Cisplatin + Radiation in SCCHN and Correlation With Oxidative Stress Markers

Patients will first be designated as either: a) Cohort 1 (locally advanced non-nasopharyngeal
SCCHN that is unresectable) OR b) Cohort 2 (resected and at high risk of recurrence with at
least one of the following criteria: extracapsular nodal extension, or invasive cancer at the
primary tumor resection margin (positive margin), lymphovascular invasion or perineural
invasion, pT3 or pT4 primary, or the presence of multilevel nodal disease. Subjects will then
be randomized to receive either Arm 1 or Arm 2 cisplatin.

Radiation and Cisplatin will be given concurrently and should start on the same day, ±1 day.
Radiation will continue without interruption whenever possible.

Treatment will consist of standard of care radiation therapy to the primary tumor of the head
and neck and involved nodal metastasis and draining nodal basin, as determined by treating
radiation oncologist. Patients will be randomized to receive cisplatin at 100 mg/m2 every 3
weeks (3 doses) during radiation versus cisplatin at 40 mg/m2 once weekly (7 doses) during
radiation. This will provide similar cumulative doses of cisplatin in all arms of the
study.IMRT will be delivered in 30-35 fractions over 6-7 weeks, 5 fractions weekly.

In the absence of treatment delays due to adverse event(s), treatment will continue for 7
weeks or until one of the following criteria applies:

Disease progression,Intercurrent illness that prevents further administration of treatment,
Unacceptable adverse event(s), Patient decides to withdraw from the study, or General or
specific changes in the patient's condition render the patient unacceptable for further
treatment in the judgment of the investigator.

Patients will be followed for 2 years after completion of chemoradiation or until death,
whichever occurs first, for toxicity and PFS.

Inclusion Criteria:

- Patients must have pathologically (histologically or cytologically) proven diagnosis
of head and neck squamous cell carcinoma (HNSCC) involving the oral cavity,
oropharynx, larynx, hypopharynx, paranasal sinuses or unknown primary squamous
carcinoma limited to the head and neck region. Cohort 1: Unresectable locally advanced
non-nasopharyngeal SCCHN without evidence of distant metastases. Cohort 2: Patients
with non-nasopharyngeal SCCHN who have undergone gross total surgical resection within
63 days prior to registration. Patients must have at least 1 of the following
high-risk pathologic features: extracapsular nodal extension, invasive cancer at the
primary tumor resection margin (positive margin), lymphovascular invasion or
perineural invasion, or the presence of multilevel nodal disease. Patients must be
without evidence of distant metastases.

- Women of childbearing potential and male participants who are sexually active must
agree to use a medically effective means of birth control.

- Cohort 1: Patients in Cohort 1 must have measurable disease, defined as at least one
lesion that can be accurately measured in at least one dimension (longest diameter to
be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2
cm) with conventional techniques or as ≥ 10 mm (≥ 1 cm) with spiral CT scan, MRI, or
calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
Cohort 2: Subjects in the post-operative setting (Cohort 2) are not required to have
measurable disease and response rate will not be assessed in cohort 2.

- Patients may have a history of prior head and neck malignancy, but must be able to
tolerate full dose radiation and chemotherapy for the current head and neck cancer, as
determined by the treating oncologist.

- Age ≥18 years.

- ECOG performance status 0, 1 or 2

- Life expectancy of greater than 12 weeks.

- Patients must have normal organ and marrow function assessed within 14 days prior to
registration as defined below: absolute neutrophil count ≥1,000/mcL, platelets
≥100,000/mcL, creatinine within normal institutional limits OR creatinine clearance
≥60 mL/min/1.73 m2 (for patients with creatinine levels above institutional normal).

- No prior chemotherapy for the current locally advanced SCCHN is allowed. Prior
radiation or chemotherapy for a previous head and neck cancer is allowed provided full
dose cisplatin and radiation can be delivered to the patient in this clinical trial
and provided the patient is in remission from the prior head and neck cancer, and can
undergo full dose radiation and chemotherapy for the current primary head and neck
cancer.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
throughout the duration of active treatment and for 4 months after completion of
chemotherapy and radiation.

- Cisplatin and radiation are known teratogens. For this reason, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry, throughout the duration of active
treatment and for 4 months after completion of chemotherapy and radiation. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of active study treatment, and for 4 months after
completion of chemotherapy and radiation (both induction and definitive)
administration.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cisplatin.

- Patients with greater than grade 2 hearing loss.

- No other prior malignancy is allowed except for the following: head and neck cancer in
remission, adequately treated basal cell or squamous cell skin cancer, in situ
cervical cancer, adequately treated previous Stage I or II cancer from which the
patient is currently in complete remission or other cancer from which the patient has
been disease-free for 2 years.

- Patients with nasopharynx or salivary gland primary site.

- Patients with distant metastatic disease (M1c) from the current head and neck cancer
including brain metastasis.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection (grade 3 or greater), symptomatic congestive heart failure, unstable angina
pectoris, symptomatic cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements. Subjects with significant
symptoms of congestive heart failure who would not be expected to tolerate the IV
hydration for cisplatin are excluded.

- Pregnant women are excluded from this study because cisplatin and radiation are agents
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with cisplatin and radiation, breastfeeding should be
discontinued if the mother is treated with cisplatin or radiation on this trial.

- HIV-positive patients with uncontrolled HIV despite combination antiretroviral therapy
are ineligible because of the potential for increased risk of lethal infections when
treated with marrow-suppressive therapy. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated