Randomized Phase II/III Trial of Adjuvant Radiation Therapy With Cisplatin, Docetaxel-Cetuximab, or Cisplatin-Atezolizumab in Pathologic High-Risk Squamous Cell Cancer of the Head and Neck

PRIMARY OBJECTIVES:

1. To select the better docetaxel-based experimental arm to improve disease-free survival (DFS) over the control arm of radiation and cisplatin. (Phase II) (COMPLETE AS OF 20-MAR-2020) 
2. To determine if the combination of docetaxel-cetuximab and intensity-modulated radiation therapy (IMRT) is superior in terms of overall survival (OS) compared to standard cisplatin and IMRT in the adjuvant treatment of pathologic high risk, human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). (Phase III) 
3. To determine if the combination of atezolizumab, cisplatin, and IMRT is superior in terms of OS compared to standard cisplatin and IMRT in the adjuvant treatment of pathologic high risk, HPV-negative HNSCC. (Phase III)

SECONDARY OBJECTIVES:

1. To compare disease-free survival (DFS) between each experimental arm and the control arm. (Phase III)
2. To determine whether each experimental arm improves local-regional disease control and the rate of distant metastasis. (Phase III)
3. To compare acute toxicity profiles between each experimental arm and the control arm. (Phase III) 
4. To compare late toxicity profiles at 1, 3, and 5 years after treatment. (Phase III) 
5. To assess long term DFS and OS between each experimental arm and the control arm. (Phase III) 
6. To compare symptom burden, as measured by the MD Anderson Symptom Inventory - Head and Neck (MDASI-HN) (primary patient-reported outcome [PRO]), and quality of life, as measured by the Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) (secondary PRO), between each experimental arm and the control arm. (Phase III)

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips), oropharynx (p16 negative), larynx, or hypopharynx
• Pts with oropharyngeal cancer must have p16-negative based on central review prior to Step 2 registration; all patients with oropharyngeal primary must consent for mandatory tissue submission for central p16 confirmation
• Pts must have undergone gross total surgical resection of high-risk oral cavity, oropharynx, larynx, or hypopharynx within 63 days prior to registration
• Pts must have at least 1 of the following high-risk pathologic features: extracapsular nodal extension or invasive cancer at the primary tumor resection margin (tumor on ink or tumor in a final separately submitted margin)
• Pathologic stage III or IV HNSCC, including no distant metastases, based upon the following minimum diagnostic workup:
  • General history and physical examination by a radiation oncologist or medical oncologist within 84 days prior to registration;
  • Examination by an ENT or head & neck surgeon prior to surgery; 
  • Pre-op Imaging of the head and neck: A neck CT or PET/CT (with contrast and of diagnostic quality) and/or an MRI of the neck of diagnostic quality (T1 with gadolinium and T2) within 84 days prior to surgery; 
  • Chest CT scan (with or without contrast) or PET/CT that includes the chest (with or without contrast) either within 84 days prior to surgery or within 120 days prior to registration
• Zubrod performance status of 0-1 within 14 days prior to registration
• Laboratory values within normal limits.
• Pts with feeding tubes are eligible for the study
• Negative urine or serum pregnancy test within 14 days prior to registration for women of childbearing potential
• Pts positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests

Exclusion Criteria:

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) with the following exceptions: T1-2, N0, M0 resected differentiated thyroid carcinoma
• Pts with simultaneous primaries or bilateral tumors are excluded.
• Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy (such as anti-EGF therapy), or immune therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, a prior anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is not permitted
• 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:
  • Pts with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents. To be eligible for this trial, patients should be class 2B or better within 6 months prior to registration
  • Transmural myocardial infarction within 6 months prior to registration;
  • Severe infections within 4 weeks prior to registration
• Other inclusion/exclusion criteria are present.  Please contact the study team for a complete list.