P53 Mutational Status and cf HPV DNA for the Management of HPV-associated OPSCC

The proposed study is a follow-up study to LCCC 1120 and 1413. The investigators have shown
that de-intensification is efficacious in these two phase II studies. A major question is
whether the investigators can de-intensify in patients with HPV-associated oropharyngeal
cancer who have smoking histories. The investigators' hypothesis is that genomic profiling of
patients' tumors (specifically for p53 mutations) will help in triaging patients to
de-intensification versus standard of care. Patients with HPV-associated OPSCC will be
enrolled regardless of smoking history and p53 mutational status will be assessed in patients
with a smoking history. The investigators will use the same de-intensification
chemoradiotherapy regimen already evaluated in LCCC 1120 and 1413 in patients with
HPV-associated OPSCC who have a minimal smoking history and in patients with a smoking
history but with wild-type p53. Patients with a smoking history who have mutated p53 will not
receive de-intensified chemoradiotherapy, but instead will receive standard doses. The
hypothesis is that by using genomics in the patients with a significant smoking history, the
investigators will better select those who can be safely de-intensified. Circulating free HPV
DNA (cf-HPV-DNA) will also be prospectively assessed from blood samples.

Inclusion Criteria:

1. ≥ 18 years of age (no upper age limit)

2. T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx

3. Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive

4. Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks
prior to treatment

5. ECOG Performance Status 0-1

6. CBC/differential obtained within 8 weeks prior to treatment, with adequate bone marrow
function defined as follows: Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl

7. Adequate renal and hepatic function within 4 weeks prior to treatment, defined as
follows: Serum creatinine < 2.0 mg/dl; Total bilirubin < 2 x the institutional ULN;
AST or ALT < 3 x the institutional ULN

8. Negative pregnancy test within 2 weeks prior to treatment for women of childbearing
potential

9. Women of childbearing potential and male participants who are sexually active must
practice adequate contraception during treatment and for 6 weeks following treatment.

10. Patients must be deemed able to comply with the treatment plan and follow-up schedule.

11. Patients must provide study specific informed consent prior to study entry

Exclusion Criteria:

1. Prior history of radiation therapy to the head and neck

2. Prior history of head and neck cancer.

3. Unresectable disease (e.g. immobile node on physical exam, nodal disease that
radiographically involves the carotid arteries, nerves)

4. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs)

5. 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
or precluding study therapy at the time of registration; Hepatic insufficiency
resulting in clinical jaundice and/or coagulation defects (Note, however, coagulation
parameters are not required for entry into this protocol); Pre-existing ≥ grade 2
neuropathy; Prior organ transplant; Systemic lupus; Psoriatic arthritis

6. Known HIV positive.