
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.

Please refer to protocol section 3.1.

All subjects will be hospitalized for the following periods:
Cycle 1:
* For the first 7 days of AMG 596 monotherapy (Arm 1)
* For the first 8 days of AMG 596 in combination with AMG 404 (Arm 2), hence
AMG 404 will be administered on day 8
* 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 day
36 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
day 36 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.

All subjects will be hospitalized for the following periods:
Cycle 1:
* For the first 7 days of AMG 596 monotherapy (Arm 1)
* For the first 8 days of AMG 596 in combination with AMG 404 (Arm 2), hence
AMG 404 will be administered on day 8
* 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 day
36 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
day 36 onwards.

For risks, see E9