Radiation Therapy in Reduced Dose and Hypofractionated Schedule after Trans-Oral Robotic Surgery to Improve Quality of Life in Patients with Intermediate Risk HPV-Mediated Oropharyngeal Squamous Cell Carcinoma

Inclusion Criteria

• STEP 1 PRE-OPERATIVE: Participant aged ≥ 18 years
• STEP 1 PRE-OPERATIVE: Diagnosis of oropharyngeal squamous cell carcinoma
• STEP 1 PRE-OPERATIVE: Eligible to receive transoral robotic surgery
• STEP 1 PRE-OPERATIVE: P16 positivity or HPV positivity by in situ hybridization on pathological sampling of lymph node or primary oropharyngeal tumor
• STEP 1 PRE-OPERATIVE: Pre-operative tumor tissue modified viral (TTMV)-HPV deoxyribonucleic acid (DNA) test collected. * Standard of care tests completed within 60 days of registration may be used for screening. * Tests results are not required to confirm eligibility for step 1 registration
• STEP 1 PRE-OPERATIVE: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• STEP 1 PRE-OPERATIVE: Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
• STEP 2 EXPERIMENTAL ARM: Completion of trans-oral robotic surgery
• STEP 2 EXPERIMENTAL ARM: Pre- and post-operative TTMV-HPV DNA test results obtained
• STEP 2 EXPERIMENTAL ARM: For participants of child bearing potential: Negative pregnancy test or evidence of permanent surgical sterilization. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * < 50 years of age: ** Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and ** Luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution * ≥ 50 years of age: ** Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or ** Had radiation-induced menopause with last menses > 1 year ago; or ** Had chemotherapy-induced menopause with last menses > 1 year
• STEP 2 EXPERIMENTAL ARM: Participants of childbearing potential must agree to use a highly effective method of contraception
• STEP 2 EXPLORATORY ARM: Completion of trans-oral robotic surgery
• STEP 2 EXPLORATORY ARM: Pre- and post-operative TTMV-HPV DNA test results obtained
• STEP 2 EXPLORATORY ARM: Meets ANY of the following criteria: * Post-operative TTMV-HPV DNA positive or indeterminate * Surgical margin positive * > 1 mm extranodal extension * ≥ 5 lymph nodes
• STEP 2 EXPLORATORY ARM: Pre-operative TTMV-HPV DNA score of ≤ 50
• STEP 2 EXPLORATORY ARM: For participants of child bearing potential: Negative pregnancy test or evidence of permanent surgical sterilization. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * < 50 years of age: ** Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and ** Luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution * ≥ 50 years of age: ** Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or ** Had radiation-induced menopause with last menses > 1 year ago; or ** Had chemotherapy-induced menopause with last menses > 1 year
• STEP 2 EXPLORATORY ARM: Participants of childbearing potential must agree to use a highly effective method of contraception

Exclusion Criteria

• STEP 1 PRE-OPERATIVE: History of prior mucosal head and neck cancer treated with radiation therapy
• STEP 1 PRE-OPERATIVE: Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this study
• STEP 1 PRE-OPERATIVE: Participant has smoked cigarettes within 1 month of registration
• STEP 1 PRE-OPERATIVE: Prior systemic anti-cancer therapy or any investigational therapy ≤ 14 days or within five half-lives prior to starting study treatment, whichever is shorter
• STEP 1 PRE-OPERATIVE: Known distant metastatic disease
• STEP 1 PRE-OPERATIVE: Current evidence of any condition that would, in the Investigator’s judgment, contraindicate the participant’s participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [participants may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• STEP 1 PRE-OPERATIVE: Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study
• STEP 2 EXPERIMENTAL ARM: Meets ALL of the following criteria for low-risk disease (Note: participants may meet some without being excluded): * Pre-operative TTMV-HPV DNA positive * Post-operative TTMV-HPV DNA negative * Disease: pT1 with ≤ 1 lymph nodes OR pT2N0 * < 10 pack year smoking * No extranodal extension * Negative surgical margins * No perineural invasion * No lymphovascular invasion
• STEP 2 EXPERIMENTAL ARM: Meets ANY of the following criteria for high-risk: * Post-operative TTMV-HPV DNA positive * Surgical margin positive * > 1 mm extranodal extension * ≥ 5 lymph nodes
• STEP 2 EXPERIMENTAL ARM: Current evidence of any condition that would, in the Investigator’s judgment, contraindicate the participant’s participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [participants may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• STEP 2 EXPLORATORY ARM: Pre-operative TTMV-HPV DNA score of > 50
• STEP 2 EXPLORATORY ARM: Current evidence of any condition that would, in the Investigator’s judgment, contraindicate the participant’s participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [participants may not receive the drug through a feeding tube], social/ psychological issues, etc.)