Randomized Phase II/III Trial of Radiation With High-Dose Cisplatin (100 mg/m2) Every Three Weeks Versus Radiation With Low-Dose Weekly Cisplatin (40 mg/m2) for Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

PRIMARY OUTCOME MEASURES:

1. Incidence of acute toxicity (Phase II) [Time Frame: Up to 180 days post-treatment]
   Measured by the T-scores.
2. Overall Survival (OS) (Phase III) [Time Frame: From randomization to death of any cause, assessed up to 9 years]
   OS rates will be estimated using the Kaplan-Meier method.
3. Incidence of acute toxicity (Phase III) [Time Frame: Up to 180 days post-treatment]
   Measured by the T-scores.

SECONDARY OUTCOME MEASURES:

1. Locoregional Failure Rates [Time Frame: Up to 9 years]
2. Progression-free survival (PFS) [Time Frame: From randomization to locoregional failure, distant metastasis or death due to any cause, whichever occurs first, assessed up to 9 years]
   PFS rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test with a two-sided alpha of 0.05 (Kaplan 1958).
3. Incidence of acute toxicity [Time Frame: Up to 180 days post-treatment]
   Measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
4. Incidence of late toxicity [Time Frame: Up to 9 years]
   Measured by CTCAE v5.0.
5. Hearing loss [Time Frame: At 6 months post-radiation therapy]
   Measured by Hearing Handicap Inventory for Adults-Screening.

Inclusion Criteria:

• Pathologically proven diagnosis of SCCHN of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary prior to registration
  • For patients with oropharyngeal cancer (OPC)/cancer of unknown primary (CUP): P16 status based on local site immunohistochemical tissue staining is required.
  • The p16 results must be reported on the pathology report being submitted. The p16 positivity is defined as > 70% of tumor cells showing strong nuclear and/or cytoplasmic immunostaining with p16 antibody.
  • For patients with laryngeal and hypopharyngeal primaries: Analysis of p16 status is NOT required
    • Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations.
    • Clinical stage, including no distant metastases based on the following diagnostic workup:
  • History/physical examination within 60 days prior to registration
  • One of the following imaging studies is required within 60 days prior to registration:
• Computed tomography (CT) scan of neck (diagnostic quality with contrast, unless contraindicated) OR
• Magnetic resonance imaging (MRI) of the neck (diagnostic quality with contrast, unless contraindicated) OR
• Fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT of the neck; the CT component should be of diagnostic quality with contrast, unless contraindicated.
  • One of the following imaging studies is required within 60 days prior to registration:
• FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR
• Chest CT
  • Exam with laryngopharyngoscopy within 70 days prior to registration;
• Eligibility by patient cohort;
  • Non-OPC/p16-negative OPC Cohort; Tumor Site: Larynx/Hypopharynx; Clinical Staging (AJCC, 8th ed.): T3-4 N0 or T1-4 N1-3 T2 N0 (hypopharynx only)
  • Tumor Site: p16-negative OPC; Clinical Staging (AJCC, 8th ed.): T2N1, T1-4 N2-3, or T3-4 N0-1
    • Age >= 18
    • Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of 0-1 within 14 days prior to registration
    • Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior to registration)
    • Platelets >= 75,000 cells/mm^3 (within 30 days prior to registration)
    • Hemoglobin >= 8.0 g/dL (within 30 days prior to registration)
    • Calculated creatinine clearance (CrCl) >= 50 mL/min by the Cockcroft-Gault formula (within 30 days prior to registration)
    • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 30 days prior to registration) (not applicable to patients with known Gilbert's syndrome)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x institutional ULN (within 30 days prior to registration)
    • Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count > 200 cells/mm^3 are eligible for this trial.
    • Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration.
    • Willing to use highly effective contraceptives for participants of childbearing potential during therapy and for 14 months (females); for 11 months (males) following the last dose of cisplatin

Exclusion Criteria:

• Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer of unknown primary (CUP)
• Recurrence of the study cancer
• Definitive clinical or radiologic evidence of distant metastatic disease
• Prior systemic chemotherapy for the study cancer; any prior exposure to cisplatin is excluded
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Severe, active co-morbidity defined as follows:
  • Unstable angina requiring hospitalization in the last 6 months
  • Myocardial infarction within the last 6 months
  • New York Heart Association Functional Classification III/IV
  • Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing
  • Patient must not have an active infection requiring IV antibiotics prior to registration;
  • Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin therapy
  • History of allogenic organ transplantation
  • Any symptomatic peripheral sensory neuropathy grade >= 2 (CTCAE version 5.0);
• Pregnancy and individuals unwilling to discontinue nursing
• Other inclusion/exclusion criteria are present.  Please contact the study team for a complete list.