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

OBJECTIVES:

Primary

• To evaluate the feasibility and toxicity of bortezomib, cetuximab, and radiotherapy with or without cisplatin in patients with stage IV squamous cell carcinoma of the head and neck.
• To identify the maximum tolerated dose of bortezomib for further clinical phase II development.

Secondary

• To evaluate the objective response rate, progression-free survival, and overall survival of patients treated with these regimens.
• To determine the effects of bortezomib and cetuximab with or without cisplatin on inhibiting activation of the NF-kB, EGFR, MAPK, and STAT3 signal pathways, expression of pro-survival and pro-angiogenesis genes regulated by these pathways, and on proliferation, apoptosis, and angiogenesis.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are simultaneously accrued to 1 of 2 treatment groups. Patients are initially accrued to group I until there are a sufficient number of patients to establish the maximum tolerated dose (MTD) of bortezomib. Patients are then accrued to group II.

• Group I: Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, 11, 22, 25, 29, 32, 43, 46, 50, and 53. Beginning on day 8 or 9, patients undergo standard intensity-modulated radiotherapy (IMRT) once daily, 5 days a week, for up to 8 weeks.

Once the MTD of bortezomib is determined, at least 6 and up to 10 additional patients are accrued and treated at the MTD.

• Group II: Patients receive cetuximab, bortezomib (beginning at one dose level below the MTD determined in group I), and IMRT as in group I. Patients also receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, and 57.

Once the MTD of bortezomib is determined, 6 additional patients are accrued and treated at the MTD.

Patients undergo blood sample collection periodically for correlative laboratory studies. Samples are analyzed for biomarkers by immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction, and ELISA.

After completion of study therapy, patients are followed periodically for 2-5 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed squamous cell carcinoma of the head and neck, including variants or undifferentiated/poorly differentiated carcinoma

• Previously untreated stage IV disease OR residual disease or regionally recurrent disease after prior surgery and/or chemotherapy
• Must be eligible to receive full-dose radiotherapy and be evaluated and accepted for treatment by a Radiation Oncologist
• No clinically measurable distant disease OR has asymptomatic small distant lesions outside the radiation field ≤ 3 cm in individual or aggregate diameter for which palliation of local and regional disease is clearly warranted
• No previously untreated nasopharyngeal cancer (any stage)

• Recurrent nasopharyngeal carcinoma allowed
• No known brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
• ANC ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin normal (indirect bilirubin ≤ 3 mg/dL in patients with Gilbert's syndrome)
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Adequate cognitive and neurologic function
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib, cetuximab, cisplatin, or other agents used in this study
• No peripheral sensory neuropathy ≥ grade 2
• No concurrent uncontrolled illness including, but not limited to, the following:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness/social situations that would preclude study compliance
• HIV-negative

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior therapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• More than 3 months since prior cisplatin
• No prior radiotherapy to the head and neck
• No prior systemic EGFR inhibitors
• No prior bortezomib
• No other concurrent investigational agents
• No other concurrent anticancer therapy
• No concurrent antiretroviral therapy
• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
• No concurrent amifostine