Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Locoregionally Advanced Head and Neck Cancer Who Cannot Take Cisplatin

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

• Patients must have pathologically confirmed, previously untreated, unresectedsquamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, orcarcinoma of unknown head/neck primary prior to step 1 registration; submission ofhematoxylin and eosin (H&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank atUniversity of California, San Francisco (UCSF) for central review for oropharyngealand unknown primaries and for p16 analysis for all other non-oropharyngeal primariesis mandatory for all patients; investigators should check with their pathologydepartment regarding release of biospecimens before approaching patients aboutparticipation in the trial; for oropharyngeal and unknown primaries, submission ofH&E and p16 stained slides (with the required block for PD-L1) to the biospecimenbank at UCSF for central review is also required prior to step 2 registration

• Note: fine needle aspirates (FNA) samples are not acceptable since they do notprovide enough material for PD-L1 and p16 testing; however, if a cell blockderived from the FNA is available, it is allowable if there are sufficientcells present in the block for PD-L1 testing; Dr. Jordan will determine thisupon receipt; for sites submitting FNA cell blocks for ALL patients they mustdo so within 7-10 business days from registering the patient; sites mustconfirm with their cytology/pathology labs to make sure they can provide therequired material as the bank must be able to retain these samples for themandatory testing

• Patients must have locoregionally advanced head and neck squamous cell carcinoma (HNSCC)

• For p16-positive oropharyngeal/unknown primaries, American Joint Committee onCancer [AJCC] 8th edition stage III and selected stage I-II based on smokingstatus in pack-years

• For laryngeal, hypopharyngeal, and oral cavity primaries and p16-negativeoropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB

• Based on the following minimum diagnostic workup within 60 days prior to step 1registration:

• General history and physical examination by a radiation oncologist ormedical oncologist or ear, nose and throat (ENT) or head & neck surgeon

• For larynx, hypopharynx, and base of tongue primaries, alaryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) isrequired, unless the patient cannot tolerate or refuses

• Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT; note that the CT portion ofthe PET/CT must be of diagnostic quality, including contrast administrationunless contraindicated. If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unlesscontraindicated) is required

• Chest imaging: chest CT with and without contrast (unless contraindicated) orPET/CT

• Patients must have a contraindication to cisplatin as defined in the followingbullet points; sites must complete the online tool at comogram.org prior to step 1registration to determine if the patient is eligible; the scores must be recorded ona case report form (CRF)

• Age >= 70 with moderate to severe comorbidity or vulnerability to cisplatin,defined as having one or more of the following conditions within 30 days priorto step 1 registration:

• Modified Charlson Comorbidity Index >= 1

• Adult Comorbidity Evaluation (ACE)-27 Index >= 1

• Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score < 0.80

• Geriatric screening (G-8) score =< 14

• Cancer and Aging Research Group (CARG) toxicity score >= 30%

• Cumulative Illness Rating scale for Geriatrics (CIRS-G) score >= 4 OR

• Age < 70 with severe comorbidity or vulnerability to cisplatin, defined ashaving two or more of the following conditions within 30 days prior to step 1registration

• Modified Charlson Comorbidity Index >= 1

• ACE-27 Index >= 1

• GCE omega PFS-score < 0.80

• G-8 score =< 14

• CARG Toxicity score >= 30%

• CIRS-G score >= 4 OR

• Age >= 18 with an absolute or relative contraindication to cisplatin, definedas one or more of the following within 30 days prior to step 1 registration:

• Creatinine clearance (CC) > 30 and < 60 cc/min; for this calculation, usethe Cockcroft-Gault formula

• Zubrod performance status 2 prior to step 1 registration

• Pre-existing peripheral neuropathy grade >= 1

• History of hearing loss, defined as either:

• Existing need of a hearing aid OR

• >= 25 decibel shift over 2 contiguous frequencies on a pretreatmenthearing test as clinically indicated

• Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (within 14 days prior to step 1registration)

• Platelets >= 100,000 cells/mm^3 (within 14 days prior to step 1 registration)

• Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention toachieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to step 1registration)

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 timesinstitutional upper limit of normal (within 14 days prior to step 1 registration)

• Serum bilirubin =< 1.5 x institutional upper limit of normal (within 14 days priorto step 1 registration)

• Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urinecollection for determination of creatinine clearance (within 14 days prior to step 1registration)

• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration; Note: women will be considered post-menopausalif they have been amenorrheic for 12 months without an alternative medical cause;the following age-specific requirements apply:

• Women < 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy)

• Women >= 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy)

• The patient or a legally authorized representative must provide study-specificinformed consent prior to step 1 registration

• PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA

• For patients with oropharyngeal or unknown primaries: p16 determination byimmunohistochemistry (defined as greater than 70% strong nuclear or nuclear andcytoplasmic staining of tumor cells), confirmed by central pathology review

• Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries,analysis of p16 status prior to step 2 registration/randomization is notrequired (p16 status will be analyzed centrally post-hoc); step 2 registrationfor these patients can be completed after step 1 registration

Exclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

• Prior invasive malignancy within the past 3 years (except for non-melanomatous skincancer, and early stage treated prostate cancer); synchronous head and neckprimaries are ineligible

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields

• Note: Prior external beam radiotherapy is excluded, but iodine 131 is allowed

• Prior immunotherapy

• Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy,or immune therapy for the study cancer

• Major surgery within 28 days prior to step 1 registration

• Proven evidence of distant metastases

• If both of the following conditions are present, the patient is ineligible:

• =< 10 pack-year smoking history

• p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC 8th Edition)

• Note: in the event that a registered patient with =< 10 pack-years has ap16-positive result on central review with the tumor and nodal stage T0-3,N0-1 (AJCC 8th Edition), then the site will be notified that the patientis ineligible

• Zubrod performance status >= 3

• Body weight =< 30 kg

• Patients with oral cavity cancer are excluded from participation if the patient ismedically operable and resection of the primary tumor is considered technicallyfeasible by an oral or head and neck cancers surgical subspecialist;(please consultthe surgical oncology co-principal investigator [PI], Steven Chang, Doctor ofMedicine [MD], if clarification is needed on an individual case)

• Sodium < 130 mmol/L or > 155 mmol/L (within 14 days of step 1 registration, unlesscorrected prior to step 1 registration)

• Potassium < 3.5 mmol/L or > 6 mmol/L (within 14 days of step 1 registration, unlesscorrected prior to step 1 registration)

• Fasting glucose < 40 mg/dl or > 400 mg/dl (within 14 days of step 1 registration,unless corrected prior to step 1 registration)

• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl (within 14days of step 1 registration, unless corrected prior to step 1 registration)

• Magnesium < 0.9 mg/dl or > 3 mg/dl (within 14 days of step 1 registration, unlesscorrected prior to step 1 registration)

• Unstable angina and/or congestive heart failure requiring hospitalization within 3months prior to step 1 registration

• Transmural myocardial infarction within 3 months prior to step 1 registration

• Respiratory illness requiring hospitalization at the time of step 1 registration

• Note: if the respiratory illness is resolved and the patient meets theeligibility status above, then the patient can be considered for the trial

• Idiopathic pulmonary fibrosis or other severe interstitial lung disease thatrequires oxygen therapy or is thought to require oxygen therapy within 1 year priorto step 1 registration

• History of (non-infectious) pneumonitis that required steroids or currentpneumonitis

• Clinically apparent jaundice and/or known coagulation defects

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.)

• The following are exceptions to this criterion:

• Patients with vitiligo or alopecia;

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stableon hormone replacement;

• Any chronic skin condition that does not require systemic therapy;

• Patients without active disease in the last 5 years may be included butonly after consultation with the medical oncology study chair;

• Patients with celiac disease controlled by diet alone

• History of active primary immunodeficiency including, but not limited to acquiredimmune deficiency syndrome (AIDS) based upon current Centers for Disease Control andPrevention (CDC) definition; Note: human immunodeficiency virus (HIV) testing is notrequired for entry into this protocol; the need to exclude patients with AIDS fromthis protocol is necessary because the treatment involved in this protocol may beimmunosuppressive; patients with known HIV, CD4 counts >= 200/uL, and undetectableviral loads who are stable on an antiretroviral regimen may be included

• Current or prior use of immunosuppressive medication within 14 days before step 1registration, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/dayof prednisone, or an equivalent corticosteroid

• Receipt of live attenuated vaccination within 30 days prior to step 1 registration

• Medical or psychiatric illness which would compromise the patient's ability totolerate treatment or limit compliance with study requirements

• Pregnancy or women of childbearing potential and men who are sexually active and notwilling/able to use medically acceptable forms of contraception during treatment andfor 6 months after the last dose of cetuximab or MEDI14736 (durvalumab); thisexclusion is necessary because the treatment involved in this study may besignificantly teratogenic; women who are breastfeeding are also excluded

• Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) orany of study drug excipients

• History of allogenic organ transplantation

• Uncontrolled hypertension

• Uncontrolled cardiac arrhythmia

• Uncontrolled serious chronic gastrointestinal condition associated with diarrhea

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis [TB]testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C; patients with a past or resolvedHBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCVribonucleic acid (RNA)