Randomized Phase II and Phase III Studies of Individualized Treatment for Nasopharyngeal Carcinoma Based on Biomarker Epstein Barr Virus (EBV) Deoxyribonucleic Acid (DNA)

• Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the nasopharynx

• Sites are required to complete Step 1 registration before submitting specimens for EBV DNA analysis.

• Patients must have detectable pretreatment plasma EBV DNA, determined by the central lab prior to Step 2 registration (see Section 10.2 for details of specimen submission).

• For patients who have detectable plasma EBV DNA tested at one of the credentialed central labs (listed on the EBV DNA Testing Specimen Transmittal form) within 28 days prior to Step 1 registration: that test result can be used for eligibility without the need for re-testing. To use this test result for eligibility, the central lab must enter the test result through the pathology portal, and the site must follow the instructions in Section 5.4.

• Stage II-IVB disease (AJCC, 7th ed.) with no evidence of distant metastasis, based upon the following minimum diagnostic workup:

• History/physical examination by a Medical Oncologist or Clinical Oncologist or Radiation Oncologist or ENT, which must include an endoscopic evaluation, a complete list of current medications, and assessment of weight and weight loss in the past 6 months within 21 days prior to registration;

• Evaluation of tumor extent required within 28 days prior to registration:

• MRI of the nasopharynx and neck; or CT of the nasopharynx and neck with ≤ 3 mm contiguous slices with contrast and bone windows (to evaluate base of skull involvement).

• Note: If a treatment planning CT scan is used, it must be with ≤ 3 mm contiguous slices with contrast and be read by a radiologist.

• Please refer to section 6.3.2 for MRI requirement for target delineation.

• To rule out distant metastasis, patients must undergo the following imaging within 28 days prior to registration:

• a CT scan with contrast of the chest and abdomen (required), and the pelvis (optional), or a total body PET/CT scan (non-contrast PET/CT is acceptable);

• a bone scan only when there is suspicion of bone metastases (a PET/CT scan can substitute for the bone scan).

• Zubrod performance status 0-1 within 21 days prior to registration

• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3

• Platelets ≥ 100,000 cells/mm^3

• Hemoglobin ≥ 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)

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

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 x institutional ULN

• Alkaline phosphatase ≤ 1.5 x institutional ULN

• Serum creatinine ≤ 1.5 mg/dl or calculated creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour urine collection or estimated by Cockcroft-Gault formula

• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

• Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control throughout protocol treatment

• Patient must provide study specific informed consent prior to study entry, including the mandatory pre-treatment plasma EBV DNA assay