Nivolumab & IRX-2 With Surgery for Resectable Stage III-IVA Oral Cavity Cancer or HPV-Positive Oropharyngeal Cancer

PRIMARY OBJECTIVES:

I. To determine the safety profile of combination immunotherapy, nivolumab + IRX-2, for HPV+
oropharyngeal squamous cell carcinoma (OPSCC) and HPV- oral cavity squamous cell carcinoma
(OCSCC).

II. To assess the oncologic efficacy of neo-adjuvant immunotherapy using pathologic
confirmation of response after surgical resection.

SECONDARY OBJECTIVES:

I. To correlate tumor microenvironment histopathology with pathologic findings, with
progression free survival (PFS) and other outcome parameters in patients with resectable
OPSCC and OCSCC after the above treatments.

II. To evaluate swallowing function before and after surgery and risk-adjusted adjuvant
therapy.

III. To evaluate quality of life (QOL), swallowing perception and performance, voice
outcomes, and head and neck symptoms.

OUTLINE: Fifteen subjects with HPV-related oropharynx HNSCC (cohort 1) and 15 subjects with
HPV-negative oral cavity HNSCC (cohort 2) patients will be included. Patients will take
nivolumab on days 1 and 15 and IRX-2 for 10 days between days 4-21. Patients will have
surgery to remove their cancer between days 25-30 (for oropharynx cancer this will be via
transoral robotic surgery, TORS). Treatment after surgery will depend on institutional
guidelines.

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

Inclusion Criteria:

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Pathologically confirmed (histology or
cytology) stage III or IVA squamous cell cancer of the oral cavity (excluding lip)

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Disease is surgically resectable with
curative intent

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Hemoglobin > 9 g/dL

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Lymphocyte count > 500/µL

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Neutrophil count > 1500/µL

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Platelet count > 100,000/µL

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Serum albumin > 3.0 g/dL

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Aspartate aminotransferase (AST/serum
glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/ serum
glutamate pyruvate transaminase [SGPT]) < 3 x the upper limits of normal (ULN)

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Alkaline phosphatase < 2 x ULN

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prothrombin time (PT) and partial
thromboplastin time (PTT) < 1.4 x ULN

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Calculated creatinine clearance > 50
mL/min

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Willing and able to give informed consent
and adhere to protocol therapy

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Eastern Cooperative Oncology Group (ECOG)
performance status < 2

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Female of childbearing potential (less
than 12 months post-menopausal) or male with a partner of childbearing potential
either agrees to be abstinent or uses a medically acceptable form of birth control
during the study and for a period of 1 year

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Negative urine/serum pregnancy test
(females only) at the time of screening and within 24 hours of study treatment, if
applicable

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Stage 1 (T1/2 N1) squamous
cell carcinoma of the oropharynx associated with HPV as determined by p16 protein
expression using immunohistochemistry (IHC) performed by a Clinical Laboratory
Improvement Act [CLIA] approved laboratory; using p16 antibody obtained from Roche mtm
laboratories AG (CINtec, clone E6H4) is recommended

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: No prior radiation above the
clavicles

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: 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

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Patients must not have
evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Hemoglobin > 9 g/dL

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Lymphocyte count > 500/µL

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Neutrophil count > 1500/µL

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Platelet count > 100,000/µL

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Serum albumin > 3.0 g/dL

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Aspartate aminotransferase
(AST/ SGOT) and alanine aminotransferase (ALT/ SGPT) < 3 x the upper limits of normal
(ULN)

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Alkaline phosphatase < 2 x
ULN

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prothrombin time (PT) and
partial thromboplastin time (PTT) < 1.4 x ULN

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Calculated creatinine
clearance > 50 mL/min

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Willing and able to give
informed consent and adhere to protocol therapy

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: ECOG performance status < 2

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Female of childbearing
potential (less than 12 months post-menopausal) or male with a partner of childbearing
potential either agrees to be abstinent or uses a medically acceptable form of birth
control during the study and for a period of 1 year

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Negative urine/serum
pregnancy test (females only) at the time of screening and within 24 hours of study
treatment, if applicable

Exclusion Criteria:

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior surgery, radiation therapy, or
chemotherapy other than biopsy or emergency procedure required for supportive care

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior treatment with an anti-PD-1,
anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4)
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior treatment with cetuximab or
epidermal growth factor receptor (EGFR) inhibitors in any treatment setting

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Any medical contraindications or previous
therapy that would preclude treatment with either nivolumab, IRX-2, the surgery,
reconstruction or adjuvant therapy required to treat the oral tumor appropriately

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Clinical status of either subject or tumor
such that administration of 10 day neoadjuvant IRX-2 1 or 2 before surgery would be
medically inappropriate

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Primary tumor of the oropharynx

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Tumor involvement of the following sites
or any of these signs or symptoms likely to be associated with T4b cancer:

- Involvement of pterygopalatine fossa, maxillary sinus, or facial skin

- Gross extension of tumor to the skull base

- Pterygoid plate erosion

- Sphenoid bone or foramen ovale involvement

- Direct extension to involve prevertebral fascia

- Extension to superior nasopharynx or Eustachian tube

- Direct extension into the neck with involvement of the deep neck musculature
(neck node fixation)

- Suspected invasion (encasement) of the common or internal carotid arteries;
encasement will be assessed radiographically and will be defined as tumor
surrounding the carotid artery 270 degrees or greater

- Direct extension of neck disease to involve the external skin

- Direct extension to mediastinal structures

- Regional metastases to the supraclavicular neck (low level VB and IVB)

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Any investigational agent within the
previous 30 days

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Daily administration of systemic
immunosuppressive therapy or corticosteroids (except in physiological doses for
hormone deficiency) during the previous 30 days

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Chronic anticoagulation, not including
aspirin, but including heparins, warfarin, oral anticoagulation or other platelet
function inhibitors

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Symptomatic cardiopulmonary disease
(including congestive heart failure and hypertension), coronary artery disease,
serious arrhythmia or chronic lung disease; patients with these conditions who are
stable with relatively minor symptoms and who are appropriate candidates for surgical
treatment of their tumor need not be excluded

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Myocardial infarction within the last 3
months

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Evidence of distant metastases (M1
disease) or other concurrent primary malignancy

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Known infection with hepatitis B,
hepatitis C, or human immunodeficiency virus (HIV)

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Signs or symptoms of systemic systemic
infection (use of antibiotics to treat superficial infection or contamination of tumor
shall not, by itself, be considered evidence of infection

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Stroke or other symptoms of cerebral
vascular insufficiency within the last 3 months

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Allergy to ciprofloxacin (or other
quinolones), acetylsalicylic acid

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Previous diagnosis of invasive cancer from
which the individual is NOT disease-free AND that has required treatment within the
past 5 years, except for superficial skin, cervical cancer in-situ,
well-differentiated thyroid or early stage prostate or bladder cancer (i.e., treatment
with curative intent and long term disease-free expectations)

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: Prior axillary dissection

- ORAL CAVITY SQUAMOUS CELL CARCINOMA COHORT: History of pneumonitis or interstitial
lung disease

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prior surgery, radiation
therapy, or chemotherapy other than biopsy or emergency procedure required for
supportive care

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: 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 checkpoint pathways

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Any medical
contraindications or previous therapy that would preclude treatment with either
nivolumab or IRX-2 or the surgery, reconstruction or adjuvant therapy required to
treat the oropharynx tumor appropriately

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Tumor of the oral cavity

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Tumor involvement of the
following sites or any of these signs or symptoms likely to be associated with T4b
cancer:

- Involvement of pterygopalatine fossa, maxillary sinus

- Gross extension of tumor to the skull base

- Pterygoid plate erosion

- Sphenoid bone or foramen ovale involvement

- Direct extension to involve prevertebral fascia

- Extension to superior nasopharynx or Eustachian tube

- Direct extension into the neck with involvement of the deep neck musculature
(neck node fixation)

- Suspected invasion (encasement) of the common or internal carotid arteries;
encasement will be assessed radiographically and will be defined as tumor
surrounding the carotid artery 270 degrees or greater

- Direct extension of neck disease to involve the external skin

- Direct extension to mediastinal structures

- Regional metastases to the supraclavicular neck (low level VB and IVB)

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Any investigational agent
within the previous 30 days

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Daily administration of
systemic immunosuppressive therapy or corticosteroids (except in physiological doses
for hormone deficiency) during the previous 30 days

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Chronic anticoagulation, not
including aspirin, but including heparins, warfarin, oral anticoagulation or other
platelet function inhibitors

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Symptomatic cardiopulmonary
disease (including congestive heart failure and hypertension), coronary artery
disease, serious arrhythmia or chronic lung disease; patients with these conditions
who are stable with relatively minor symptoms and who are appropriate candidates for
surgical treatment of their tumor need not be excluded

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Myocardial infarction within
the last 3 months

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Evidence of distant
metastases (M1 disease) or other concurrent primary malignancy

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Known infection with
hepatitis B, hepatitis C, or HIV

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Signs or symptoms of
systemic bacterial infection (use of antibiotics to treat superficial infection or
contamination of tumor shall not, by itself, be considered evidence of infection)

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Stroke or other symptoms of
cerebral vascular insufficiency within the last 3 months

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Allergy to ciprofloxacin (or
other quinolones), acetylsalicylic acid

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Previous diagnosis of
invasive cancer from which the individual is NOT disease-free AND that has required
treatment within the past 5 years, except for superficial skin, cervical cancer
in-situ, well-differentiated thyroid or early stage prostate or bladder cancer (i.e.,
treatment with curative intent and long term disease-free expectations)

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: Prior axillary dissection

- HPV-ASSOCIATED OROPHARYNX SQUAMOUS CELL CARCINOMA COHORT: History of pneumonitis or
interstitial lung disease