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.
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.
Inclusion Criteria:
- PHASE II INCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
- 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
- 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
- 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)
- 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
- Zubrod performance status of 0-1 within 14 days prior to registration
- Absolute granulocyte count (AGC) >= 1,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
- Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration on
study)
- 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 < 2 x institutional upper limit of normal (ULN) within 14 days prior
to registration
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional
ULN within 14 days prior to registration
- 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
- Negative urine or serum pregnancy test within 14 days prior to registration for women
of childbearing potential
- 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
- Patients with feeding tubes are eligible for the study
- Women of childbearing potential and male participants who are sexually active must
agree to use a medically effective means of birth control
- 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
- 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
- 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
- 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
- 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)
- 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
- PHASE III: Zubrod performance status of 0-1 within 14 days prior to registration
- PHASE III: Leukocytes >= 2,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
- PHASE III: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14
days prior to registration on study)
- PHASE III: Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to
registration on study)
- 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)
- 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)
- PHASE III: AST or ALT =< 3 x institutional ULN (within 14 days prior to registration)
- PHASE III: Alkaline phosphatase =< 2.5 x institutional ULN (within 14 days prior to
registration)
- 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
- PHASE III: Patients with feeding tubes are eligible for the study
- PHASE III: Negative urine or serum pregnancy test within 14 days prior to registration
for women of childbearing potential
- PHASE III: All patients must provide study specific informed consent prior to study
entry
- 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
Exclusion Criteria:
- PHASE II EXCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in
situ of the breast, oral cavity, or cervix are all permissible) are permitted even if
diagnosed and treated < 3 years ago
- Patients with simultaneous primaries or bilateral tumors are excluded, with the
exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
- Prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for the
study cancer; note that prior chemotherapy for a different cancer is allowable
- 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 and/or congestive heart failure requiring hospitalization within
6 months prior to registration
- Transmural myocardial infarction within 6 months prior to registration
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration
- Idiopathic pulmonary fibrosis or other severe interstitial lung disease that
requires oxygen therapy or is thought to require oxygen therapy within 1
year prior to registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for coagulation parameters are not required
for entry into this protocol
- Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease and Control and Prevention (CDC) definition; note: human
immunodeficiency virus (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; protocol-specific requirements may also
exclude immuno-compromised patients.
- Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events
[CTCAE], version [v.] 4):
- Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5
mg/dl (> 3.1 mmol/L) despite intervention to normalize levels
- Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14 mmol/L)
- Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention
to normalize levels
- Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels
- Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic
- Prior allergic reaction to cetuximab
- PHASE III: 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; Note that noninvasive cancers (For
example, carcinoma in situ of the breast, oral cavity, or cervix) are permitted even
if diagnosed and treated < 3 years ago
- PHASE III: Patients with simultaneous primaries or bilateral tumors are excluded, with
the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
- PHASE III: 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
- PHASE III: Prior radiotherapy to the region of the study cancer that would result in
overlap of radiation therapy fields
- PHASE III: Severe, active co-morbidity, defined as follows:
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of
cardiac function using the New York Heart Association Functional Classification;
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 including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe
pneumonia;
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration; Note: Patients receiving prophylactic antibiotics (e.g., for
prevention of a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible.
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of
registration;
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in a prior radiation field
(fibrosis) is permitted, provided that field does not overlap with the planned
radiation field for the study cancer;
- Patients with active tuberculosis (TB) are excluded;
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease;
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface ant
