Nivolumab, Ipilimumab, and Radiation Therapy in Treating Patients With Stage IVA-B Head and Neck Cancer

PRIMARY OBJECTIVES:

I. To investigate the safety of the combination of nivolumab and ipilimumab with radiation
treatment for definitive management of patients with locally advanced squamous cell carcinoma
of the head and neck.

SECONDARY OBJECTIVES:

I. To estimate the 1 year progression-free survival (PFS) in all patients treated.

II. To assess the overall response rate and overall survival of patients at one year

TERTIARY OBJECTIVES:

I. To explore whether PDL1 expression is associated with treatment response. II. To explore
whether there is a net change in the Th1/Th2 ratio (IFN-gamma, IL-4, IL10, etc) or cell
subset frequencies (M2 monocytes, myeloid-derived suppressor cells, etc) within a patient's
peripheral blood either at baseline or in response to treatment is associated with treatment
response.

III. To explore whether exosomes or other immune related serum biomarkers change after
combination therapy.

Inclusion Criteria:

- Pathologically confirmed squamous cell carcinoma of the head and neck (SCCHN), not
previously treated

- Stage IVA-B disease of 1) oral cavity, 2) oropharynx, 3) larynx, 4) hypopharynx

- Oropharyngeal primaries have to be human papillomavirus (HPV) p16 negative unless by
AJCC 7th edition staging they are cT4a, cT4b, cN2 and/or cN3 tumors.

- Tumor sample must be available for HPV p16 and PD-L1 testing

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- White blood cells 2000/ul or more

- Absolute neutrophil count 1500/ul or more

- Platelets 100,000/ul or more

- Hemoglobin 9 g/dl or more

- Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with
Gilbert syndrome, who can have total bilirubin < 3 mg/dl)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
to 3 x the upper limit of normal

- Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the
Cockcroft-Gault formula or Serum creatinine less than or equal to 1.5 x upper limit of
normal (ULN)

- Women of reproductive potential should have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours of the start of study drugs

- Women of reproductive potential must use highly effective contraception methods to
avoid pregnancy for 23 weeks after the last dose of study drugs; "women of
reproductive potential" is defined as any female who has experienced menarche and who
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or
who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea
in a woman over 45 in the absence of other biological or physiological causes; in
addition, women under the age of 55 must have a documented serum follicle stimulating
hormone (FSH) level more than 40 mIU/mL

- Men of reproductive potential who are sexually active with women of reproductive
potential must use any contraceptive method with a failure rate of less than 1% per
year; men who are receiving the study medications will be instructed to adhere to
contraception for 31 weeks after the last dose of study drugs; men who are azoospermic
do not require contraception

- Informed consent: all subjects must be able to comprehend and sign a written informed
consent document

Exclusion Criteria:

- Primary nasopharyngeal carcinoma

- Patients with brain metastases

- Patients who have participated in a study with an investigational agent or device
within 2 weeks of initiation of treatment

- Any prior radiotherapy to the neck

- Patients with known contraindications to radiotherapy, including inherited syndromes
associated with hypersensitivity to ionizing radiation (e.g., Ataxia-Telangiectasia,
Nijmegen Breakage Syndrome)

- Any prior chemotherapy or radiation therapy for the current diagnosis

- Any prior therapy with anti-PD-1, anti-PD-L2, anti-CTLA-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways

- Any history of a sever hypersensitivity reaction to any monoclonal antibody

- Any history of allergy to the study drug components

- Any concurrent malignancies- exceptions include- basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical
cancer that has undergone potentially curative therapy; patients with a history of
other prior malignancy must have been treated with curative intent and must have
remained disease-free for 3 years post-diagnosis

- Any diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 14 days of initiation of therapy

- Patients that have an active autoimmune disease requiring systemic treatment within
the past 3 months or a documented history of clinically severe autoimmune disease, or
a syndrome that requires systemic steroids (> 10 mg daily prednisone equivalents) or
immunosuppressive agents; subjects with vitiligo, type I diabetes mellitus, or
resolved childhood asthma/atopy would be an exception to this rule; subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study

- Patients with evidence of interstitial lung disease or active, non-infectious
pneumonitis

- Patients with a known human immunodeficiency virus infection (HIV 1/2 antibodies) or
acquired immunodeficiency syndrome (HIV/AIDS), active hepatitis B (e.g., hepatitis B
surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV]
ribonucleic acid [RNA] [qualitative] is detected)

- Patients who have received a live vaccine within 30 days prior to the radiation
therapy

- Patients must not be receiving any other investigational agents

- Patients with uncontrolled intercurrent illnesses including, but not limited to an
active infection requiring systemic therapy or a known psychiatric or substance abuse
disorder(s) that would interfere with cooperation with the requirements of the trial

- Women must not be pregnant (as above) or breastfeeding