Ferumoxytol MRI in Assessing Response to Pembrolizumab in Patients With Brain Tumors From Melanoma and Glioblastoma

PRIMARY OBJECTIVES:

I. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV)
measured by steady state MRI with ferumoxytol in identifying true versus (vs)
pseudoprogression in melanoma patients with brain metastases that receive pembrolizumab with
standard of care stereotactic radiosurgery. (Arm 1) II. Determine the sensitivity and
specificity of relative cerebral blood volume (rCBV) measured by steady state MRI with
ferumoxytol in identifying true vs pseudoprogression in patients with newly diagnosed
glioblastoma multiforme (GBM) receiving pembrolizumab with standard of care chemo-radiation.
(Arm 2)

SECONDARY OBJECTIVES:

I. Determine the safety and toxicity of pembrolizumab when used in combination with standard
of care stereotactic radiation (arm 1) and chemo radiation (arm 2).

II. Determine the progression free survival (PFS), overall survival (OS), clinical response
and duration of best response for each arm.

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 (serum biomarker) and correlate clinical
as well as radiological response with systemic immune response to pembrolizumab as measured
by immunological panel.

III. Compare the changes in PDL-1 expression in the biopsy tissue before and after therapy at
the time of progression and correlate PD-L1 expression with response rates and survival.

IV. 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 determined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1
and immune related response criteria [irRC]).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 3 weeks for up to 2 years or 35 courses in the absence of disease progression or
unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI scans at
baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or
chemoradiotherapy, at suspected radiographic progression, and within 4 weeks from 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 life expectancy of at least 6 months

- Have a histologically confirmed diagnosis of:

- Arm 1: melanoma, with =< 5 measurable (as defined by Response Assessment in
Neuro-Oncology-Bone Marrow [RANO-BM]) new brain metastases clinically eligible
for stereotactic radiosurgery (SRS); tissue diagnosis of the brain metastasis is
not required for enrollment if history and imaging is consistent with melanoma
and a histopathology is available from the systemic disease; however, a biopsy or
surgical excision of one or more of the brain lesions may be performed, if
clinically indicated; patient must consent to providing 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

- Arm 2: newly diagnosed glioblastoma (World Health Organization [WHO] grade IV)

- Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 on stable
or reducing dose of steroids for symptom management (not more than 8 mg of
dexamethasone or equivalent per day) for 5 days prior to enrollment; change in
glucocorticoid dose for any purpose other than to modulate symptoms from an adverse
event; Note: The use of physiologic doses (e.g., prednisone 10 mg) of corticosteroids
may be approved after consultation with Merck & Co; use of prophylactic
corticosteroids to avoid allergic reactions (e.g. IV contrast dye) is permitted

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

- 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) OR 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 glutamic pyruvic 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 time (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 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, including but not limited to, abstinence from heterosexual
activity starting with the first dose of study therapy through 120 days after the last
dose of study therapy

- 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

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

- ARM I INCLUSION CRITERIA: Subject is eligible for and agrees to receive standard of
care stereotactic radio surgery with or without prior neuro-surgical intervention

- ARM I INCLUSION CRITERIA: There are no restrictions on the number of prior lines of
treatment for systemic disease

- ARM I INCLUSION CRITERIA: If subjects have known brain metastases (mets) that were
treated previously with local therapies, surgery, and/or radiation, these lesions must
be stable for at least 30 days prior to enrollment

- ARM I INCLUSION CRITERIA: Subjects are currently on checkpoint inhibitor (anti-PD-1,
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated
antigen-4 (CTLA-4) antibody, or antibodies to tumor necrosis factor family including
OX40) or tumor vaccine for systemic disease who develop new brain metastases, must
have documented stable systemic disease within 30 days of signing consent

- ARM I INCLUSION CRITERIA: Subjects who have completed prior checkpoint inhibitor
(anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or antibodies to tumor necrosis
factor family including OX40) or tumor vaccine for systemic disease but are now off
therapy with documented stable systemic disease within 30 days of signing consent may
be enrolled after discussion with the Merck & Co clinical team

- ARM II INCLUSION CRITERIA: Subject is eligible for and agrees to receive standard of
care radiation and temozolamide after biopsy or maximum safe surgical resection

Exclusion Criteria:

- 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

- Evidence of leptomeningeal disease on MRI or in cerebrospinal fluid (CSF) for arm 1;
ocular or mucosal disease specifically for patients with melanoma in arm 1

- Has a diagnosis of immunodeficiency including human immunodeficiency virus (HIV) (HIV
1/2 antibodies) and is not on continuous daily immunosuppressive therapy within 7 days
prior to the first dose of trial treatment; (an exception to this is the use of
steroids for brain edema and resulting symptom); subjects may receive a stable or
reducing dose of steroids (up to 8 mg dexamethasone or equivalent for at least 5 days
prior to signing consent) to prevent or manage cerebral edema; subjects requiring over
8mg of dexamethasone per day on or five days prior to signing consent are excluded)

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

- 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

- 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: 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 (e.g. 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 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 (Ferumoxytol Investigator?s Drug Brochure, 2009); subjects with
significant drug or other allergies or autoimmune diseases may be enrolled at the
investigator?s discretion

- Subjects who have a contraindication for 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

- ARM I EXCLUSION CRITERIA: Any evidence of progressive systemic disease (by RECIST
1.1); those with stable systemic lesion(s) may be considered for enrollment