Neoadjuvant Immunoradiotherapy in Head & Neck Cancer

This clinical trial uses nivolumab and radiotherapy prior to definitive surgical resection of
tumors in patients with Head and Neck Squamous Cell Carcinoma (OHNSCC) with the primary
objective of determining the safety and feasibility of preoperative immunoradiotherapy. In
addition, tumor tissue, microbiome samples, and peripheral blood will be obtained for
exploratory immunologic end points including measurements of tumor infiltrating immune cell
populations based on flow cytometry and immunohistochemistry as well as circulating
immunological parameters. This is the first study to evaluate the safety and efficacy of
neoadjuvant radiation + PD-1 blockade in patients with HNSCC.

Estimated duration of 20 weeks: neoadjuvant immunoradiotherapy +/- surgery, followed by 6
doses of nivolumab 480mg IV q4wks +/- risk-adapted adjuvant therapy, per standard of care.

Phase I safety lead-in study (n = 6) evaluating the safety of neoadjuvant immunoradiotherapy
in HNSCC, followed by phase II efficacy study (n = 28, total) to assess rate of down-staging
after neoadjuvant immunoradiotherapy using Simon's two-stage design (futility assessment at n
= 12).

The phase 1 portion of this study will require 6 patients and is therefore expected to
complete in 6 months. Although non-surgical patients are eligible to enroll, they will not be
counted toward accrual for either the primary safety endpoint, (as by definition, unplanned
delay of surgery cannot exist); nor the secondary efficacy endpoint, as potential for
surgical staging is absent.

So long as 2 or fewer surgical delays are observed (primary safety endpoint), the phase 2
portion of study will proceed (secondary efficacy endpoint). Patients will be followed for
disease free and overall survival at 5 years.

Eligible patients may be enrolled unless a rate of unplanned surgical delay attributed to
immunoradiotherapy is found to exceed 33% after enrollment of the first 6 patients. We
estimate 10 to 20 patients per year will be enrolled.

Inclusion Criteria:

1. Patients with squamous cell carcinoma of the head and neck region, (including
mucosal,cutaneous, or nodal) who are planned for surgical resection and in the opinion
of the investigator are able to safely undergo neoadjuvant anti-PD-1 and radiation. In
addition, the following are eligible (but will not contribute toward total accrual):
non-surgical cases that are planned for palliative RT or that refuse or are unfit for
definitive concurrent chemotherapy.

2. HPV status as determined by p16 immunostain

3. Cohort 3: HPV-positive patients only

4. Cohort 4: HPV-negative patients only

5. Age 18 years or above with ability to give informed consent, comply with the protocol,
and sign a study-specific consent document. Patients with history of psychiatric
illness must be judged by the investigator as able to understand the investigational
nature and risks associated with the therapy.

6. Eastern Cooperative Oncology Group (ECOG) performance status deemed suitable by
investigator for study requirements.

7. Laboratory values (most recent), must be within 6 weeks of week 0 on study:

- WBC ≥ 2000/uL, ANC ≥ 1000/uL

- Hgb > 8g/dL (patients may be transfused to reach this level)

- Platelets > 50,000 cells/mm3

- Creatinine ≤ 3 x ULN

- AST/ALT ≤ 5 x ULN for subjects without liver metastasis; or ≤ 8 x ULN for
subjects with liver metastasis, [per investigator brochure]

- Total bilirubin ≤ 3 x ULN, (except subjects with Gilbert's Syndrome, who must
have a total bilirubin less than 3.0 mg/dL)

- Negative pregnancy test (bHCG urine or serum, women of childbearing potential
only)

8. Women of child-bearing potential (WOCBP) must agree to follow adequate contraceptive
practices to avoid pregnancy for the duration of treatment with nivolumab plus 5
half-lives of nivolumab (75 days) plus 30 days (duration of ovulatory cycle) for a
total of 105 days post-treatment completion.

9. Males who are sexually active with WOCBP must agree to follow adequate contraceptive
practices to avoid pregnancy for the duration of treatment with study drug (s) plus 5
half lives of the study drug (75 days) plus 90 days (duration of sperm turnover) for a
total of 165 days post-treatment completion.

Exclusion Criteria:

1. Any clinical factors such as bleeding, active infection, or psychiatric factors that
in the judgment of the investigator would preclude safe participation and compliance
with study procedures.

2. HNSCC for which radiation is not indicated during normal treatment course.

3. Need for chronic maintenance with oral steroids ≥20mg daily prednisone equivalent;
inhaled, topical or non-absorbed steroids are acceptable.

4. History of or current active autoimmune disease, [e.g. including but not limited to
inflammatory bowel diseases [IBD], rheumatoid arthritis, autoimmune hepatitis,
systemic sclerosis (scleroderma and variants), systemic lupus erythematosus,
autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre syndrome)],
which in the judgment of the investigator poses an active and significant morbidity
risk. Vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism
are not exclusionary. Patient and investigator may opt to accept risk of autoimmune
disease flare, based on shared-decision making with consideration of risk/benefit.