Targeting PD-1 Therapy Resistance With Focused High or High and Low Dose Radiation in SCCHN

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational treatment to learn whether the treatment works in
treating a specific disease. "Investigational" means that the treatment is being studied.

MK-3475 is a humanized monoclonal antibody. An antibody is a common type of protein made in
the body in response to a foreign substance (particles not typically found in the body such
as bacteria or viruses). Antibodies attack foreign substances and protect against infection.
Antibodies can also be produced in the laboratory for use in treating patients. MK-3475 is
designed to restore the natural ability of the immune system to recognize and target cancer
cells.

The FDA recently granted approval to MK-3475 as a treatment for patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC). This study is testing whether using
radiation in combination with MK-3475 will make this drug work better in participants that
might otherwise be unlikely to benefit from this drug because they have not responded to
either this same drug given without radiation or another similar drug.

Inclusion Criteria:

- Pathologically confirmed squamous cell carcinoma of the head and neck with evidence of
metastatic disease considered incurable by local therapies. Patients without
pathologic or cytologic evidence of metastatic disease should have unequivocal
evidence of metastasis from physical examination or radiologic evaluation.

- Patients must have evidence of radiologic or clinical disease progression during
previous treatment with systemic PD-1 directed therapy, or have stable disease on
prior PD-1 therapy (at least 6 doses) and/or have been deemed not to derive clinical
benefit from PD-1 directed treatment.

- Patients must have least 3 measurable non-CNS based lesions that have not previously
been irradiated. Palliative radiation must be potentially indicated for at least one
of these lesions.

- Patients must agree to undergo a research biopsy, if tumor is accessible, at baseline
(mandatory) and at the end of cycle 2 of pembrolizumab (optional). .

- Prior systemic therapy: Patients must be at least 2 weeks from prior chemotherapy,
biological agents, immunotherapy or any investigational drug product, with adequate
recovery of toxicity. For investigational agents, the minimum time from prior therapy
is 5 half-lives if this is longer than 2 weeks in duration.

- Prior radiation therapy: Patients must be at least 2 weeks from prior radiation
therapy

- Concurrent administration of other cancer specific therapy during the course of this
study is not allowed.

- Only patients 18 years and older are eligible. There is no upper age limit but the
patients must be able to medically tolerate the regimen. Adverse event data are
currently unavailable on the use immune checkpoint blockade for participants < 18
years of age, and thus children are excluded from this study.

- ECOG performance status <=1 (see Appendix A).

- Ability to understand and the willingness to sign a written informed consent document

- Female subjects of childbearing potential must have a negative serum pregnancy test at
screening.

- Female and male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in section 5.7.1. Contraception is required prior
to study entry and for the duration of study participation and 4 months after
completion of pembrolizumab administration.

--Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcl

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin >= 9 g/dl

- total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

- AST(SGOT)/ALT(SGPT) For patients with documented liver metastases, ≤ 5 ×
institutional ULN

- creatinine ≤1.5 ×within normal institutional ULN OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above institutional ULN.

- International normalized ratio (INR) or Prothrombin Time (PT) <1.5 times the
upper limit of normal unless subject is receiving anticoagulant therapy, as long
as PT or PTT is within therapeutic range of intended use of anticoagulants.

- Activated Partial Thromboplastin Time (aPTT) <1.5 times the upper limit of normal
unless subject is receiving anticoagulant therapy, as long as PT or PTT is within
therapeutic range of intended use of anticoagulants.

- Laboratory tests required for eligibility must be completed within 14 days prior study
entry. Baseline tumor measurements must be documented from tests within 28 days of
study entry. Other non-laboratory tests must be performed within 28 days of study
entry.

Exclusion Criteria:

- Metastatic disease impinging on the spinal cord or threatening spinal cord
compression.

- Surgical fixation of bone lesion to be irradiated is required and indicated to provide
mechanical stability.

- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with previously diagnosed brain metastases are eligible if they
have completed treatment at least 2 weeks prior to trial therapy initiation, are
neurologically stable, and have recovered from the acute effects of radiotherapy or
surgery. Any corticosteroid use for brain metastases must have been discontinued
without the subsequent appearance of symptoms for ≥2 weeks before the initiating
protocol therapy. Treatment for brain metastases may include surgery, whole brain
radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating
physician.

- Participants who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab or previous toxicity attributed to pembrolizumab or other
PD-1 directed therapy that led to drug discontinuation.

- Uncontrolled intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Clinically significant electrocardiogram (ECG) abnormality, including a marked
Baseline prolonged QT/QTc ([QT interval/corrected QT interval], e.g., a repeated
demonstration of a QTc interval >500 ms).

- Pregnant women are excluded from this study because immunotherapy has the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk of adverse events in nursing infants secondary to treatment of the mother with
immunotherapy, breastfeeding should be discontinued if the mother is treated on this
protocol.

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances: if they have been disease-free for at least 2 years and are
deemed by the investigator to be at low risk for recurrence of that malignancy; or if
diagnosed and treated for cervical cancer in situ or basal cell or squamous cell
carcinoma of the skin.

- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for interaction between immunotherapy and these medications.

- Has history of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non infectious pneumonitis.

- Active, suspected or prior documented autoimmune disease that has required systemic
treatment in the last 2 years with immune modifying agents (e.g. replacement therapy
such as thyroxine, insulin or physiologic corticosteroids is not an exclusion
criteria).

- The subject is known to be positive for HepBsAg, or HCV RNA.

- Lack of availability for follow up assessments.

- The investigator's belief that the subject is medically unfit to receive pembrolizumab
and or unsuitable for any other reason.

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