Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab

• Response rate (CR+PR) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Will be summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm. The Fisher exact/Chi-square test and logistics regression will be considered to study the relationship between various disease or patient characteristics/ gene expression/ proteomic groups and response by arm and/or overall.
• Overall survival [ Time Frame: From study entry to death of any causes, assessed up to 3 years ] [ Designated as safety issue: No ]
  Will be summarized with the Kaplan-Meier curve by arm. Confidence intervals for the median and survival rates at different time points will be constructed when appropriate.
• Toxicity assessed using NCI CTCAE v4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  Will be addressed using mostly descriptive statistics.
• Gene expression levels [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Will be addressed using mostly descriptive statistics.
• Proteomic profiles [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Will be addressed using mostly descriptive statistics.

Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cetuximab is more effective when given alone or together with sorafenib tosylate in treating patients with head and neck cancer. This randomized phase II trial is studying cetuximab to see how well it works when given together with or without sorafenib tosylate in treating patients with refractory, recurrent, and/or metastatic head and neck cancer

PRIMARY OBJECTIVES:

I. Compare the progression free survival (PFS) of the combination of cetuximab and sorafenib to that of cetuximab alone in patients with recurrent, refractory or metastatic squamous cell carcinoma of the head and neck (SCCHN).

SECONDARY OBJECTIVES:

I. To evaluate the response rate, overall survival (OS) and toxicity of the combination of cetuximab and sorafenib and of cetuximab alone.

II. To evaluate the presence of EGFRvIII mutation, increased EGFR gene copy number and activated EGFR gene expression signature, and correlate with clinical parameters (RR, OS and PFS) in the cetuximab alone and cetuximab/sorafenib arms.

III. To evaluate whether VEGF receptor family and their ligand expression can predict response to cetuximab/sorafenib.

IV. To determine the proteomic profiles in serum and tumors that can predict the response and survival upon the treatment with cetuximab or cetuximab/sorafenib.

V. To evaluate the effect of therapy on both general and head and neck specific functionality, symptom burden and QOL.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral placebo twice daily on days 1-21. (oral placebo closed as of 02/18/2010).

ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral sorafenib tosylate twice daily on days 1-21.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Paraffin embedded tissue samples are collected at baseline for pharmacogenomic studies and blood samples are collected at baseline and for the first 3 courses for research purposes. Quality of life and symptom burden are assessed by Vanderbilt Head and Neck Symptom Survey, FACT-HN, and Fatigue and Pain Inventory questionnaires at baseline, at day 43, and at 3 and 6 months.

After completion of study treatment, patients are followed periodically for 3 years.

• Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
• Recurrent Metastatic Squamous Neck Cancer With Occult Primary
• Recurrent Salivary Gland Cancer
• Recurrent Squamous Cell Carcinoma of the Hypopharynx
• Recurrent Squamous Cell Carcinoma of the Larynx
• Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
• Recurrent Squamous Cell Carcinoma of the Nasopharynx
• Recurrent Squamous Cell Carcinoma of the Oropharynx
• Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Recurrent Verrucous Carcinoma of the Larynx
• Recurrent Verrucous Carcinoma of the Oral Cavity
• Salivary Gland Squamous Cell Carcinoma
• Stage IV Squamous Cell Carcinoma of the Hypopharynx
• Stage IV Squamous Cell Carcinoma of the Nasopharynx
• Stage IVA Salivary Gland Cancer
• Stage IVA Squamous Cell Carcinoma of the Larynx
• Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage IVA Squamous Cell Carcinoma of the Oropharynx
• Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Stage IVA Verrucous Carcinoma of the Larynx
• Stage IVA Verrucous Carcinoma of the Oral Cavity
• Stage IVB Salivary Gland Cancer
• Stage IVB Squamous Cell Carcinoma of the Larynx
• Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage IVB Squamous Cell Carcinoma of the Oropharynx
• Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Stage IVB Verrucous Carcinoma of the Larynx
• Stage IVB Verrucous Carcinoma of the Oral Cavity
• Stage IVC Salivary Gland Cancer
• Stage IVC Squamous Cell Carcinoma of the Larynx
• Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage IVC Squamous Cell Carcinoma of the Oropharynx
• Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Stage IVC Verrucous Carcinoma of the Larynx
• Stage IVC Verrucous Carcinoma of the Oral Cavity
• Tongue Cancer
• Untreated Metastatic Squamous Neck Cancer With Occult Primary

• Biological: cetuximab
  Given IV
  Other Names:

  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
• Other: placebo
  Given orally
  Other Name: PLCB
• Drug: sorafenib tosylate
  Given orally
  Other Names:

  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
• Other: laboratory biomarker analysis
  Correlative studies
• Procedure: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment

• Placebo Comparator: Arm I (cetuximab and placebo)
  Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral placebo twice daily on days 1-21.
  Interventions:

  • Biological: cetuximab
  • Other: placebo
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
• Experimental: Arm II (cetuximab and sorafenib tosylate)
  Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral sorafenib tosylate twice daily on days 1-21.
  Interventions:

  • Biological: cetuximab
  • Drug: sorafenib tosylate
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment

Inclusion Criteria:

• Patients with recurrent, refractory or metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx or paranasal sinus, head and neck unknown primary or nasopharyngeal carcinoma WHO type 1; patients with recurrent, refractory or metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx or paranasal sinus, head and neck unknown primary or nasopharyngeal carcinoma WHO type 1; patients may have had up to 1 prior palliative chemotherapy for recurrent or metastatic disease; please note that chemotherapy given as part of a regimen for curative intent for recurrent disease does not count as "prior chemotherapy;" patients must not presently be candidates for curative therapy
• ECOG performance status 0, 1 or 2
• Hemoglobin >= 9.0/dl
• Absolute-neutrophil count (ANC) >= 1500/mm^3
• Platelet count >= 100,000/mm^3
• Total bilirubin =< 1.5 x ULN
• ALT and AST =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement)
• INR < 1.5 or a PT and PTT within normal limits
• Creatinine =< 1.5 x ULN
• If primary therapy was given for curative intent, at least 4 weeks must have elapsed after completion of primary therapy prior to enrollment on this clinical trial; however, toxicities from prior treatment must have resolved to grade 1 or less
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of the treatment; women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation (i.e, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for a minimum of 3 months following the last dose of chemotherapy; male subject agrees to use an acceptable method for contraception for the duration of the study and for a minimum of 3 months following the last dose of chemotherapy
• Patients must have a measurable disease defined by RECIST criteria
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial

Exclusion Criteria:

• Prior treatment with sorafenib or cetuximab
• Patients with active clinically significant infection or with a fever >= 38.5º C within 3 days of the first scheduled day of protocol treatment
• History of prior malignancy within the past 3 years except for curatively treated basal cell carcinoma and squamous cell carcinoma of the skin, CIN or localized prostate cancer with a current PSA < 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of study entry
• Patients with known hypersensitivity to sorafenib or cetuximab
• Prior severe infusion reaction to a monoclonal antibody
• History of hand-foot syndrome
• Pregnant or lactating; sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized
• Known untreated brain metastasis; patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis or progression of brain metastasis; patients with treated brain metastasis are eligible for study as long as no evidence of progression of CNS disease; hemorrhagic brain metastases are not allowed on study
• Uncontrolled comorbid illness
• Patients with HIV who are taking antiretroviral mediations will be excluded because of the potential interactions of anti-retroviral medications with these agent; however, given the potential immune modulating effects of sorafenib, investigators should still be very cautious about placing HIV positive patients on this trial as the effects of these medications on the HIV virus itself are not know
• History of allogeneic transplant
• Patient has received other investigational drugs within 28 days before enrollment
• Cardiac disease: congestive heart failure > class II NYHA; patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months; significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension (defined as defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction will also be excluded from study; cardiac ventricular arrhythmias requiring anti-arrhythmic therapy will also be excluded from study
• Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months
• Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of first dose of study drug
• Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of first dose of study drug
• Tumor that invades the carotid artery as shown unequivocally by imaging studies
• Serious non-healing wound, ulcer, or bone fracture
• Evidence or history of bleeding diathesis or coagulopathy
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug
• Use of St. John's Wort or rifampin (rifampicin)
• Use of the following medications will not be allowed within 4 weeks prior to enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital; products containing grapefruit juice will not be allowed while on study
• Known or suspected allergy to sorafenib or any agent given in the course of this trial
• Any malabsorption problem
• Known HIV positive patients will be excluded from trial due to the potential immune modulation that these agents may cause