Using CircuLating Tumor DNA to Risk Adapt Post-Operative Therapy for HPV-associated Oropharyngeal Cancer

Inclusion Criteria:

• AJCC 8th edition T0-3N0-2 p16-positive oropharyngeal (tonsil, base of tongue,glossotonsillar sulcus, soft palate, oropharyngeal wall) squamous cell carcinoma orsquamous cell carcinoma of unknown primary involving the cervical lymph nodes.Cytologic diagnosis from a cervical lymph node is sufficient for diagnosis in thepresence of clinical evidence of a primary tumor in the oropharynx.

• For patients with pT0 tumors (unknown primary), there must be at least onemetastatic lymph node present in cervical level II.

• p16 is strongly positive by immunohistochemistry or high-risk HPV is detected byin-situ hybridization.

• Have undergone or will undergo gross total resection of all known disease in thehead and neck via transoral robotic surgery. For patients with clinical unknownprimary tumors, a patient must undergo both ipsilateral tonsillectomy and base oftongue resection unless the primary is identified clinically or pathologically atthe time of surgery. If the primary is identified, then only resection of theprimary site is required. If the primary tumor is resected with negative marginswith a non-robotic surgery, such as a diagnostic tonsillectomy, this is consideredacceptable and further robotic surgery is not necessary.

• Have undergone or will undergo neck dissection.

• Have at least one of the following after surgery:

• Pathologic stage T3

• 2 or more positive lymph nodes

• At least one lymph node >3cm

• Contralateral lymph node involvement

• Lymphovascular invasion

• Perineural invasion

• Extranodal extension

• Close/positive margins: Close margins are considered ≤3mm from the peripheralmargins and ≤1mm from the deep margin on the en bloc specimen, unless the areaof close margin is re-resected and without carcinoma.

• Patients consented preoperatively are required to have detectable cTTMV-HPV DNAbased on pre-operative NavDx testing. For patients consented post-operatively, NavDxtesting should be performed on the tumor tissue to ensure detectable HPV DNA and forHPV subtyping.

• Age ≥ 18 years old

• ECOG performance status 0 or 2 within 56 days of start of chemoradiation.

• Women of childbearing potential require a negative serum or urine pregnancy testwithin 28 days prior to start of chemoradiation.

• Written informed consent obtained from subject and ability for subject to complywith the requirements of the study.

• Adequate hematologic and renal function within 56 days of start of chemoradiation,defined as:

• Hemoglobin ≥ 9.0 g/dL

• Platelets ≥ 100, 000 cells/mm3

• ANC ≥ 1.5 X 109/L

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase/alanine aminotransferase ≤ 3.0 x upper limit ofnormal (ULN)

• Serum creatinine ≤1.5 x upper limit of normal (ULN) OR a calculated creatinineclearance ≥50 mL/min estimated using the following Cockcroft-Gault equation

Exclusion Criteria:

• AJCC 8th edition pT4 or cN3 disease.

• Radiologic or clinical evidence of distant metastasis.

• Recurrent disease.

• Inability to achieve gross total resection at time of surgery.

• Greater than 56 days (8 weeks) after surgical resection of the primary site.

• Prior radiation to the head and neck > 30 Gy.

• Prior active invasive (not in situ) malignancy within the prior 2 years, excludingcutaneous basal cell or squamous cell carcinoma, low or intermediate risk prostatecancer, papillary thyroid cancer, stage T1aN0 kidney cancer, low-grade T1-2N0salivary cancer, AJCC 8th edition stage I-II breast cancer, well-differentiatedneuroendocrine tumors (e.g., carcinoid tumors), low grade non-Hodgkin lymphoma, orStage 0, I, and III cutaneous melanomas. Patients with synchronous or multifocaloropharyngeal cancers are not excluded, as long as at least one of these tumors meetinclusion criteria for the trial.

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of enrollment

• Hepatic insufficiency resulting in clinical jaundice and/or known coagulationdefects

• Moderate to severe hearing loss.

• Active connective tissue disease (e.g. systemic lupus erythematous, scleroderma)requiring immunosuppression.

• Pregnant or breast-feeding women.

• Prior allergic reaction to cisplatin.

• Live vaccines within 30 days prior to the first dose of chemoradiation. Examples oflive vaccines include, but are not limited to, the following: measles, mumps,rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral vaccine). Seasoninfluenza vaccines for injection are generally killed virus vaccines and areallowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuatedvaccines and are not allowed.