Summary

This phase II/III trial studies how well radiation therapy works when given together with cisplatin, docetaxel, cetuximab, and/or atezolizumab after surgery in treating patients with high-risk stage III-IV head and neck cancer the begins in the thin, flat cells (squamous cell). Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The purpose of this study is to compare the usual treatment (radiation therapy with cisplatin chemotherapy) to using radiation therapy with docetaxel and cetuximab chemotherapy, and using the usual treatment plus an immunotherapy drug, atezolizumab.

Objectives

PRIMARY OBJECTIVES:
I. 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)
II. 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)
III. 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:
I. To compare disease-free survival (DFS) between each experimental arm and the control arm. (Phase III)
II. To determine whether each experimental arm improves local-regional disease control and the rate of distant metastasis. (Phase III)
III. To compare acute toxicity profiles between each experimental arm and the control arm. (Phase III)
IV. To compare late toxicity profiles at 1, 3, and 5 years after treatment. (Phase III)
V. To assess long term DFS and OS between each experimental arm and the control arm. (Phase III)
VI. 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)

EXPLORATORY OBJECTIVE:
I. To collect blood and tissue specimens for future translational research. (Phase III)

OUTLINE: Patients are randomized to 1 of 3 arms - Phase II (Arms 1, 2 or 3) and for Phase III (Arms 1, 3 or 4).

ARM 1: Patients undergo intensity modulated radiation therapy (IMRT) once daily (QD) five days a week for 6 weeks and receive concurrent cisplatin intravenously (IV) over 1-2 hours once weekly for 6 weeks.

ARM 2: Patients undergo IMRT as in Arm I and receive concurrent docetaxel IV over 60 minutes once weekly for 6 weeks. (CLOSED AS OF 20-MAR-2020)

ARM 3: Patients receive cetuximab IV over 120 minutes on week 1 and over 60 minutes once weekly on weeks 2-7. Patients undergo IMRT as in Arm I and concurrently receive docetaxel once weekly for 6 weeks.

ARM 4: Patients undergo IMRT QD five days a week for 6 weeks and receive concurrent cisplatin IV over 1-2 hours once weekly for 6 weeks. Starting 1 week before IMRT, patients also receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 8 doses (weeks -1, 3, 6, 9, 12, 15, 18, and 21) in the absence of disease progression and unacceptable toxicity.

All patients undergo computed tomography (CT) scans and/or magnetic resonance imaging (MRI), and collection of blood during follow-up.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Eligibility

1. PHASE II INCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
2. 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
3. Patients must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to registration; Note: patients may have biopsy under general anesthesia in an operating room followed by definitive ablative cancer surgery representing gross total resection; the gross total resection has to be done within 63 days prior to registration; if, however, patients have ablative resection but shortly recur or are determined to have persisting disease requiring re-resection to achieve gross total resection, then the patient is not eligible
4. Patients 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)
5. 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 and/or medical oncologist within 84 days prior to registration; * Examination by an ear nose throat (ENT) or head & neck surgeon prior to surgery; a laryngopharyngoscopy (mirror and/or fiber optic and/or direct procedure), if appropriate, is recommended but not required; intra-operative examination is acceptable documentation * Pre-operative (op) Imaging of the head and neck: A neck computed tomography (CT) (with contrast) or CT/positron emission tomography (PET) (with contrast) and/or an magnetic resonance imaging (MRI) of the neck (T1 with gadolinium and T2) within 84 days prior to surgery; Note: this imaging data (diagnostic pre-operative scan showing gross disease) is to be submitted in Digital Imaging and Communications in Medicine (DICOM) format via TRIAD; the report is to be uploaded into Rave * Chest CT scan (with or without contrast) or CT/PET that includes the chest (with or without contrast) either within 84 days prior to surgery or within 120 days prior to registration; Note: if the CT/PET with or without contrast is done within 84 days prior to surgery, it fulfills the chest imaging requirement
6. Zubrod performance status of 0-1 within 14 days prior to registration
7. Age >= 18
8. Absolute granulocyte count (AGC) >= 1,500 cells/mm^3 (obtained within 14 days prior to registration on study)
9. Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration on study)
10. Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
11. Total bilirubin < 2 x institutional upper limit of normal (ULN) within 14 days prior to registration
12. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional ULN within 14 days prior to registration
13. Serum creatinine institutional ULN within 14 days prior to registration or; creatinine clearance (CC) >= 50 ml/min within 14 days prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula
14. Negative urine or serum pregnancy test within 14 days prior to registration for women of childbearing potential
15. The following assessments are required within 14 days prior to registration: sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), and albumin; Note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator’s discretion
16. Patients with feeding tubes are eligible for the study
17. Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control
18. Patient must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for epidermal growth factor receptor (EGFR) analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis
19. PHASE III: 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
20. PHASE III: Patients 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
21. PHASE III: Patients must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to registration; note: patients may have biopsy under general anesthesia in an operating room followed by definitive ablative cancer surgery representing gross total resection; the gross total resection has to be done within 63 days prior to registration; if, however, patients have ablative resection but shortly recur or are determined to have persisting disease requiring re-resection to achieve gross total resection, then the patient is not eligible
22. PHASE III: Patients 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)
23. PHASE III: Pathologic stage III or IV HNSCC (American Joint Committee on Cancer [AJCC] 7th edition), 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; a laryngopharyngoscopy (mirror or fiberoptic or direct procedure), if appropriate, is recommended but not required. Intra-operative examination is acceptable documentation. * Pre-op Imaging of the head and neck: A neck CT (with contrast and of diagnostic quality) 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; Note: this imaging data (diagnostic pre-operative scan showing gross disease) is to be submitted in DICOM format via TRIAD. The report is to be uploaded into Rave. * 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; Note: If the PET/CT with or without contrast is done within 84 days prior to surgery, it fulfills the chest imaging requirement
24. PHASE III: Zubrod performance status of 0-1 within 14 days prior to registration
25. PHASE III: Leukocytes >= 2,500 cells/mm^3 (obtained within 14 days prior to registration on study)
26. PHASE III: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14 days prior to registration on study)
27. PHASE III: Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration on study)
28. PHASE III: Hemoglobin >= 8.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb >= 8.0 g/dL is acceptable) (obtained within 14 days prior to registration on study)
29. PHASE III: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x institutional ULN may be enrolled) (within 14 days prior to registration)
30. PHASE III: AST or ALT =< 3 x institutional ULN (within 14 days prior to registration)
31. PHASE III: Alkaline phosphatase =< 2.5 x institutional ULN (within 14 days prior to registration)
32. PHASE III: Creatinine clearance (CrCl) >= 50 mL/min within 14 days prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula
33. PHASE III: Patients with feeding tubes are eligible for the study
34. PHASE III: Negative urine or serum pregnancy test within 14 days prior to registration for women of childbearing potential
35. PHASE III: All patients must provide study specific informed consent prior to study entry
36. PHASE III: Patients 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

Treatment Sites in Georgia