ERBITUX® Followed by Adjuvant Treatment With Chemoradiation and ERBITUX® for Locally Advanced Head and Neck Squamous Cell Carcinoma

This prospective phase II clinical trial of preoperative, single-agent cetuximab treated patients is being conducted in order to obtain specimens before and after 4 weeks of cetuximab for immune biomarker studies. Stage III/IV HNC patients will be treated with definitive surgical resection and observed for disease recurrence. Cetuximab will be administered for a 3-4 week preoperative period to study biomarker modulation in correlation clinical response by CT scan and tumor apoptosis/proliferation after tumor excision, immediately after neoadjuvant cetuximab but before surgery. We will biopsy the skin/acneiform rash in all patients to correlate rash with biomarker modulation and clinical response. Cetuximab may also be given in the adjuvant setting. A primary scientific hypothesis will be tested: does short term pre-operative exposure to cetuximab modulate blood immune biomarkers and is immune modulation associated with anti-tumor effect? Forty (n=40) patients with complete specimens (tumor, peripheral blood mononuclear cells (PBMC) and serum) are necessary to enable adequate statistical power to be reached using paired specimens. A secondary set of hypotheses will evaluate the association between pre-operative biomarker levels and modulation with disease recurrence. The proposed trial will accrue stage II, III or IV surgical candidates without distant metastasis.

Inclusion criteria

• Histologically or cytologically confirmed, previously untreated HNC. Clinical stage III or IVA disease without distant metastases as determined by CT, and as defined by the American Joint Committee on Cancer Staging System, Sixth edition (See Appendix I).
• Primary tumors of the oral cavity, oropharynx, hypopharynx, or larynx will be included. Primary tumors of the sinuses, paranasal sinuses, or nasopharynx, or unknown primary tumors are NOT allowed.
• Macroscopic complete resection of the primary tumor must be planned.
• Age greater than or equal to 18 years.
• ECOG performance status 0-1.
• Adequate hematologic, renal and hepatic function, as defined by:

• Absolute neutrophil count (ANC) greater than or equal to 1,500/ul, platelets greater than or equal to 100,000/ul.
• Creatinine clearance > 40
• Bilirubin less than or equal to 1.5 x ULN, AST or ALT less than or equal to 2.5 x ULN.
• Have signed written informed consent.

Exclusion criteria

• Subjects who fail to meet the above criteria.
• Prior severe infusion reaction to a monoclonal antibody.
• Pregnancy or breastfeeding. Women of childbearing potential (WOCBP) must practice acceptable methods of birth control to prevent pregnancy. Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control.
• All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. The Investigator must immediately notify BMS in the event of a confirmed pregnancy in a patient participating in the study.
• Subjects with an ECOG performance status of 2 or worse.
• Evidence of distant metastasis.
• Any other malignancy active within 5 years except for non-melanoma skin cancer or carcinoma in situ of the cervix, DCIS or LCIS of the breast.
• Prior history of HNC.
• Prior therapy targeting the EGFR pathway.
• Any unresolved chronic toxicity greater than or equal to grade 2 from previous anticancer therapy (except alopecia), according to Common Terminology Criteria for Adverse Events v4.0 (CTCAE).
• Acute hepatitis, known HIV, or active uncontrolled infection.
• History of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within prior 6 months, untreated known coronary artery disease, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.
• Uncontrolled peptic or gastric ulcer disease, or gastrointestinal bleeding within prior 6 months.
• Active alcohol abuse or other illness that carries a likelihood of inability to comply with study treatment and follow-up.
• Treatment with a non-approved or investigational drug within 30 days prior to Day 1 of study treatment.