Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Undergone Surgery

PRIMARY OBJECTIVES:

I. To evaluate the disease-free survival (DFS) of patients with stage III-IV squamous cell
carcinoma of the head and neck (SCCHN) and disruptive p53 mutations after primary surgical
resection followed by postoperative radiotherapy (PORT) alone or PORT with concurrent
cisplatin.

SECONDARY OBJECTIVES:

I. To evaluate the DFS of patients with stage III-IV SCCHN and non-disruptive p53 mutations
after primary surgical resection followed by PORT alone or PORT with concurrent cisplatin.

II. To evaluate the DFS of patients with stage III-IV SCCHN and p53 wild type after primary
surgical resection followed by PORT alone or PORT with concurrent cisplatin.

III. To evaluate toxicities of PORT alone or PORT with concurrent cisplatin. IV. To evaluate
p53 mutation as a predictive biomarker of survival benefit given post-operative concurrent
radiation and cisplatin.

V. To identify potential genomic alterations in addition to TP53 mutations that may be
developed to a novel treatment approach.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a
week for 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo IMRT QD 5 days a week and receive cisplatin intravenously (IV) over
1-2 hours weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years and
then every 12 months for 7 years.

Inclusion Criteria:

- PRE-REGISTRATION (STEP 0)

- Pathologically proven diagnosis of squamous cell carcinoma (including variants such as
verrucous carcinoma, spindle cell carcinoma, carcinoma not otherwise specified [NOS])
of the head/neck (oral cavity, oropharynx, hypopharynx or larynx); pathologic stage
III or IVA (American Joint Committee on Cancer [AJCC] 8): T3-T4a, N0-3, M0 or T1-T2,
N1-3, M0

- Patient has undergone total resection of the primary tumor with curative intent

- NOTE: Patient is to be pre-registered to screening (Step 0) and tissue submitted
to Foundation Medicine as soon as possible after surgery in order to meet the 8
week deadline to register the patient to Step 1 after surgery; full assay minimum
turn-around time is 17-24 days

- For oropharynx primary tumors, the patient must have negative human papillomavirus
(HPV) status of the tumor as determined by p16 protein expression using
immunohistochemistry (IHC)

- Patients with, per the operative and/or pathology report, positive margin(s) (tumor
present at the cut or inked edge of the tumor) which is not superceded by an
additional margin of tumor-negative tissue, nodal extracapsular extension, and/or
gross residual disease after surgery are not eligible

- A paraffin-embedded surgical tumor tissue specimen has been located is available for
shipment to Foundation Medicine, Inc. following pre-registration

- NOTE: Complete the EA3132-specific FoundationOne requisition form

- Patients with a history of a curatively treated malignancy must be disease-free for at
least two years except for carcinoma in situ of cervix and/or non-melanomatous skin
cancer; patients must not have received chemotherapy or investigational therapy within
two years of surgical resection of the primary tumor

- Patient must not have had previous irradiation to the head and neck that would result
in overlap in radiation fields for the current disease

- Patients with recurrent disease or multiple primaries are ineligible

- RANDOMIZATION (STEP 1)

- NOTE: Patient must meet all eligibility criteria outlined in pre-registration; patient
may not be randomized until site has been notified that the central determination of
p53 mutation status of the surgical tumor tissue has been completed and site has been
notified of assay completion

- Per the operative report, the gross total resection of the primary tumor with curative
intent was completed within 8 weeks prior to randomization

- The patient must have the following assessments done =< 8 weeks prior to
randomization:

- Examination by a head and neck surgeon

- Chest x-ray (or chest computed tomography [CT] scan or CT/positron emission
tomography [PET] of the chest or magnetic resonance imaging [MRI]) to rule out
distant metastatic disease

- Patient has Eastern Cooperative Oncology Group (ECOG) performance status 0-1 within 2
weeks prior to randomization

- Women must not be pregnant or breast-feeding; females of childbearing potential must
have a blood or urine study within 2 weeks prior to randomization to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception or to abstain from sexual
intercourse for the duration of their participation in the study and until 60 days
from the last study treatment

- Absolute neutrophil count >= 1,500/mm^3 within 4 weeks prior to randomization

- Platelets >= 100,000/mm^3 within 4 weeks prior to randomization

- Total bilirubin =< the upper limit of normal (ULN) within 4 weeks prior to
randomization

- Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula
within 4 weeks prior to randomization

- Patient must not have an intercurrent illness likely to interfere with protocol
therapy