Induction Chemotherapy Followed by Risk and Response-Stratified Treatment in Patients with HPV+ Oropharyngeal Squamous Cell Cancer

Inclusion Criteria

• Subjects must have pathologically confirmed HPV-positive head and neck squamous cell carcinoma of the oropharynx. Confirmed HPV-positive disease of other subsites are uncommon but also eligible
• HPV testing must be compliant with the following criteria: * p16 immunohistochemistry (IHC) positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al) * p16 IHC positivity is to be validated using an HPV polymerase chain reaction (PCR) which is anticipated to result during the induction phase. This is essential as HPV genotype influences treatment arm allocation, with HPV18 strain being considered high risk * HPV PCR must demonstrate HPV16 or HPV18 subtype
• Availability of >= 10 unstained 5 micron slides (to be provided to Human Tissue Resource Center [HTRC] at the University of Chicago). Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study
• Patients must be at least 18 years of age
• Subjects with American Joint Committee on Cancer (AJCC) (8th edition, 2018) N1 (if single node, must be >= 3 cm), N2-N3 nodal disease or T3-T4 primary tumor
• Measurable disease (either primary site and/or nodal disease) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• No previous radiation or chemotherapy for a head and neck cancer
• No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or biopsies will occur after baseline scans are performed and measurable lesions are identified
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Leukocytes >= 3000/mm^3
• Platelets >= 100,000/mm^3
• Absolute neutrophil count >= 1,500
• Hemoglobin >= 9.0 gm/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal
• Alkaline phosphatase =< 2.5 x upper limit of normal
• Albumin > 2.9 gm/dL
• Total bilirubin =< 1.5 mg/dL
• Creatinine clearance > 45 mL/min, normal within 2 weeks prior to start of treatment (Of note, the standard Cockcroft and Gault formula must be used to calculate creatinine clearance [CrCl] for enrollment or dosing)
• Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug
• Women must not be breastfeeding
• Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment
• Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s)

Exclusion Criteria

• Unequivocal demonstration of distant metastatic disease (M1 disease)
• Non-HPV16/18 subtype
• Unidentifiable primary site
• Intercurrent medical illnesses which would impair patient tolerance to therapy or limit survival. This includes but is not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance. Patients with clinically stable and/or chronically managed medical illnesses that are not symptomatic and/or are not expected to impact treatment on protocol are still eligible (conditions to be reviewed by the principal investigator [PI] to confirm eligibility)
• Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment as discussed above
• Patients receiving other investigational agents
• Prior systemic anti-cancer treatment within the last 8 weeks
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence life expectancy in the subsequent 3 years without active treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has a history of human immunodeficiency virus (HIV)
• Has known active hepatitis B or hepatitis C. If eradicated, patient is eligible
• Has received a live vaccine within 28 days of planned start of study therapy