Adjuvant De-Escalated Radiation + Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

This study aims to enroll 135 patients (male and female, age 18+) who are newly diagnosed
with resectable, squamous cell carcinoma or undifferentiated carcinoma of the oropharynx.
Survival rate and treatment response of OPSCC varies based on HPV infection status and
genotype; therefore, in this study, only patients who are HPV seropositive and have HPV type
16 will be enrolled. All patients will receive the same treatment, i.e. there is no active
control group.

In this trial, patients will undergo transoral surgery followed by de-intensified adjuvant
radiotherapy plus nivolumab. The radiotherapy will consist of 45 or 50 Gy (depending on tumor
volume) in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at a
fixed dose of 240 mg over 30 minutes IV every 2 weeks during radiotherapy, and at 480 mg over
60 minutes IV every 4 weeks for 6 doses after radiotherapy. The first dose will be given
prior to the first fraction of radiation (Day 1) on Day -3 (+/- 2 days), and continued every
2 weeks (+/- 2 days). Nivolumab will thus be given in weeks 2 and 4 of radiotherapy. Adjuvant
nivolumab will then be given for a total of 6 additional doses after the completion of
radiotherapy every 4 weeks (+/- 7 days), starting in the second or third week after the
completion of radiotherapy. Doses of nivolumab may be interrupted, delayed, or discontinued
depending on how well the subject tolerates the treatment. Relevant outcome measures include
disease free survival (2 year post surgery); percutaneous gastronomy dependence (1-year
postsurgery); acute and late toxicity; patient-reported Quality of Life measures,
locoregional control and distant metastatic control.

Inclusion Criteria:

- Age >/= 18 years.

- ECOG performance status of 0 or 1.

- Patients must have newly diagnosed, histologically or cytologically confirmed squamous
cell carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have
been determined to have resectable oropharyngeal disease. Patients with primary tumor
or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not
eligible.

- Patients must have intermediate risk factors, as described below as determined by
imaging studies (performed < 45 days prior to registration) and complete neck exam,
from the skull base to the clavicles. The following imaging is required: CT scan with
IV contrast or MRI. PET scan of HN and chest with IV contrasted CT correlation is
encouraged prior to enrollment.

Intermediate risk features: Tobacco <10 pk-yr: T0-3 plus any one of the following: >N2b (>
5 LN's +), N2c/N3, +ENE >1 mm, or + margin (if approved by surgical chair) OR Tobacco >10
pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE >1 mm, or + margin (if approved
by surgical chair)

- Patients must have no evidence of distant metastases (M0)

- Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of
invasive squamous cell carcinoma may have been obtained from the primary tumor or
metastatic lymph node. It is required that patients have a positive p16 IHC (as
surrogate for HPV) status from either the primary tumor or metastatic lymph node.

- Carcinoma of the oropharynx associated with HPV as determined by p16 protein
expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory.
Using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is
recommended.

- No prior radiation above the clavicles.

- Patients with a history of a curatively treated malignancy must be disease-free for at
least two years except for carcinoma in situ of cervix, differentiated thyroid cancer,
melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer, or
clinically negligible in judgement of investigator.

- Patients with the following within the last 6 months prior to registration must be
evaluated by a cardiologist and / or neurologist prior to entry into the study.

- Congestive heart failure > NYHA Class II

- CVA / TIA

- Unstable angina

- Myocardial infarction (with or without ST elevation)

- Patients must have acceptable renal and hepatic function within 4 weeks prior to
registration as defined below:

- Absolute neutrophil count ≥1,500/mm3

- Platelets ≥ 100,000/mm3

- Total bilirubin ≤ the upper limit of normal (ULN)

- Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault
formula: (140-age)*wt(kg)/([Cr]*72). For women the calculation should be
multiplied by 0.85

- Women must not be pregnant or breast-feeding due to the teratogenicity of therapy. All
females of childbearing potential must have a blood test or urine study within 2 weeks
prior to registration to rule out pregnancy. A female of childbearing potential is any
woman, regardless of sexual orientation or whether they have undergone tubal ligation,
who meets the following criteria: 1) has not undergone a hysterectomy or bilateral
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive
months (i.e., has had menses at any time in the preceding 24 consecutive months).

- Patient without intercurrent illness likely to interfere with protocol therapy.

- Patients must not have uncontrolled diabetes, uncontrolled infection despite
antibiotics or uncontrolled hypertension within 30 days prior to registration.

Exclusion Criteria:

- Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results.

- Patients with a history of a curatively treated malignancy must be disease-free for at
least two years except for carcinoma in situ of cervix, melanoma in-situ (if fully
resected), and/or non-melanomatous skin cancer, superficial bladder cancer, or
carcinoma in situ of the prostate, cervix, or breast.

- Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.

- Prior radiation above the clavicles.

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or immune
checkpoint pathways.

- Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
investigational therapy within 30 days of first administration of study treatment
(subjects with prior radiation, cytotoxic or investigational products < 4 weeks prior
to treatment might be eligible after discussion between investigator and sponsor, if
toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version
4).

- Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Subjects
who test positive for HCV antibody but negative for HCV ribonucleic acid are permitted
to enroll.

- Known history of testing positive for human immunodeficiency virus (HIV) and CD4 count
< 200 or known acquired immunodeficiency syndrome (AIDS).

- Any Grade 4 laboratory abnormalities.

- Patients with the following within the last 6 months prior to registration must be
evaluated by a cardiologist and / or neurologist prior to entry into the study.

- Congestive heart failure > NYHA Class II

- CVA / TIA

- Unstable angina

- Myocardial infarction (with or without ST elevation)

- History of allergy to study drug components.

- History of severe hypersensitivity reaction to any human monoclonal antibody.

- Prisoners or subjects who are involuntarily incarcerated.

- Subjects compulsorily detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness.