Phase I/II Trial of Radiotherapy in Combination With Atezolizumab Prior to Surgical Resection for HPV-unrelated Squamous Cell Carcinoma of the Head and Neck (HNSCC)

• Provision to sign and date the consent form

• Stated willingness to comply with all study procedures and be available for the duration of the study

• Histologically or cytologically confirmed: stage II-IVB oral cavity, stage III-IVB larynx, stage III-IVB hypopharynx, stage III-IVB sinonasal, or stage III-IVB HPV- and/or p16-negative intermediate-high risk oropharynx head and neck cancer (AJCC 8th edition)

• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>10 mm by CT, PET/CT or MRI or \>10 mm on visual inspection by clinical exam

• Patients who are deemed resectable by ENT surgeon without pre-existing medical conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse surgery

• Age ≥ 18 years at time of study entry

• ECOG performance status ≤ 1

• Body weight \>30 kg

• Adequate normal organ and marrow function as defined below:

‣ Hemoglobin ≥9.0 g/dL

⁃ Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥ 1500 per mm3) without granulocyte colony-stimulating factor support.

⁃ Lymphocyte count ≥0.5 × 109/L (500/μL)

⁃ Platelet count ≥100 x 109/L (≥100,000 per mm3) without transfusion

⁃ Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.

⁃ AST (SGOT)/ALT (SGPT)/ ALP ≤2.5 x institutional upper limit of normal

⁃ Serum albumin ≥ 25 g/L (2.5 g/dL)

⁃ For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN

⁃ For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

⁃ Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

• Males:

• Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

• Females:

• Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

⁃ Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. See section 6.12 for additional details and contraception requirements for patients on study. Women will be considered post-menopausal if 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 been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)

‣ Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

⁃ Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up