Individualized Treatment in Treating Patients With Stage II-IVB Nasopharyngeal Cancer Based on EBV DNA

PRIMARY OBJECTIVES:

I. To determine whether substituting adjuvant concurrent high dose cisplatin (CDDP) and
fluorouracil (5-FU) with gemcitabine (gemcitabine hydrochloride) and paclitaxel will result
in superior progression-free survival. (Detectable Plasma Epstein Barr Virus [EBV]
Deoxyribonucleic Acid [DNA] Cohort randomized Phase II) II. To determine whether omitting
adjuvant CDDP and 5-FU (observation alone in the adjuvant setting) will result in
non-inferior overall survival as compared with those patients receiving adjuvant CDDP and
5-FU chemotherapy. (Undetectable Plasma EBV DNA Cohort Phase III)

SECONDARY OBJECTIVES:

I. Time to distant metastasis. (Randomized Phase II and Phase III) II. Time to local
progression. (Randomized Phase II and Phase III) III. Time to regional progression.
(Randomized Phase II and Phase III) IV. Progression-free survival (Undetectable Cohort). V.
Overall survival (Detectable Cohort). VI. Acute and late toxicity profiles based on
clinician-reported Common Terminology Criteria for Adverse Events (CTCAE), version (v.) 4.
(Randomized Phase II and Phase III) VII. Death during or within 30 days of end of protocol
treatment. (Randomized Phase II and Phase III) VIII. Quality of life (general and physical
well-being). (Randomized Phase II and Phase III) IX. Quality of life (hearing). (Randomized
Phase II and Phase III) X. Quality of life (peripheral neuropathy). (Randomized Phase II and
Phase III) XI. Cost effectiveness. (Randomized Phase II and Phase III)

OUTLINE:

Patients undergo intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week
for 6.5 weeks and receive low-dose cisplatin intravenously (IV) over 30-60 minutes once
weekly during IMRT. Beginning 1 week after chemoradiation, plasma samples are collected for
EBV DNA analysis.

PHASE II: Patients with detectable EBV DNA from pre-treatment analysis are randomized to 1 of
2 treatment arms.

ARM I: Patients receive PF regimen comprising cisplatin IV over 60-120 minutes and
fluorouracil IV over 96 hours continuously beginning at least 4 weeks after completion of
IMRT. Treatment repeats every 28 days for 3 courses in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive GT regimen comprising paclitaxel IV over 1 hour and gemcitabine
hydrochloride IV over 30 minutes on days 1 and 8 at least 4 weeks after completion of IMRT.
Treatment repeats every 21 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

PHASE III:

Patients with undetectable EBV DNA from pre-treatment analysis are randomized to 1 of 2
treatment arms.

ARM III: Patients receive PF regimen as in Arm I.

ARM IV: Patients undergo clinical observation.

After completion of study treatment, patients are followed up every 4 months for 2 years,
every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

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

- Patients must have detectable pretreatment plasma EBV DNA, determined by the central
lab prior to Step 2 registration

- Stage II-IVB disease (American Joint Committee on Cancer [AJCC], 7th edition [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 Ear, Nose, Throat specialist (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 with magnetic resonance imaging (MRI) of the
nasopharynx and neck within 28 days prior to registration; if MRI is medically
contraindicated, obtain computed tomography (CT) scan 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

- 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, abdomen, and/or pelvis or a total body
positron emission tomography (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) or 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

Exclusion Criteria:

- Prior invasive malignancy (except node negative, non-melanomatous skin cancer) unless
disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of
the breast, oral cavity, or cervix are all permissible)

- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable; however, at least 6-weeks recovery is necessary if the
last regimen included nitrosourea or mitomycin

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- Patients with hearing loss assessed to be primarily sensorineural in nature, requiring
a hearing aid, or intervention (i.e. interfering in a clinically significant way with
activities of daily living); a conductive hearing loss that is tumor-related is
allowed

- >= Grade 2 peripheral sensory neuropathy (CTCAE, v. 4.0)

- Severe, active co-morbidity, defined as follows:

- Major medical or psychiatric illness, which in the investigator's opinion would
interfere with the completion of therapy and follow up or with full understanding
of the risks and potential complications of the therapy

- Unstable angina and/or uncontrolled congestive heart failure within the past 6
months

- Myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration; note that patients switched from IV antibiotics and currently on
oral antibiotics whose infection is assessed to be adequately treated or
controlled are eligible

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days prior to
registration

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this protocol

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Prior allergic reaction to the study drug(s) involved in this protocol

- Patients with undetectable pre-treatment plasma EBV DNA