The Addition of Pembrolizumab to Postoperative Radiotherapy in Cutaneous Squamous Cell Cancer of the Head and Neck

Primary Objective:

To assess safety and estimate 1-year PFS of postoperative radiation therapy (RT) + concurrent
and adjuvant Pembrolizumab in high risk resected cutaneous squamous cell cancer of the head
and neck (cSCC-HN).

Secondary Objectives

1. To evaluate the relationship of baseline programmed death-ligand 1 (PD-L1) expression by
tumor and tumor-infiltrating lymphocytes (TILs) to preliminary efficacy .

2. To phenotype tumor infiltrating lymphocytes and peripheral blood lymphocytes (PBLs), and
investigate tumor suppressor populations including Tregs, myeloid-derived suppressor
cells (MDSCs) and cluster of differentiation 8 (CD8) suppressor cells and assess ex vivo
for effector function by cytokine production and cytotoxicity assays as well as
suppressor function in assays with autologous PBLs.

3. To evaluate the tumor microenvironment (TME), and immune markers at the invasive margin
of the tumor, including CD8, PD-1, PD-L1, TIM-3, galectin-9 or HMGB-1, BTLA and HVEM, as
well as Lag-3, CTLA-4 and others.

4. To evaluate the genomic and/or transcriptomic profile of these tumors using RNA-seq
/Whole Transcriptome Shotgun Sequencing

Trial Design:

This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose
pembrolizumab in combination with standard intensity-modulated radiation therapy (IMRT), in
order to establish safety and estimate efficacy of this regimen to be tested in a subsequent
randomized registration trial.

Thirty seven patients will be enrolled.

Inclusion Criteria:

- Histologic diagnosis of cutaneous squamous cell carcinoma of the head and neck that
has been resected with no evidence of gross residual disease (margin positivity is
acceptable)

- Patients must have undergone resection of the disease and demonstrate high risk
pathologic features including:

- T4

- Node positive disease

- T2/T3N0 disease with any 1 additional feature, including:

- Recurrent Disease

- Perineural invasion

- Lymphovascular space invasion

- Poorly differentiated histology

- Positive Margins

- Satellitosis or in-transit metastases

- Patients are required to have computerized tomography (CT) neck and chest or positron
emission tomography/computerized tomography (PET/CT) and have no documented evidence
of distant metastases

- Patients must not have a history of the following immunosuppressive conditions:bone
marrow transplantation and/or organ transplants and/or chronic rheumatic conditions
that require active immunosuppressive therapy. Patients with a history of chronic
lymphoid or leukemic malignancies which are not under active therapy (no active
therapy within the last 3 months) will be eligible. Patients with chronic lymphoid or
leukemic malignancies are eligible with or without active disease as long as they have
not had treatment within the past three months.

- Patients may not have had prior therapy with a checkpoint inhibitor (e.g. anti-CTLA-4,
anti-PD-1 or anti-PD-L1 therapy)

- Patients may not have had prior radiotherapy (>30Gy) to the area requiring treatment
that would result in any overlap of tissue in both fields

- Patients may have received chemotherapy or radiation for a previous, curatively
treated malignancy provided at least 2 years have elapsed and there is no current
evidence of disease (patients with previous or concurrent additional skin cancers are
eligible)

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

- 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.

- Patients must have adequate laboratory values

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9g/dL or ≥5.6mmol/L without transfusion

- Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or measured creatinine
clearance ≥60mL/min for subject with creatinine levels >1.5 times institutional
ULN

- Serum bilirubin ≤ 1.5 times ULN or direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST (SGOT)) and alanine aminotransferase (ALT (SPGT))
≤ 2.5 times ULN or ≤ 5 times ULN for subjects with liver metastases

- Albumin ≥ 2.5mg/dL

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.

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

- Hypersensitivity to pembrolizumab.

- Has a history of the following immunosuppressive conditions: bone marrow
transplantation, and/or organ transplants and/or chronic rheumatic conditions that
require active immunosuppressive therapy. Patients with chronic lymphoid/leukemic
malignancies that have undergone treatment in the last 3 months will be ineligible.

- 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 radiotherapy 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.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or a separate primary squamous
cell carcinoma of the skin or a separate primary squamous cell carcinoma of the skin.
Patients with chronic lymphoid or leukemic malignancies are eligible with or without
active disease as long as they have not had treatment within the past three months.

- Has metastatic disease.

- 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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is
detected).

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