Radiotherapy With Cisplatin vs. Docetaxel-cetuximab in HNSCC: ERCC1 Biomarker Enrichment and Interaction Design

If randomized to the cisplatin arm, you will receive cisplatin, 40 mg/m2, administered
intravenously (IV) once a week (+/- 2 days) for 7 weeks. Per investigator discretion, if
radiation continues beyond 7 weeks due to technical factors (not toxicity delays), an 8th
dose of concurrent cisplatin may be added.

It is strongly preferred that cisplatin be administered on Monday, Tuesday, or Wednesday of
each treatment week to maximize overlap with radiation; administration on Thursday or Friday
for logistical purposes will be noted however will not constitute a protocol violation.
Cisplatin can be given either before or after the radiation therapy fraction that is given on
the same day. If a dose of cisplatin is omitted when radiotherapy is ongoing, it will not be
made up or added to the end of treatment. The omitted dose and the reason for the omission
should be recorded in the site's source documentation. If radiotherapy is held, cisplatin
should be held during the treatment break and resumed when radiation restarts. In this case,
the cisplatin dose is not considered skipped or omitted, but delayed.

If you are randomized to arm you will receive cetuximab, 250 mg/m2, IV over 60 minutes on a
weekly schedule (+/- 2 days). . Cetuximab may be administered either before or after the
radiation fraction that is given on the same day. Docetaxel will be administered at least 30
minutes following cetuximab. It is not permitted to make up missed doses of cetuximab or
docetaxel. If a radiation therapy treatment break occurs, cetuximab should be held. When
radiation restarts, cetuximab should resume.

It is strongly preferred that cetuximab be administered on Monday, Tuesday, or Wednesday of
each treatment week to maximize overlap with radiation; administration on Thursday or Friday
for logistical purposes will be noted however will not constitute a protocol violation.
Cetuximab will be given once a week (+/- 2 days) for a total of 7 doses concurrent with
radiation therapy and docetaxel.

Inclusion Criteria:

- Pathologically confirmed squamous cell carcinoma, undifferentiated carcinoma, or
poorly differentiated carcinoma of the oropharynx, larynx, or hypopharynx with no
evidence of distant metastasis. Biopsy sampling of primary tumor with pathology report
documenting diagnostic tissue type is required.

- Patients must have stage III, IVa or IVb disease as determined by imaging studies and
complete head and neck exam. Staging evaluation should be in accordance with the
American Joint Committee on Cancer Staging Manual, 7th edition.

- Patients with oropharyngeal squamous cell carcinoma may have p16(+) or p16(-) disease;
in these patients, p16 status must be known prior to randomization. Assessment of p16
status may occur locally or centrally. Note: The definition of p16(+) disease is
diffuse nuclear and cytoplasmic staining in ≥ 70% of tumor cells.

- Patients must be untreated with curative-intent surgery for current diagnosis of Stage
III, IVa, or IVb disease. Diagnostic biopsy of primary tumor and/or nodal sites is
permitted.

- Diagnostic simple tonsillectomy is permitted, provided patient has RECIST-measurable
residual tumor and/or nodal disease.

- Patients with a second HNSCC primary tumor are eligible for this study, provided more
than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was
managed with surgery only (no adjuvant chemotherapy/radiotherapy), and has not
recurred.

- 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.

- No prior systemic treatment (chemotherapy or biologic/molecular targeted therapy) or
radiation treatment for head and neck cancer.

- Patients may have received chemotherapy or radiation for a previous, curatively
treated non-HNSCC malignancy, provided at least 2 years have elapsed.

- Patients must be untreated with radiation above the clavicles.

- Patients with a history of curatively-treated non-HNSCC malignancy must be
disease-free for at least 2 years except for carcinoma-in-situ of cervix,
non-melanomatous skin cancer, or T1-2, N0, M0 resected differentiated thyroid
carcinoma.

- Diagnostic primary tumor tissue must be available for ERCC1 staining

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (See Appendix 8)

- Age ≥ 18

- Patients must have measurable disease according to RECIST 1.1

- Patients must have the following laboratory values measured within 14 days of
registration:

- Absolute neutrophil count (ANC) > 1500/mm3

- Hemoglobin (Hb) > 8.0 g/dL

- Platelet count (PLT) > 100,000/mm3

- Creatinine clearance ≥ 45 ml/min determined by 24-hour collection or estimated by the
Cockraft-Gault formula:

Calculated Creatinine Clearance = [(140-age) X (actual body weight in kg) X (0.85 if
female)]/(72 X serum creatinine)

- Serum bilirubin < 2 mg/dL

- AST (aspartate aminotransferase) and ALT (alanine aminotransferase) < 3 times upper
limit of normal (ULN)

- The following assessments are required within 14 days prior to registration: Na, K,
Cl, glucose, Ca, Mg, and albumin. The following metabolic values will exclude patients
from study enrollment:

- 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

- Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention
to normalize levels

- Potassium < 3.5 mmol/L or > 6 mmol/L despite intervention to normalize levels

- Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels 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 (eg, magnesium oxide) at
the investigator's discretion.

- No prior severe infusion reaction to a monoclonal antibody

- Written informed consent must be obtained from all patients prior to beginning
therapy. Patients should have the ability to understand and the willingness to sign a
written informed consent document.

- Informed consent must be obtained from all patients prior to beginning therapy,
including consent for mandatory tissue submission for ERCC1 staining (and p16 staining
if not locally conducted). Patients should have the ability to understand and the
willingness to sign a written informed consent document.

- No unstable angina or myocardial infarction within the prior 6 months; no symptomatic
congestive heart failure; no serious cardiac arrhythmia requiring medication; no
cerebrovascular ischemia or stroke within the past 6 months.

- No uncontrolled intercurrent illness including active infection, uncontrolled
diabetes, uncontrolled hypertension, or uncontrolled psychiatric illness which in the
investigator's opinion would limit compliance with study requirements or compromise
patient safety.

- Women must not be pregnant or breast feeding because chemotherapy and/or cetuximab may
be harmful to the fetus or the nursing infant. Pregnant women are excluded from this
study because chemotherapy and/or cetuximab have the potential for teratogenic or
abortifacient effects.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation. Should a woman become pregnant or suspect she is
pregnant while in this study, she should inform her treating physician immediately.
All females of childbearing potential must have a blood test or urine study within 14
days of registration to rule out pregnancy.

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible drug interactions with study drugs. Appropriate studies
will be undertaken in patients receiving combination anti-retroviral therapy when
indicated. Note: HIV testing is not required for entry into this protocol.

- Patients may not be receiving any other anti-neoplastic investigational agents.