This a study protocol that details a phase 1 trial investigating a new approach using image-guided proton therapy for dose escalation treatments for selected patients with HPV-negative, locally advanced head and neck cancer. The PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3–6 months after radiation. The accrual of patients at MDACC started in May 2021. Two patients have been enrolled in the study at current standing. The total accrual time of the 18 HNC patients is expected to be within 2 years.