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

IRB NRG-HN001

CC 14-691

Hospital Fairview, Main Campus, Mansfield, North Coast Cancer, Strongsville

Phase Phase 2, Phase 3

Disease Head and Neck, Nasopharyngeal Carcinoma

Drug Cisplatin, Fluorouracil, Gemcitabine , Paclitaxel

Description

1. Detectable Plasma EBV DNA Cohort (randomized phase II): The primary objective is to determine whether substituting adjuvant CDDP and 5-FU with gemcitabine and paclitaxel will result in superior progression-free survival.
2. Undetectable Plasma EBV DNA Cohort (phase III): The primary objective is to determine whether omitting adjuvant CDDP and 5-FU (observation alone in the adjuvant setting) will result in noninferior overall survival as compared with those patients receiving adjuvant CDDP and 5-FU chemotherapy.

• To compare the following between arms:
  • Time to distant metastasis;
  • Time to local progression;
  • Time to regional progression;
  • Progression-free survival (Undetectable Cohort);
  • Overall survival (Detectable Cohort);
  • Acute and late toxicity profiles based on clinician-reported CTCAE, v. 4;
  • Death during or within 30 days of end of protocol treatment;
  • Quality of life (general and physical well-being);
  • Quality of life (hearing);
  • Quality of life (peripheral neuropathy);
  • Cost effectiveness.

Inclusion Criteria

1. Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the nasopharynx;
2. Detectable pretreatment plasma EBV DNA;
3. 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 and/or Radiation Oncologist, 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 MRI of the nasopharynx and neck within 28 days prior to registration; if MRI is medically contraindicated, obtain 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 pelvis or a total body PET/CT scan;
     • a bone scan, if a PET/CT scan is not performed.
4. Zubrod Performance Status 0-1 within 21 days prior to registration;
5. Age ≥ 18;
6. CBC/differential obtained within 21 days prior to registration, with adequate bone marrow function defined as follows:
   • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm³;
   • 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.);
7. Adequate hepatic function within 21 days prior to registration, defined as follows:
   • Total bilirubin ≤ 1.5 x institutional ULN;
   • AST or ALT ≤ 1.5 x institutional ULN;
   • Alkaline phosphatase ≤ 1.5 x institutional ULN.
8. Adequate renal function within 21 days prior to registration, defined as follows:
   • 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:
     • CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)]
     • CCr female = 0.85 x (CrCl male)
9. Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential;
10. 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;
11. Patient must provide study specific informed consent prior to study entry, including the mandatory pre-treatment plasma EBV DNA assay.

Exclusion Criteria

1. 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);
2. 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.
3. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
4. 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 from tumor-related otitis media is allowed.
5. ≥ grade 2 peripheral sensory neuropathy (CTCAE, v. 4.0);
6. 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;
   • 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 CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
7. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception;
8. Prior allergic reaction to the study drug(s) involved in this protocol;