Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With Stage III or Stage IV Head and Neck Cancer

OBJECTIVES:

Primary

- Evaluate whether the addition of cetuximab to a concurrent radiation-cisplatin regimen
will improve progression-free survival in patients with stage III or IV squamous cell
carcinoma of the oropharynx, hypopharynx, or larynx.

Secondary

- Determine the impact of the addition of cetuximab to a concurrent radiation-cisplatin
regimen on overall survival, local-regional control, acute and late toxic effects,
quality of life, and health utilities in these patients.

- Correlate the expression of epidermal growth factor receptor (EGFR) and its down-stream
molecules with outcome in patients participating in this component of the trial.

- Correlate pre-treatment positron emission tomography (PET) scan findings with
progression-free survival, overall survival, and local-regional control in patients
participating in this component of the trial.

- Correlate post-treatment PET scan findings with nodal response and nodal relapse in
patients participating in this component of the trial.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified
according to primary site (larynx vs non-larynx), nodal stage (N0 vs N1, N2a, N2b vs N2c,
N3), Zubrod performance status (0 vs 1), use of intensity modulated radiotherapy (IMRT) (no
vs yes), and pre-treatment PET/CT scan (no vs yes). Patients are randomized to 1 of 2
treatment arms.

NOTE: *A neck dissection is optional for patients with multiple lymph nodes or lymph nodes >
3 cm in diameter who achieve a complete clinical and radiographic response in the neck.

Quality of life is assessed at baseline, once during the last 2 weeks of treatment, at 3 and
12 months from the start of treatment, and then annually for 4 years.

After completion of study treatment, patients are followed periodically for 5 years and then
annually thereafter.

Inclusion criteria:

- Pathologically (histologically or cytologically) proven (from primary lesion and/or
lymph nodes) diagnosis of squamous cell carcinoma of the oropharynx, hypopharynx, or
larynx;

- Selected stage III or IV disease (T2N2-3M0, T3-4 any N M0); Note: Patients with T1,
any N, or T2N1 tumors are not eligible.

- Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:

- History/physical examination within 4 weeks prior to registration, including
assessment of weight and weight loss in past 6 months and an examination by a Medical
Oncologist;

- Chest x-ray (or Chest CT scan or PET/CT scan) within 6 weeks prior to registration;

- CT scan or MRI of the head and neck (of the primary tumor and neck nodes) or PET/CT
scan within 6 weeks prior to registration; see Section 6.11 for details of PET scans.
Note: A PET/CT can only be used instead of a CT scan or MRI if the CT is a high
quality scan with contrast.

- Left ejection fraction determined by echocardiogram and/or multiple gated acquisition
(MUGA) technique within 12 weeks of registration;

- Zubrod Performance Status 0-1;

- Age > 18;

- Adequate bone marrow function, defined as follows:

- Absolute neutrophil count (ANC) > 1,800 cells/mm3 based upon CBC/differential obtained
within 2 weeks prior to registration on study;

- Platelets > 100,000 cells/mm3 based upon complete blood count (CBC)/differential
obtained within 2 weeks prior to registration on study;

- Hemoglobin > 8.0 g/dl based upon CBC/differential obtained within 2 weeks prior to
registration on study (Note: The use of transfusion or other intervention to achieve
Hgb > 8.0 g/dl is acceptable.)

- Adequate hepatic function, defined as follows:

- Bilirubin < 1.5 mg/dl within 2 weeks prior to registration on study; For patients with
Gilbert's disease as the sole cause of elevated bilirubin, please contact the PI, Dr.
Ang.

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2x the upper
limit of normal within 2 weeks prior to registration on study;

- Adequate renal function, defined as follows:

- Serum creatinine < 1.5 mg/dl within 2 weeks prior to registration

- Creatinine clearance (CCr) ≥ 50 ml/min within 2 weeks prior to registration determined
by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age)
x (wt in kg)]/[(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)

- Pregnancy test within 2 weeks prior to registration for women of childbearing
potential;

- Women of childbearing potential and male participants must agree to use a medically
effective means of birth control throughout their participation in the treatment phase
of the study (until at least 60 days following the last study treatment);

- Patient must sign study specific informed consent prior to study entry.

Exclusion criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years;

- Patients with simultaneous primaries or bilateral tumors are excluded.

- Gross total excision (e.g., by tonsillectomy) of the primary tumor; however, partial
removal of the tumor to alleviate an impending airway obstruction does not make the
patient ineligible.

- Prior systemic chemotherapy 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;

- Primary site of tumor of oral cavity, nasopharynx, sinuses, or salivary glands;

- Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal
sampling of neck disease; radical or modified neck dissection is not permitted.

- Severe, active co-morbidity, defined as follows:

- Current uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable
angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive
heart failure, and cardiomyopathy with decreased ejection fraction;

- Left Ventricular Ejection Fraction < 45%;

- Transmural myocardial infarction within the last 6 months;

- 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;

- Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that 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.

- Any uncontrolled condition, which in the opinion of the investigator, would interfere
in the safe and timely completion of study procedures;

- CTCAE, v. 3.0 grade 3-4 electrolyte abnormalities:

- Calcium < 7 mg/dl or > 12.5 mg/dl;

- Glucose < 40 mg/dl or > 250 mg/dl;

- Magnesium < 0.9 mg/dl or > 3 mg/dl;

- Potassium < 3 mmol/L or > 6 mmol/L;

- Sodium < 130 mmol/L or > 155 mmol/L

- Pregnant or lactating women 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 the study drug(s) involved in this protocol;

- Prior therapy that specifically and directly targets the EGFR pathway;

- Prior severe infusion reaction to a monoclonal antibody.