Risk Adapted De-Intensification of Radio-Chemotherapy for Oropharyngeal Squamous Cell Carcinoma

This study builds on the results of several prior studies that we have been involved with to test the hypothesis that Risk-Adapted De-Intensification of Radiation Therapy and chemotherapy based on HPV subtype, plasma circulating free HPV DNA (cfHPV DNA) level, and cfHPV DNA clearance rate produces Local-Regional Control rates that are similar to what has been achieved with more aggressive therapy in patients with Favorable Prognosis Oropharyngeal Squamous Cell Carcinoma (OPSCC).

Inclusion Criteria:

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

2. T0-3 ≤4cm, N0 to N2, M0 squamous cell carcinoma of the oropharynx by AJCC 8th Edition staging. If T0 the adenopathy must be predominantly in Level 2.

3. Tissue diagnosis of HPV and/or p16 positivity from the primary site or an associated lymph node.

4. Radiologic confirmation of the absence of lung metastasis within 12 weeks prior to treatment; at a minimum, CT of the chest is required. PET-CT is acceptable.

5. ECOG Performance Status 0-2

6. ≤10 pack-years of smoking or no smoking for ≥ 10 years

7. Eligible for chemotherapy

8. CBC/differential obtained within 12 weeks prior to treatment, with adequate bone

Marrow function defined as follows:

• 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.)

1. Adequate renal and hepatic function within 12 weeks prior to treatment, defined as

Follows:

• Serum creatinine < 2.0 mg/dl

• Total bilirubin < 2 x the institutional ULN (upper limit of normal)

• AST or ALT < 3 x the institutional ULN

• Note that physician attestation of patient having no known history of liver disease can take the place of bilirubin and AST/ALT labs.

1. Negative pregnancy test within 3 weeks prior to treatment for women of childbearing

potential.

1. People of childbearing potential (POCBP) must be using an adequate method of

contraception to avoid pregnancy throughout the study and for at least 14 months

after the last dose of study drug to minimize the risk of pregnancy. Prior to study

enrollment, people of childbearing potential must be advised of the importance of

avoiding pregnancy during trial participation and the potential risk factors for an

unintentional pregnancy.

POCBP includes any person who has experienced menarche and who has not undergone

successful surgical sterilization (hysterectomy, bilateral tubal ligation, or

bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or

• For people with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

1. Subjects with partners of child-bearing potential must agree to use

physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)

throughout the study and should avoid conceiving children for 14 months following

the last dose of study drug.

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

Exclusion Criteria:

1. Prior radiotherapy or chemotherapy for this cancer.

2. Prior surgery with curative intent for this OPSCC.

3. Patients who have undergone tonsillectomy for diagnosis or excisional biopsy of a neck node for diagnosis are eligible provided there is "gross" cancer present at the primary site or in the neck at the start of radiation therapy on this protocol with "gross" defined as visible on an imaging study.

4. Prior history of radiation therapy to the head and neck, with the exception of skin cancer treated with a small (≤ 9cm3) field with 6 9 MeV electron beam or 50 250 kVp photon beam.

5. Prior history of chemotherapy or immunotherapy for cancer within the last 10 years

6. Prior history within 5 years of invasive cancer with the exception of:

   • Basal cell carcinoma of the skin

   • Squamous cell carcinoma of the skin, stage 1-2

   • Prostate cancer without distant metastases (stage M0)

   • Thyroid cancer without distant metastases (stage M0)

7. Prior history of invasive squamous cell carcinoma of a mucosal site in the head or neck treated with surgery alone within the last 5 years.

8. Prior history of invasive malignant melanoma or Merkel cell carcinoma of the head or neck treated with surgery alone in the past 5 years.

9. Inhalation smoking of tobacco within the last 10 years with > 10 pack-year equivalent history.

10. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) or immunosuppressive

medication, for example as for organ transplant or multiple sclerosis.

1. 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.

• Evidence of ACTIVE systemic lupus or scleroderma

• Psoriatic arthritis

1. Known HIV positivity. HIV positive patients are known to have worse clinical

outcomes especially for local, regional, and distant cancer control. This poorer

prognosis is thought to be secondary to a compromised immune system. Thus,

de-intensification of radiation and chemotherapy is not justifiable in this

population. HIV testing at the time of enrollment is not required.

1. Subjects of childbearing potential who are unwilling or unable to use an acceptable

method to avoid pregnancy for the entire study period and for at least 14 months

after the last dose of study drug.

1. People who are pregnant or breastfeeding.

2. Prisoners or subjects who are involuntarily incarcerated, or subjects who are

compulsorily detained for treatment of either a psychiatric or physical illness.