A Study on Using Cell-Free Tumor DNA (ctDNA) Testing to Decide When to StartRoutine Treatment in People With Human Papilloma Virus (HPV)- Associated Oropharynx Cancer (OPC)

Inclusion criteria

• Age ≥ 18
• ECOG 0-2
• HPV-16 squamous cell carcinoma of the oropharynx or HPV-16 head and neck squamous cell carcinoma of unknown primary . HPV status must be confirmed by in-situ hybridization.
• HPV ctDNA detectable by HPV digital PCR (Naveris assay) with a minimum of 50 copies/mL pre-operatively.
• Surgical resection of all gross disease with no gross disease visualized on post-operative imaging.

o For patients with pT0 (unknown primary) evaluation for the primary should include PET/CT, direct laryngoscopy, ipsilateral tonsillectomy, and targeted biopsy. This should be followed by a neck dissection.

• Two, undetectable (<1 copy/mL) post-operative HPV ctDNA within 2-6 weeks following surgery (blood drawn at least one week apart preferred).
• A minimum of one of the following pathologic criteria: (Arm A)

• AJCC 7 Stage: pT0N1-N2b, pT1N1, pT2N1, or ≥pT3
• AJCC 7 ≥pN2
• Lymphovascular invasion
• Perineural invasion
• Close pathologic margin (≤ 3 mm)
• Signed informed consent form by the participant or their legally authorized representative (LAR).
• A minimum of one of the following pathologic criteria (Arm B):

• Microscopic positive margin
• Extracapsular extension
• Signed informed consent form by the participant or their legally authorized representative (LAR).

Additional criteria for Arm B only:

• Adequate hematologic function within 30 days prior to registration, defined as follows:

• White Blood Count (WBC) ≥ 2 K/mcL
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
• Platelets ≥ 100,000 cells/mm3
• Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable
• Adequate renal function within 30 days prior to registration, defined as follows:

• Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula:
• CCr male = [(140 - age) x (wt in kg)] divided by [(Serum Cr mg/dl) x (72)]
• CCr female = 0.85 x (CrCl male)
• Adequate hepatic function within 30 days prior to registration, defined as follows:

• Bilirubin < 2 mg/dl o AST or ALT < 3 x the upper limit of normal
• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

Exclusion criteria

• Metastatic disease
• Non-HPV16 genotype (i.e. HPV-18,-31, -33, -35)
• Patients who receive surgery at outside institution. Exceptions can be made for high-volume surgical centers at the discretion of the PI/co-PI
• Prior head and neck radiation
• Patients without pre-operative HPV ctDNA or pre-operative HPV ctDNA ≤ 50 copies/mL
• Subjects with simultaneous primary cancers outside of the oropharynx

o Note: Exceptions can be made for patients with simultaneous primaries outside of the oropharynx if determined by the PI/Co-PI, then the patient can proceed with protocol activities

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 3 years or if cure rate from treatment at 5 years is 90% or greater

o Note: Exceptions can be made for patients with prior invasive malignancy if determined by the PI/Co-PI, then the patient can proceed with protocol activities

• Prior systemic chemotherapy for the study cancer

o Note: prior chemotherapy for a different cancer is allowable

• Severe, active co-morbidity defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 30 days of registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Lack of ability to understand and willingness to sign a written informed consent and complete questionnaires.