A Study Evaluating Efficacy and Safety of Multiple Treatment Combinations in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (Morpheus-Head and Neck Cancer)

This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with locally advanced squamous cell carcinoma of the head and neck (SCCHN). The study will enroll treatment-naive participants with resectable Stage III-IVA human papillomavirus (HPV)-negative, programmed death-ligand 1 (PD-L1)-positive SCCHN with measurable disease, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) who have not received systemic treatment for their disease.


Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Oncology Group Performance Status of 0 or 1
* Histologically confirmed, resectable Stage III-IVA SCCHN
* Eligible candidate for R0 resection with curative intent at the time of screening
* HPV-negative test for oropharyngeal carcinoma, as determined locally by p16 immunohistochemistry (IHC), in situ hybridization, or polymerase chain reaction-based assay
* Measurable disease (at least one target lesion), as assessed according to RECIST v1.1
* PD-L1 expression, defined as a combined positive score (CPS) \>= 1
* Adequate hematologic and end-organ function
* Negative HIV test with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count \>= 200/μL, and have an undetectable viral load.
* Negative hepatitis B surface antigen (HBsAg) test at screening
* Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: Negative total hepatitis B core antibody (HBcAb), Positive total hepatitis B core antibody (HBcAb) followed by a negative quantitative hepatitis B virus (HBV) DNA.

Exclusion Criteria:

* HPV-positive oropharyngeal cancer, as determined locally by p16 IHC, in situ hybridization, or by polymerase chain reactions-based assay
* Distantly metastasized SCCHN
* Any prior therapy for SCCHN, including immunotherapy, chemotherapy, or RT
* Prior treatment with any of the protocol-specified study treatments
* Treatment with investigational therapy within 42 days prior to initiation of study treatment
* Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
* Prior allogeneic stem cell or solid organ transplantation
* Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment
* Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment
* Active or history of autoimmune disease or immune deficiency
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT scan)
* History of malignancy other than SCCHN within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5 -year OS rate\>90%)
* Active tuberculosis
* Severe infection within 4 weeks prior to initiation of study treatment
* Treatment with therapeutic or prophylactic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment
* Significant cardiovascular disease such a New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhytmia, or unstable angina
* Major surgical procedure, other than for diagnosis, within 4 weeks prior to study initiation of study treatment, or anticipation of need for a major surgical procedure other than tumor resection, during the study
* Any of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of investigational drug, may affect the interpretation of the results, impair the ability of the patient to participate in the study, or renders the patient at high risk form treatment complications
* History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
* Known allergy or hypersensitivity to any of the study drugs or their excipients
* Known intolerance to any of the drugs required for premedication
* Pregnancy or breastfeeding, or intention of becoming pregnant during the study
* Eligible only for the control arm
* Active EBV infection or known or suspected chronic EBV infection at screening

Specific Exclusion Criteria for Atezo+Tira+CP:

* Known severe allergy or hypersensitivity to placlitaxel, platinum or platinum-containing compounds
* Known history of severe hypersensitivity to products containing Cremophor EL
* Creatinine clearance \<45m./min (Calculated using the Cockcroft-Gault formula)