The Quarterback Trial: A Randomized Phase III Clinical Trial Comparing Reduced and Standard Radiation Therapy Doses for Locally Advanced HPV16 Positive Oropharynx Cancer

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed squamous cell
carcinoma of the oropharynx, unknown primary, or nasopharynx that is HPV 16 positive
as determined by PCR and p16 positive as determined by IHC. Tissue from the primary
site must be available for biomarker studies. PCR and IHC must be performed in the
central laboratory (Zhang, MSSM)

- Stage 3 or 4 disease without evidence of distant metastases.

- At least one clinically evaluable or uni- or bi-dimensionally measurable lesion by
RECIST 1.1 criteria.

- Age > 18 years.

- No previous surgery, radiation therapy or chemotherapy for SSCHN (other than biopsy
or tonsillectomy) is allowed at time of study entry.

- ECOG performance status of 0 or 1.

- No active alcohol addiction (as assessed by medical caregiver and defined as at least
6 months without activity).

- Participants must have adequate bone marrow, hepatic and renal functions as defined
in the protocol.

- Ability to understand and the willingness to sign a written informed consent
document.

- Patients with Gilbert's Disease and absent hepatic pathology by history and clinical
assessment maybe treated on study with bilirubins > the ULN for the institution if
other liver function studies are within the normal range

Exclusion Criteria:

- Pregnant or breast feeding women, or women and men of childbearing potential not
willing to use adequate contraception while on treatment and for at least 3 months
thereafter.

- Previous or current malignancies at other sites, with the exception of adequately
treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the
skin, thyroid cancer, or other cancer curatively treated by surgery and with no
current evidence of disease for at least 5 years.

- Symptomatic peripheral neuropathy ≥ grade 2 by NCI Common Terminology Criteria
(NCI-CTC) version 4.

- Symptomatic altered hearing > grade 2 by NCI-CTCv4 criteria.

- Other serious illnesses or medical conditions including but not limited to:

1. Unstable cardiac disease despite treatment, myocardial infarction within 6
months prior to study entry

2. History of significant neurologic or psychiatric disorders including dementia or
seizures

3. Active clinically significant uncontrolled infection

4. Active peptic ulcer disease defined as unhealed or clinically active

5. Hypercalcemia

6. Active drug addiction including alcohol, cocaine or intravenous drug use defined
as occurring within the 6 months preceding diagnosis

7. Chronic Obstructive Pulmonary Disease, defined as being associated with a
hospitalization for pneumonia or respiratory decompensation within 12 months of
diagnosis. This does not include obstruction from tumor

8. Autoimmune disease requiring therapy, prior organ transplant, or HIV infection

9. Interstitial lung disease

10. Hepatitis C (test required)

- Patients that have experienced an involuntary weight loss of more than 25% of their
body weight in the 2 months preceding study entry.

- Concurrent treatment with any other anticancer therapy.

- Participation in an investigational therapeutic drug trial within 30 days of study
entry.

- Active smoking within the past 20 years with a cumulative Pack Year history of > 20
Pack Years or active smoking (Defined as > 1 cigarette per day) within the last 2
years