Ipilimumab, Nivolumab, and Radiation Therapy in Treating Patients With HPV Positive Advanced Oropharyngeal Squamous Cell Carcinoma

PRIMARY OBJECTIVES:

I. To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab when
administered concurrently with reduced-field radiotherapy (intensity-modulated radiation
therapy [IMRT]).

II. To evaluate the clinical complete response rate to ipilimumab, nivolumab and IMRT with
reduced field at six months as indicated by fluorodeoxyglucose - positron emission
tomography/computed tomography (FDG-PET/CT) post completion of radiation therapy (RT).

III. To evaluate the 2-year progression-free survival (PFS) rate of subjects with
low-intermediate volume, local-regionally advanced, human papilloma virus (HPV)-positive
squamous cell carcinoma of the head and neck (SCCHN) treated with ipilimumab, nivolumab and
reduced-field IMRT.

SECONDARY OBJECTIVES:

I. To evaluate overall response rate to six weeks of induction immunotherapy (IO).

II. To evaluate the frequency of pharyngeal dysphasia as measured by Dynamic Imaging (Dynamic
Imaging Grade of Swallowing Toxicity [DIGEST]) grade on modified barium swallow (MBS) and
patient-reported symptoms (MD Anderson Dysphagia Inventory [MDADI]) at 6 month, 1 and 2 years
after radiotherapy ([IMRT] or intensity modulated proton therapy [IMPT]).

III. To measure acute and chronic toxicities per Patient-Reported Outcomes Common Terminology
Criteria for Adverse Events (CTCAE PRO).

IV. To measure acute toxicity profiles at the end of radiation therapy and IO and at 6
months.

V. To measure late toxicity profiles at 1 and 2 years.

VI. To determine local and regional control at 6 and 12 months.

VII. To determine patterns of failure (local-regional relapse vs. distant) at 1 and 2 years.

VIII. To determine overall survival (OS) at 1 and 2 years.

CORRELATIVE OBJECTIVES:

I. To evaluate associations between total mutational load, interferon (INF) gamma score, T
cell clonality at diagnosis with clinical response to induction, combination CTLA-4 PD-1
checkpoint blockade.

II. To evaluate changes in the tumor immune microenvironment (CD8 + INF gamma score, T cell
clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO).

III. To evaluate dynamic changes in and clearance of oral HPV and cell-free deoxyribonucleic
acid (cfDNA) viral load during therapy and to investigate associations with PFS and OS.

EXPLORATORY OBJECTIVES:

I. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles
before and after induction IO.

II. To evaluate changes in the T cell receptor repertoire in tumor-infiltrating lymphocyte
(TIL) and the peripheral blood in tumor biopsy specimens pre and post induction IO.

III. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine
profiles before and after radiation therapy with IMRT versus IMPT.

IV. To determine the negative and positive predictive values (NPV and PPV) of FDG-PET/CT
12-14 weeks after end of RT for 1 year and 2 year PFS and OS.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and
ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 courses in
the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 2,
patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 weeks, every 3 months for
2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

- Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma
(including the histological variants of papillary or basaloid) of the oropharynx
(tonsil, base of tongue, soft palate, or oropharyngeal walls)

- Clinical American Joint Committee on Cancer (AJCC) 7th edition stage T1N2a-N2CM0,
T2N1-N2CM0, T3N0-N2CM0, equivalent to (The International Collaboration on
Oropharyngeal Cancer Network for Staging [ICON-S]) stage 1 and 2 (T1 N2, T2 N1-N2, T3
N0-N2) excluding T1N0-N1 and T2N0

- Tumor positive for p16 immunohistochemistry (IHC) (defined as greater than 70% strong
nuclear or nuclear and cytoplasmic staining of tumor cells) and HPV DNA in situ
hybridization or HPV messenger ribonucleic acid (mRNA) RNAScope. Repeat samples may be
required if adequate diagnostic tissue is unavailable for testing

- Zubrod Performance Status of 0-1

- Patients must have radiographically evident measurable disease at the primary site or
at nodal stations per response evaluation criteria in solid tumors (Response
Evaluation Criteria in Solid Tumors [RECIST]) 1.1 documented by diagnostic quality CT
or magnetic resonance imaging (MRI) of the neck with contrast within 28 days prior to
registration; a FDG-PET/CT of the neck performed for the purposes of radiation
planning is acceptable as a substitute if the CT is of diagnostic quality

- Diagnostic quality cross sectional imaging of the thorax within 28 days prior to
registration. A 18-FDG-PET/CT or conventional CT are acceptable

- FDG-PET/CT of the neck is required within 28 days prior to registration for comparison
to post treatment FDG-PET/CT

- History and physical exam within 1 month prior to registration

- Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct
procedure) by radiation oncologist, medical oncologist or ear, nose, throat (ENT)/head
and neck surgeons within 45 days prior to registration

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 2 weeks prior to
registration)

- Platelets >= 100,000 cells/mm^3 (within 2 weeks prior to registration)

- Hemoglobin >= 8.0 g/dl; Note: The use of transfusion or other intervention to achieve
Hgb >= 8.0 g/dl is acceptable (within 2 weeks prior to registration)

- Serum creatinine =< 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by
24-hour collection or estimated by Cockcroft-Gault formula (within 2 weeks prior to
registration)

- Bilirubin =< 2 mg/dl (within 2 weeks prior to registration)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper
limit of normal (within 2 weeks prior to registration)

- Sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg),
albumin, amylase, lipase, thyroid stimulating hormone (TSH) within 2 weeks prior to
registration

- Negative serum pregnancy test within 2 weeks prior to registration for women of
childbearing potential

- Seronegative for active hepatitis-B or hepatitis-C infection and seronegative for
human immunodeficiency virus (HIV)

- Mandatory submission of hematoxylin and eosin (H&E) and paraffin-embedded tumor block
or unstained slides

- Patients must provide their personal smoking history by use of a computer assisted,
self-interview (CASI) application. Repeat imaging for variability of within 96 hours
of this time frame should be allowed to avoid unnecessary re-imaging and its financial
and potential physical consequences for patients

Exclusion Criteria:

- Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip),
or the nasopharynx, hypopharynx, or larynx, even if p16 positive

- Carcinoma of the neck of unknown primary site origin (even if p16 positive)

- Definitive clinical or radiologic evidence of metastatic disease or adenopathy below
the clavicles

- Gross total excision of both primary and nodal disease with curative intent; this
includes tonsillectomy, local excision of primary site, and nodal excision that
removes all clinically and radiographically evident disease

- Simultaneous primary cancers or separate bilateral primary tumor sites

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast,
oral cavity, or cervix are all permissible)

- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable

- Prior RT to the region of the study cancer that would result in overlap of radiation
therapy fields

- Severe, active co-morbidity defined as any of the following: Unstable angina and/or
congestive heart failure requiring hospitalization within the last 6 months; acute
bacterial or fungal infection requiring intravenous antibiotics at the time of
registration; chronic obstructive pulmonary disease exacerbation or other respiratory
illness requiring hospitalization or precluding study therapy within 30 days of
registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation
defects; a diagnosis of immunodeficiency or use of any form of systemic
immunosuppressive therapy. The use of physiologic doses of corticosteroids may be
approved after consultation with the Sponsor

- Active autoimmune disease that has required systemic treatment in past 2 years (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment. Steroid premedications for contrast allergy allowed

- Has evidence of active, non-infectious pneumonitis

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

- Pregnancy or breast-feeding; this exclusion is necessary because the treatment
involved in this study may be significantly teratogenic

- History of severe hypersensitivity or contraindication to CT or PET contrast material
uncontrolled with pre-medications (steroids, antihistamines)