Testing Docetaxel-Cetuximab or the Addition of an Immunotherapy Drug, Atezolizumab, to the Usual Chemotherapy and Radiation Therapy in High-Risk Head and Neck Cancer

Inclusion Criteria:

• PHASE II INCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)

• Pathologically (histologically or cytologically) proven diagnosis of head and necksquamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips),oropharynx (p16 negative), larynx, or hypopharynx

• Patients must have undergone gross total surgical resection of high-risk oralcavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior toregistration; Note: patients may have biopsy under general anesthesia in anoperating room followed by definitive ablative cancer surgery representing grosstotal resection; the gross total resection has to be done within 63 days prior toregistration; if, however, patients have ablative resection but shortly recur or aredetermined to have persisting disease requiring re-resection to achieve gross totalresection, then the patient is not eligible

• Patients must have at least 1 of the following high-risk pathologic features:extracapsular nodal extension or invasive cancer at the primary tumor resectionmargin (tumor on ink)

• Pathologic stage III or IV HNSCC, including no distant metastases, based upon thefollowing minimum diagnostic workup:

• General history and physical examination by a radiation oncologist and/ormedical oncologist within 84 days prior to registration;

• Examination by an ear nose throat (ENT) or head & neck surgeon prior tosurgery; a laryngopharyngoscopy (mirror and/or fiber optic and/or directprocedure), if appropriate, is recommended but not required; intra-operativeexamination is acceptable documentation

• Pre-operative (op) Imaging of the head and neck: A neck computed tomography (CT) (with contrast) or CT/positron emission tomography (PET) (with contrast)and/or an magnetic resonance imaging (MRI) of the neck (T1 with gadolinium andT2) within 84 days prior to surgery; Note: this imaging data (diagnosticpre-operative scan showing gross disease) is to be submitted in Digital Imagingand Communications in Medicine (DICOM) format via TRIAD; the report is to beuploaded into Rave

• Chest CT scan (with or without contrast) or CT/PET that includes the chest (with or without contrast) either within 84 days prior to surgery or within 120days prior to registration; Note: if the CT/PET with or without contrast isdone within 84 days prior to surgery, it fulfills the chest imaging requirement

• Zubrod performance status of 0-1 within 14 days prior to registration

• Age >= 18

• Absolute granulocyte count (AGC) >= 1,500 cells/mm^3 (obtained within 14 days priorto registration on study)

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

• Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention toachieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

• Total bilirubin < 2 x institutional upper limit of normal (ULN) within 14 days priorto registration

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 xinstitutional ULN within 14 days prior to registration

• Serum creatinine institutional ULN within 14 days prior to registration or;creatinine clearance (CC) >= 50 ml/min within 14 days prior to registrationdetermined by 24-hour collection or estimated by Cockcroft-Gault formula

• Negative urine or serum pregnancy test within 14 days prior to registration forwomen of childbearing potential

• The following assessments are required within 14 days prior to registration: sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), andalbumin; Note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) mayreceive corrective magnesium supplementation but should continue to receive eitherprophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator's discretion

• Patients with feeding tubes are eligible for the study

• Women of childbearing potential and male participants who are sexually active mustagree to use a medically effective means of birth control

• Patient must provide study specific informed consent prior to study entry, includingconsent for mandatory tissue submission for epidermal growth factor receptor (EGFR)analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis

• PHASE III: Pathologically (histologically or cytologically) proven diagnosis of headand neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips),oropharynx (p16 negative), larynx, or hypopharynx

• PHASE III: Patients with oropharyngeal cancer must have p16-negative based oncentral review prior to Step 2 registration. All patients with oropharyngeal primarymust consent for mandatory tissue submission for central p16 confirmation

• PHASE III: Patients must have undergone gross total surgical resection of high-riskoral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days priorto registration

• Note: Patients may have biopsy under general anesthesia in an operating roomfollowed by definitive ablative cancer surgery representing gross totalresection. The gross total resection has to be done within 63 days prior toregistration. If, however, patients have ablative resection but shortly recuror are determined to have persisting disease requiring re-resection to achievegross total resection, then the patient is not eligible

• PHASE III: Patients must have at least 1 of the following high-risk pathologicfeatures: extracapsular nodal extension or invasive cancer at the primary tumorresection margin (tumor on ink or tumor in a final separately submitted margin)

• PHASE III: Pathologic stage III or IV HNSCC (American Joint Committee on Cancer [AJCC] 7th edition), including no distant metastases, based upon the followingminimum diagnostic workup:

• General history and physical examination by a radiation oncologist or medicaloncologist within 84 days prior to registration;

• Examination by an ENT or head & neck surgeon prior to surgery; alaryngopharyngoscopy (mirror or fiberoptic or direct procedure), ifappropriate, is recommended but not required. Intra-operative examination isacceptable documentation.

• Pre-op Imaging of the head and neck: A neck CT (with contrast and of diagnosticquality) or PET/CT (with contrast and of diagnostic quality) and/or an MRI ofthe neck of diagnostic quality (T1 with gadolinium and T2) within 84 days priorto surgery; Note: this imaging data (diagnostic pre-operative scan showinggross disease) is to be submitted in DICOM format via TRIAD. The report is tobe uploaded into Rave.

• Chest CT scan (with or without contrast) or PET/CT that includes the chest (with or without contrast) either within 84 days prior to surgery or within 120days prior to registration; Note: If the PET/CT with or without contrast isdone within 84 days prior to surgery, it fulfills the chest imaging requirement

• PHASE III: Zubrod performance status of 0-1 within 14 days prior to registration

• PHASE III: Age >= 18

• PHASE III: Leukocytes >= 2,500 cells/mm^3 (obtained within 14 days prior toregistration on study)

• PHASE III: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14days prior to registration on study)

• PHASE III: Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior toregistration on study)

• PHASE III: Hemoglobin >= 8.0 g/dL (Note: The use of transfusion or otherintervention to achieve Hgb >= 8.0 g/dL is acceptable) (obtained within 14 daysprior to registration on study)

• PHASE III: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 xinstitutional ULN may be enrolled) (within 14 days prior to registration)

• PHASE III: AST or ALT =< 3 x institutional ULN (within 14 days prior toregistration)

• PHASE III: Alkaline phosphatase =< 2.5 x institutional ULN (within 14 days prior toregistration)

• PHASE III: Creatinine clearance (CrCl) >= 50 mL/min within 14 days prior toregistration determined by 24-hour collection or estimated by Cockcroft-Gaultformula

• PHASE III: Patients with feeding tubes are eligible for the study

• PHASE III: Negative urine or serum pregnancy test within 14 days prior toregistration for women of childbearing potential

• PHASE III: All patients must provide study specific informed consent prior to studyentry

• PHASE III: Patients positive for human immunodeficiency virus (HIV) are allowed onstudy, but HIV-positive patients must have:

• A stable regimen of highly active anti-retroviral therapy (HAART);

• No requirement for concurrent antibiotics or antifungal agents for theprevention of opportunistic infections;

• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standardpolymerase chain reaction (PCR)-based tests

Exclusion Criteria:

• PHASE II EXCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma insitu of the breast, oral cavity, or cervix are all permissible) are permitted evenif diagnosed and treated < 3 years ago

• Patients with simultaneous primaries or bilateral tumors are excluded, with theexception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0resected differentiated thyroid carcinoma, who are eligible

• Prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for thestudy 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 ofradiation therapy fields

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin 6 months prior to registration

• Transmural myocardial infarction within 6 months prior to registration

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration

• Idiopathic pulmonary fibrosis or other severe interstitial lung diseasethat requires oxygen therapy or is thought to require oxygen therapywithin 1 year prior to registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulationdefects; note, however, that laboratory tests for coagulation parameters arenot required for entry into this protocol

• Acquired immune deficiency syndrome (AIDS) based upon current Centers forDisease and Control and Prevention (CDC) definition; note: humanimmunodeficiency virus (HIV) testing is not required for entry into thisprotocol; the need to exclude patients with AIDS from this protocol isnecessary because the treatments involved in this protocol may besignificantly immunosuppressive; protocol-specific requirements may alsoexclude immuno-compromised patients.

• Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 4):

• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5mg/dl (> 3.1 mmol/L) despite intervention to normalize levels

• Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14 mmol/L)

• Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despiteintervention to normalize levels

• Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels

• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels

• Pregnancy or women of childbearing potential and men who are sexually active and notwilling/able to use medically acceptable forms of contraception; this exclusion isnecessary because the treatment involved in this study may be significantlyteratogenic

• Prior allergic reaction to cetuximab

• PHASE III: Prior invasive malignancy (except non-melanomatous skin cancer) unlessdisease free for a minimum of 1095 days (3 years) with the following exceptions:T1-2, N0, M0 resected differentiated thyroid carcinoma; Note that noninvasivecancers (For example, carcinoma in situ of the breast, oral cavity, or cervix) arepermitted even if diagnosed and treated < 3 years ago

• PHASE III: Patients with simultaneous primaries or bilateral tumors are excluded,with the exception of patients with bilateral tonsil cancers or patients with T1-2,N0, M0 resected differentiated thyroid carcinoma, who are eligible

• PHASE III: Prior systemic therapy, including cytotoxic chemotherapy,biologic/targeted therapy (such as anti-EGF therapy), or immune therapy for thestudy cancer; note that prior chemotherapy for a different cancer is allowable,however, a prior anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is not permitted

• PHASE III: Prior radiotherapy to the region of the study cancer that would result inoverlap of radiation therapy fields

• PHASE III: Severe, active co-morbidity, defined as follows:

• Patients with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association FunctionalClassification; to be eligible for this trial, patients should be class 2B orbetter within 6 months prior to registration

• Transmural myocardial infarction within 6 months prior to registration;

• Severe infections within 4 weeks prior to registration including, but notlimited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia;

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration; Note: Patients receiving prophylactic antibiotics (e.g.,for prevention of a urinary tract infection or chronic obstructive pulmonarydisease exacerbation) are eligible.

• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration;

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest computedtomography (CT) scan. History of radiation pneumonitis in a prior radiationfield (fibrosis) is permitted, provided that field does not overlap with theplanned radiation field for the study cancer;

• Patients with active tuberculosis (TB) are excluded;

• Known clinically significant liver disease, including active viral, alcoholic,or other hepatitis; cirrhosis; fatty liver; and inherited liver disease;

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.

• Patients positive for hepatitis C virus (HCV) antibody are eligible onlyif polymerase chain reaction (PCR) is negative for HCV RNA.

• History of allogeneic bone marrow transplantation or solid organtransplantation.

• A diagnosis of immunodeficiency:

• Acquired immune deficiency syndrome (AIDS) based upon current CDCdefinition; note: HIV testing is not required for entry into thisprotocol; the need to exclude patients with AIDS from this protocol isnecessary because the treatments involved in this protocol may besignificantly immunosuppressive.

• Is receiving treatment with systemic immunosuppressive medications (including,but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeksprior to registration.

• Note: Patients who have received acute, low dose, systemicimmunosuppressant medications (e.g., a one-time dose of dexamethasone fornausea) may be enrolled.

• Note: The use of inhaled corticosteroids and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension oradrenocortical insufficiency is allowed.

• History or risk of autoimmune disease, including, but not limited to, systemiclupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascularthrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis,Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis.

• Patients with a history of autoimmune hypothyroidism who are asymptomaticand/or are on a stable dose of thyroid replacement hormone are eligible.

• Patients with controlled Type 1 diabetes mellitus on a stable insulinregimen are eligible.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligowith dermatologic manifestations only (e.g., patients with psoriaticarthritis would be excluded) are permitted provided that they meet thefollowing conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids)

• PHASE III: Grade 3-4 electrolyte abnormalities (CTCAE, v. 4) within 14 days prior toregistration:

• Serum calcium (ionized or adjusted for albumin) < 7 mg/dL (1.75 mmol/L) or > 12.5 mg/dL (> 3.1 mmol/L) despite intervention to normalize levels;

• Glucose < 40 mg/dL (< 2.2 mmol/L) or > 250 mg/dL (> 14 mmol/L);

• Magnesium < 0.9 mg/dL (< 0.4 mmol/L) or > 3 mg/dL (> 1.23 mmol/L) despiteintervention to normalize levels;

• Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels;

• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels.

• PHASE III: Pregnancy or women of childbearing potential and men who are sexuallyactive and not willing/able to use medically acceptable forms of contraception forup to 5 months from last study treatment; this exclusion is necessary because thetreatment involved in this study may be significantly teratogenic. Women who arebreastfeeding and unwilling to discontinue are also excluded

• PHASE III: History of severe allergic, anaphylactic, or other hypersensitivityreactions to chimeric or humanized antibodies or fusion proteins

• PHASE III: Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Useof bisphosphonate therapy for other non-oncologic reasons (e.g., osteoporosis) isallowed

• PHASE III: Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) fornon-oncologic reasons who cannot discontinue it before registration

• PHASE III: Patients with known distant metastatic disease are excluded

• PHASE III: Known hypersensitivity to Chinese hamster ovary cell products or otherrecombinant human antibodies

• PHASE III: Major surgical procedure within 28 days prior to registration oranticipation of need for a major surgical procedure during the course of the study

• PHASE III: Administration of a live, attenuated vaccine within 4 weeks prior toregistration or anticipation that such a live, attenuated vaccine will be requiredduring the study and for patients receiving atezolizumab, up to 5 months after thelast dose of atezolizumab.

• Influenza vaccination should be given during influenza season only (approximately October to