Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases

PRIMARY OBJECTIVE:

I. To determine the safety of three different stereotactic radiosurgery (SRS) radiation arms
in combination with pembrolizumab for melanoma and non-small cell lung cancer (NSCLC) brain
metastasis (BM) patients.

SECONDARY OBJECTIVES:

I. To evaluate intracranial outcomes - control of the treated lesion in the brain with SRS+
pembrolizumab (i.e. local control), development of additional sites of disease in the brain
that were not initially treated with SRS (i.e. anywhere intra-cranial failure), intra-cranial
progression free survival (local control of the area that received SRS and anywhere
intra-cranial failure), extra-cranial disease response (overall progression free survival),
rate of leptomeningeal dissemination, and overall survival.

II. To determine the overall response rate and overall survival of combination SRS and
pembrolizumab compared to SRS alone (historical control).

III. To determine the overall response rate and overall survival of combination SRS and
pembrolizumab compared to pembrolizumab alone (historical control).

IV. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the
abscopal effect) with all three arms.

V. To compare differences in potential immune biomarkers, pretreatment, during treatment, and
post treatment.

OUTLINE: Patients are assigned to 1 of 3 arms.

ARM A (SRS 6 Gy): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Courses repeat every 3 weeks (Q3W) for at least 2 years in the absence of disease progression
or unacceptable toxicity. Patients undergo 5 SRS fractions between days 2-15 of course 1.

ARM B (SRS 9 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 3 SRS
fractions between days 2-15 of course 1.

ARM C (SRS 18-21 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 1 SRS
fraction between days 2-3 of course 1.

After completion of study treatment, patients are followed up every 12 weeks or at
physician's discretion by radiologic imaging to monitor disease.

Inclusion Criteria:

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

- Eastern Cooperative Oncology Group (ECOG) performance scale (PS) of 0-1; Karnofsky
performance status ≥ 70%

- Patients must have histological diagnosis of melanoma or non-small cell lung cancer
(biopsy will be done per standard of care, if needed to prove metastatic melanoma
and/or NSCLC as well as for clinically relevant mutation analysis); additional biopsy
will be per standard of care

- Patients can be treated either in first line or in the refractory setting; programmed
death-ligand 1 (PD-L1) positivity is not required for enrollment

- All melanoma patients may be tested for proto-oncogene B-Raf (BRAF) as part of routine
standard of care, but is not a requirement for the trial; all NSCLC patients may be
tested for with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase
(ALK) as part of standard of care, but is not a requirement of the trial

- Having gotten prior programmed cell death protein 1 (PD1) therapy is allowed for,
especially if they have previously progressed on it; progression may include
extra-cranial as well as intra-cranial progression; after progressing on PD1 therapy,
intervening chemotherapy and/or targeted therapy (BRAF inhibitors [BRAFi], etc) is
allowed; if they are on intervening chemotherapy and/or targeted therapy (BRAFi, etc),
they have to have progression intra-cranially and/or extra-cranially and must be off
intervening therapy for at least 2 weeks

- Patient must be asymptomatic at time of getting SRS (day 0) on trial; prednisone <
10mg/day for at least 7 days prior to treatment is allowed

- Patients with ocular, mucosal and unknown primary melanoma will also be eligible

- Patients with 1-10 untreated brain metastases at time of initial brain metastases
diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for
diagnostic purposes and/or for standard of care purposes is acceptable)

- Largest brain metastases volume measures less than 14.15 cc³

- Prior radiation to the primary and/or regional radiotherapy for melanoma and/or NSCLC
is acceptable

- Baseline labs as within standard of care (complete blood count [CBC], basic metabolic
panel [BMP], lactate dehydrogenase [LDH], erythrocyte sedimentation rate [ESR], etc)
are required within 14 days of enrollment

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

- Patients must have at least 14 days to recover from all prior treatment, including
surgery, chemotherapy, immunotherapies, prior to enrollment on this protocol

- Demonstrate adequate organ function, all screening labs should be performed within 14
days of treatment initiation

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

- Platelets ≥ 100,000/microliters (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 (creatinine clearance should be
calculated per institutional standard)

- 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 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 subject of childbearing potential should have a negative urine or serum
pregnancy within 2 weeks 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

- Abstinence is acceptable, if this is the usual life style and preferred
contraception for the patient

Exclusion Criteria:

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- If they have brain metastases located in the brain stem (including midbrain, pons, or
medulla)

- Inability to undergo magnetic resonance imaging (MRI) evaluation for treatment
planning and follow-up

- 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 a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

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

- Hypersensitivity to pembrolizumab or any of its recipients

- 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 (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 (non-infectious) pneumonitis that required steroids or current
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 specific 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