A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
Condition: Head and Neck Cancer; Squamous Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Head and Neck Neoplasms
Intervention: Cetuximab; Bevacizumab
Intervention description: Cetuximab 400 mg/m2 IV over 120 minutes on day 1 of cycle 1 ONLY
Cetuximab dose will be 250 mg/m2 IV over 60 minutes weekly on ALL subsequent administrations; Once every 3 weeks, 15 mg/kg of bevacizumab will be given by IV infusion after cetuximab has been given
Intervention MeSH terms: Bevacizumab; Cetuximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 98 Years
Healthy volunteers: No
Keywords: head and neck cancer; cetuximab; bevacizumab; squamous cell carcinoma; SCCHN; Squamous Cell Carcinoma of the Head and Neck

Summary:

      The purpose of this study is to determine if the combination of two new drugs, cetuximab
      (Erbitux) and bevacizumab (Avastin) can increase the effectiveness of treatment for head and
      neck cancer. Cetuximab has recently been approved by the FDA for head and neck cancer (that
      is locally or regionally advanced) when used in combination with radiation therapy. Cetuximab
      is also approved by the FDA for the treatment of colorectal cancer
    

Eligibility criteria:

        Eligibility Criteria

        Patients must have histologically or cytologically confirmed Squamous Cell Cancer of the
        Head and Neck either (a) metastatic (i.e. American Joint Committee on Cancer Staging
        System, 6th edition, stage IVC) or (b) recurrent, judged incurable by surgery or radiation.

        Patients must have measurable disease, defined as at least one lesion that can be
        accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm
        with conventional techniques or as >10 mm with CT scan). RECIST criteria will be used (see
        section 9).

        Therapeutic history in conformance with the following:

        No more than one prior adjuvant/neoadjuvant chemotherapy and/or concomitant
        chemoradiotherapy regimen that may have included biologic/targeted agent.

        No more than one prior regimen (chemotherapy or biologic/targeted) for recurrent/metastatic
        disease

        ECOG performance status of 0-2 (Karnofsky > 60%; see Appendix A).

        Patients must have normal organ and marrow function as defined below:

        absolute neutrophil count > 1,000/L platelets > 75,000/L total bilirubin within normal
        institutional limits

        AST(SGOT)/ALT(SGPT) 5 X institutional upper limit of normal creatinine within normal
        institutional limits

        OR

        creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above
        institutional normal

        Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio
        (see Appendix). For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level
        should be <1000 mg for patient enrollment.

        Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC
        ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is
        calculated using on of the following formula:

        [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/Dl
        [(urine protein) x0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L

        All patients should have baseline tumor tissue available for EGFR determination
        (therapeutic target of cetuximab) and biomarker studies. Patients without available tissue
        at baseline may undergo tumor biopsy. Patients who provide consent and have accessible
        tumors will have a repeat biopsy 14 days (an interval between 12-16 days is acceptable)
        post initiation of therapy. Priority for study entry will be given to patients with easily
        accessible tumor and who consent to repeat biopsy. Study entry will not be restricted to
        patients who agree to further biopsies. If a patient enrolls on study and later refuses
        biopsy (excluding diagnostic), he/she may remain on study.

        No prior treatment with cetuximab or bevacizumab or other EGFR or VEGF targeting agents.

        Patients should not have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
        mitomycin C) and biologic/targeted agents within 3 weeks. At least 3 months should have
        elapsed after prior therapy with monoclonal antibodies.

        At least 3 weeks should have elapsed from prior radiotherapy.

        Patients must have no history of gross hemoptysis (defined as bright red blood of a ½
        teaspoon or more) or coagulopathy. Patients with history of major tumor-related bleeding
        that is not controlled despite locoregional treatment or at high risk of recurrent
        tumor-related bleeding will be excluded.

        Patients should not have a history of thrombosis (e.g. pulmonary embolism or deep venous
        thrombosis) and should not be on therapeutic anticoagulation (prophylactic use of warfarin
        1 mg per day is allowed) and INR should be less than 1.5 at registration.

        Patients with history of hypertension must be well-controlled (≤150/100) on a stable
        regimen of anti-hypertensive therapy.

        Patients with tumors that invaded major vessels (e.g. the carotid) as shown unequivocally
        by imaging studies will be excluded due to the possibility of increased risk for tumor
        bleeding with bevacizumab therapy.

        No major surgical procedure, open biopsy, or significant traumatic injury within 28 days
        prior to study enrollment, or anticipation of need for major surgical procedure during the
        course of the study. No history of abdominal fistula, gastrointestinal perforation, or
        intra-abdominal abscess within 28 days prior to registration. No serious non-healing wound,
        ulcer, or bone fracture.

        No unstable angina or myocardial infarction within the previous 6 months; no uncontrolled
        hypertension; no symptomatic congestive heart failure; no serious cardiac arrhythmia
        requiring medication; no clinically significant peripheral vascular disease; no history of
        any CNS cerebrovascular ischemia or stroke within the last 6 months; no active serious
        infection.

        No other coexisting medical condition that would preclude full compliance with the study.

        Patients may not be receiving any other investigational agents.

        Patients with known brain metastases should be excluded from this clinical trial because of
        their poor prognosis and because of increased risks with bevacizumab.

        Patients should not have a history of prior severe infusion reaction to a monoclonal
        antibody. Patients with known hypersensitivity of Chinese hamster ovary cell products or
        other recombinant human antibodies.

        No history of prior malignancy, with the exception of curatively treated squamous cell or
        basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year
        disease-free interval.

        Age > 18 years. Because no dosing or adverse event data are currently available on the use
        of cetuximab and bevacizumab in patients <18 years of age, children are excluded from this
        study but will be eligible for future pediatric single-agent trials, if applicable.

        Ability to understand and the willingness to sign a written informed consent document.

        Pregnant women are excluded from this study because cetuximab and bevacizumab have the
        potential for teratogenic or abortifacient effects. Because there is an unknown but
        potential risk for adverse events in nursing infants secondary to treatment of the mother
        with cetuximab and bevacizumab, breastfeeding should be discontinued if the mother is
        treated with cetuximab and bevacizumab. The effects of cetuximab and bevacizumab on the
        developing human fetus at the recommended therapeutic dose are unknown. For this reason
        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.

        HIV-positive patients receiving combination anti-retroviral therapy are excluded from the
        study because of possible drug interactions with cetuximab and bevacizumab. Appropriate
        studies will be undertaken in patients receiving combination anti-retroviral therapy when
        indicated.

        Inclusion of Women and Minorities

        Both men and women and members of all ethnic groups are eligible for this trial. The
        proposed study population is illustrated in the table below.

        Inclusion of Women in Plan: The gender distribution of our head and neck cancer patients is
        detailed in the table below. All efforts are made to recruit women patients with head and
        neck cancer to the University of Pittsburgh Medical Center.