Durvalumab, Cetuximab and Radiotherapy in Head Neck Cancer

Inclusion Criteria: * Written informed consent and any locally-required authorization obtained from the patients prior to performing any protocol-related procedures, including screening evaluations * Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx, hypopharynx and larynx * For patients with oropharyngeal cancer only: confirmed HPV status by HPV- DNA ISH prior to registration * Confirmed PD-L1-positive or -negative status by the Ventana SP263 IHC assay * Patients agree to provide their smoking history prior to registration * Clinical stage of HPV-negative oropharynx and all hypopharynx and larynx: T1-2, N2a-N3 or T3-4, any N (AJCC 7th ed.), including no distant metastases * Clinical stage of HPV-positive oropharynx: T2-4, N2b-N3 (AJCC 7th ed.), including no distant metastases with smoking history ≥ 10 pack/years * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate bone marrow: absolute neutrophil count ≥ 1,500/μl, platelets ≥ 100,000/μl, hemoglobin ≥ 9 g/dL * Adequate hepatic function: total bilirubin ≤ 1.5 X upper normal limit (UNL), aspartate aminotransferase (AST) ≤ 2.5 X UNL, alanine aminotransferase (ALT) ≤ 2.5 X UNL * Adequate renal function: calculated serum creatinine clearance \>40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection Exclusion Criteria: * Histologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including patients with SCCHN of unknown primary or non-squamous histologies (eg, nasopharynx or salivary gland) * Clinical stage of HPV-negative oropharynx and all hypopharynx and larynx: T1-2, N0-1 (AJCC 7th ed.) * Clinical stage of HPV-positive oropharynx: T1-2, N0-N2a (AJCC, 7th ed.) or any T, any N with smoking history of \< 10 pack/years * History of another primary malignancy except for: malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease (eg, carcinoma in situ of the breast, oral cavity and cervix are all permissible); low risk prostate cancer based on NCCN criteria on active surveillance, not candidate to any curative treatment given the extremely low likelihood of disease progression * Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease * Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable * Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields * Prior use of cetuximab or other anti-EGFR therapy * Any previous treatment with PD-1 or PD-L1 inhibitors, including Durvalumab * Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction * Current or prior use of immunosuppressive medication within 28 days before the first dose of Durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid * Any unresolved toxicity (\>CTCAE grade 2) from previous anti-cancer therapy * Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1 * Active or prior documented autoimmune disease within the past 2 years (subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment within the past 2 years are not excluded) * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) * History of primary immunodeficiency * History of allogeneic organ transplant * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent * Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction 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 * Known history of active infection including tuberculosis