Pembrolizumab and Magnetic Resonance Imaging With Ferumoxytol in Treating Patients With Non-small Cell Lung Cancer and Brain Metastases

PRIMARY OBJECTIVES:

I. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV)
measured by steady state magnetic resonance imaging (MRI) with ferumoxytol in predicting true
vs pseudoprogression after stereotactic radiosurgery (SRS) and intravenous (IV) pembrolizumab
in subjects with brain metastases from non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. Evaluate the safety and tolerability of pembrolizumab when given with SRS in subjects with
brain metastasis.

II. Evaluate progression free survival, overall survival, best response in brain disease,
best response in systemic disease, and duration of best responses of brain and systematic
diseases.

TERTIARY OBJECTIVES:

I. Compare the immune response as determined by the volume, pattern and intensity of delayed
(24 hour [hr]) ferumoxytol uptake between subjects who develop true vs pseudoprogression.

II. Investigate the serum immunological parameters and correlate clinical as well as
radiological response with systemic immune response to pembrolizumab as measured by
immunological panel.

III. Compare the changes percentage expression in PDL-1 in the biopsy tissue before and after
therapy at the time of progression.

IV. In subjects with measurable systemic lesions, investigate the feasibility of measuring
vascular volume fraction (VVF), vessel size index (VSI) and vessel density index (VDI) as
surrogate for response (true vs. pseudoprogression, as measured with Response Evaluation
Criteria in Solid Tumors [RECIST] 1.1 criteria).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat
every 3 weeks for up to 2 years (or up to 32 courses) in the absence of disease progression
or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI at baseline,
12 weeks after radiation, at suspected radiographic progression, and 6 weeks after suspected
radiographic progression.

After completion of study treatment, patients are followed up at 30 days, every 12 weeks for
up to 1 year, and then every 6 months thereafter.

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial

- Have a histologically confirmed diagnosis of NSCLC

- Have up to five measurable (by Response Assessment in Neuro-Oncology Criteria [RANO])
brain metastasis planned for stereotactic radiosurgery

- Subjects should have PD-L1 expression (tumor proportion score [TPS] >= 50%, determined
by the Food and Drug Administration [FDA] approved Merck 22C3 antibody PD-L1 test) in
the first-line setting and have a TPS > 1% by 22C3 or equivalent PD-L1 expression by
an approved immunohistochemistry (IHC) test, in the second-line setting in order to be
eligible for pembrolizumab treatment on the current protocol; patients with < 1% PD-L1
expression are not eligible

- Subjects may already be receiving PD-(L)1 (including pembrolizumab or other PD-[L]1
inhibitors such as nivolumab, atezolizumab, avelumab, durvalumab) for the treatment of
systemic disease; systemic disease must be in complete remission or be stable by
RECIST 1.1; a washout period of at least 3 weeks is required from the last dose of
PD-(L)1 inhibitor

- Subjects with EGFR or ALK genomic tumor aberrations should have documented disease
progression on FDA-approved therapy for these aberrations; subjects with EGFR or ALK
genomic tumor aberrations who develop isolated brain metastases with good response
outside the central nervous system (CNS) while on FDA-approved therapy for these
aberrations may be included at the discretion of the treating oncologist

- Be willing to provide tissue from archival biopsy tissue or newly obtained excisional
biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 6
weeks (42 days) prior to initiation of treatment on day 1

- At least 30 days from any major surgeries including brain biopsy and have complete
resolution of its effects

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >= 1,500 /mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment)

- Serum creatinine =< 1.5 X upper limit of normal (ULN) measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases

- Albumin >= 2.5 mg/dL

- International normalized ratio (INR) or prothrombin rime (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; if
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year; male subjects should agree to use an adequate
method of contraception starting with the first dose of study therapy through 120 days
after the last dose of study therapy

- Subject may also provide consent/assent for future correlative research; subjects may
participate in the main trial without participating in future correlative research

Exclusion Criteria:

- Has any evidence of progressive systemic disease (by RECIST 1.1); those with stable
systemic lesion may be considered for enrollment

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment

- Has evidence of leptomeningeal disease on MRI or in cerebrospinal fluid (CSF)

- If tumor demonstrates EGFR or ALK genomic tumor aberrations, subject should have
documented disease progression on FDA-approved therapy for these aberrations

- Has a diagnosis of immunodeficiency and is not on continuous daily immunosuppressive
therapy within 7 days prior to the first dose of trial treatment; (subjects may
receive steroids before or after SRS to prevent or manage cerebral edema; inhalational
steroids are permitted)

- Has previously progressed on a PD-1 or PD-L1 checkpoint inhibitor for systemic disease

- Has a known history of active TB (Bacillus tuberculosis)

- Has hypersensitivity to pembrolizumab, gadolinium, or ferumoxytol or any of their
excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Note: The use of denosumab is an exception to this criterion

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered agent

- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: Subjects with =< grade 2 hematologic toxicities are an exception to this
criterion and may qualify for the study

- Note: Subjects with =< grade 2 fatigue are an exception to this criterion and may
qualify for the study

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject?s
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Has received a live vaccine within 30 days of planned start of study therapy

- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed

- Subjects with clinically significant signs of uncal herniation, such as acute
pupillary enlargement, rapidly developing motor changes (over hours), or rapidly
decreasing level of consciousness, are not eligible

- Subjects with known allergic or hypersensitivity reactions to parenteral iron,
parenteral dextran, parenteral iron-dextran, or parenteral iron-polysaccharide
preparations; subjects with significant drug or other allergies or autoimmune diseases
may be enrolled at the investigator?s discretion

- Subjects who have a contraindication for 3 tesla (3T) MRI: metal in their bodies (a
cardiac pacemaker or other incompatible device), are severely agitated, or have an
allergy to gadolinium containing contrast material

- Subjects with known iron overload (genetic hemochromatosis); in subjects with a family
history of hemochromatosis, hemochromatosis must be ruled out prior to study entry
with normal values of the following blood tests: transferrin saturation (TS) test and
serum ferritin (SF) test; all associated costs will be paid by the study

- Subject who have received ferumoxytol within 3 weeks of study entry

- Subjects with three or more drug allergies from separate drug classes