Proton Spatially Fractionated Radiotherapy or Photon Stereotactic Body Radiotherapy in Combination With Pembrolizumab Before Surgery for the Treatment of Locally Advanced and Radiation-Naive Locoregionally Recurrent Oral Cavity Cancer, OSPRI Trial

• Biopsy Procedure (Procedure), also known as Biopsy, BIOPSY_TYPE, Bx: Undergo tissue biopsy
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT or PET/CT
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo PET/MRI
• Pembrolizumab (Biological), also known as BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475: Given IV
• Photon Stereotactic Body Radiation Therapy (Radiation), also known as Photon SBRT: Receive photon SBRT
• Positron Emission Tomography (Procedure), also known as Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT: Undergo PET/CT or PET/MRI
• Spatially-fractionated Radiation Therapy (Radiation), also known as GRID Therapy, SFRT, Spatially Fractionated Radiation Therapy: Receive proton SFRT
• Surgical Procedure (Procedure), also known as Operation, Surgery, Surgery Type, Surgery, NOS, Surgical, Surgical Intervention, Surgical Interventions, Surgical Procedures, Type of Surgery: Undergo surgical resection

Primary outcomes

• Improvement in major pathologic response rate (MPR) [At the time of surgical resection]: MPR is defined from pathologic evaluation of the surgically resected tumor, demonstrating less than 10% of residual tumor in the resection sample (≥90% disease reduction). Will be assessed using a Bayesian pick-the-winner randomized phase-II clinical trial design.

Secondary outcomes

• Pathologic complete response rate [At the time of surgical resection]: Pathologic complete response rate is defined from pathologic evaluation of the surgically resected tumor, demonstrating no signs of residual disease following immuno-radiation. This will be calculated separately for Arm A and for Arm B.
• Percent of patients receiving the prescribed therapy [Up to 1 year]: Will be defined as the number of patients who received the prescribed therapy divided by the number of evaluable patients who signed a consent form and began treatment. This will be calculated separately for Arm A and Arm B.
• Incidence of Adverse Events (AEs) Prior to Surgery: [From the time of registration until surgery]: Overall AEs, overall toxicities, and by maximum grade per type of AE per patient of the AEs that occur before surgery will be explored and summarized descriptively, mainly through the use of frequency tables. Toxicity is defined as an adverse event that is classified as possibly, probably, or definitely related to study treatment. AEs are graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with histologically confirmed human papillomavirus (HPV)/p16-unrelated squamous cell carcinoma of the oral cavity and:

  * Either locally advanced (T3-T4) non-metastatic disease, or
  * Radiation-naïve locoregionally recurrent disease (prior radiation to a site outside of the treatment fields is permitted)
* Age ≥ 18 years old
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
* Eligible to receive immunotherapy on multidisciplinary evaluation
* Ability to complete questionnaire(s) by themselves or with assistance
* Provide signed written informed consent in accordance with ethical, regulatory, and institutional requirements
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* Willing to consent to and provide tissue and blood samples for correlative research purposes (not the optional Riskguard and OncoExtra testing)
* PD-L1 combined positive score ≥ 1

Exclusion Criteria:

* Participation in another clinical study with an investigational product during the last 3 months (12 weeks)

  * Exception: Unless it is an observational (non-interventional) clinical study during the follow-up period of the study
* Contraindications to pembrolizumab
* Prior radiation therapy to the head and neck
* Previous anticancer therapeutic received ≤ 30 days prior to registration, or adequate washout period on a per-agent basis, or concurrent anti-cancer therapeutic not specified by this protocol
* Uncontrolled pre-existing condition(s), such as infection, congestive heart failure, hypertension, angina, arrhythmia, chronic diarrhea, psychiatric conditions, or others, that in the opinion of the treating investigator limits the ability to provide consent or longitudinal participation in this study
* Inability to place 2 or more SFRT spheres within the tumor target
* Prophylactic placement of feeding tubes is not allowed

• Daniel K. Ebner, MD, MPH, Principal investigator, Mayo Clinic in Rochester