<h3>Purpose/Objective(s)</h3> To determine the maximum-tolerated dose (MTD) of Dose-Escalated Hypofractionated Adaptive Radiation Therapy (DEHART) delivered with concurrent atezolizumab (Genentech) in patients with locally advanced or <i>de novo</i> metastatic head and neck squamous cell carcinomas (HNSCCs). (ClinicalTrials.Gov Identifier NCT04477759) We hypothesize that using DEHART we will be able to safely deliver ablative radiation doses for HNSCC in 15 fractions. <h3>Materials/Methods</h3> This is an NIH-funded (R21 CA256144-01) Phase I dose-escalation trial to determine the MTD of weekly adapted MR-guided radiation therapy delivered using the DEHART regimen with concurrent atezolizumab for patients with locoregionally advanced or <i>de novo</i> metastatic HNSCCs. Eligible patients are 18 years or older including all patients presenting with <i>de novo</i> metastatic HNSCC or patients presenting with localized AJCC 8<sup>th</sup> edition T3-T4 N0-N3, T0-T4 N1-N3 HNSCC who meet at least one of the following criteria: 1) they are not candidates for concurrent bolus cisplatin; 2) they refuse concurrent cisplatin-based chemoradiation; 3) they have unresected or unresectable oral cavity cancer; or 4) they have recurrent disease after definitive surgical resection. DEHART is a novel adaptive MR-guided radiation regimen in which the gross tumor volume (GTV) plus a 3 mm PTV margin receives the experimental dose (50 Gy, 55 Gy or 60 Gy) in 15 fractions, a 1 cm anatomically-confined margin on the GTV plus a 3 mm PTV margin receives 45 Gy in 15 fractions, and elective lymph node basins plus a 3 mm PTV margin receives 40 Gy in 15 fractions. On fractions 6 and 11 of radiation, the GTV volume is adapted based on MR-documented tumor regression. All patients are treated on a linear accelerator. All patients receive the DEHART radiation regimen with concurrent and adjuvant monthly atezolizumab for 1 year. Atezolizumab (1680 mg) is delivered on the first day of radiation and every 4 weeks thereafter for up to 1 year after treatment. The primary endpoint of the study is the MTD of DEHART determined using a modified Time-To-Event Continual Reassessment Methodology (TITE-CRM). The MTD is the radiation dose at which there is a 30% rate of dose-limiting toxicity (DLT) up to 12 months after completion of radiation therapy. DLTs include an inability to complete radiation within 30 days of starting radiation deemed not to be related to disease progression and any Grade 4+ toxicity probably or definitely related to treatment with radiation and/or atezolizumab. Secondary study endpoints include locoregional control, overall survival, and patient quality-of-life as measured by the MD Anderson Symptom Inventory for Head and Neck (MDASI-HN) and the MD Anderson Dysphagia Inventory (MDADI-HN). <h3>Results</h3> TBD <h3>Conclusion</h3> TBD