Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer
Condition: Cancer
MeSH terms: Head and Neck Neoplasms
Intervention: Bevacizumab; Cetuximab; Pemetrexed; Radiation therapy
Intervention description: Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy.; Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments.; Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy.; Radiation therapy standard fractionation 2 Gy/day without planned interruptions beginning on day 1 (Monday or Tuesday preferred). Radiation will be given 5 days/week, Monday through Friday, for 7 consecutive weeks
Intervention MeSH terms: Bevacizumab; Cetuximab; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: head and neck cancers

Summary:

      The purpose of this study is to compare the effects (good and bad) of chemoradiotherapy with
      or without Bevacizumab (Avastin). Chemoradiotherapy is the combination of chemotherapy (the
      drugs pemetrexed and cetuximab) and radiation. Pemetrexed is not approved by the Food and
      Drug Administration (FDA) for head and neck cancer when used in combination with radiation
      therapy. Cetuximab is also approved by the FDA for head and neck cancers in patients who have
      failed other chemotherapy treatments. Bevacizumab is approved by the Food and Drug
      Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of
      chemotherapy. In this study, the use of bevacizumab is investigational.
    

Eligibility criteria:

        Inclusion Criteria:

          -  All patients must have pathologically confirmed AJCC 6th edition (see Appendix) stage
             III or IV (M0) squamous cell carcinoma or undifferentiated or poorly differentiated
             carcinoma of the oropharynx, larynx, or hypopharynx with no evidence of distant
             metastasis. Biopsy sampling of primary tumor with pathology report documentation of
             confirmed diagnostic tissue type is required. Patients should be evaluated by a
             Radiation Oncologist, Medical Oncologist and Otolaryngologist prior to enrolling on
             study.

          -  No prior treatment for head and neck cancer. Limited, organ-preserving surgery is
             allowed

          -  ECOG performance status 0-1

          -  Unidimensionally measurable disease is not required. However, patients should require
             treatment with full dose radiotherapy (not postoperative)

          -  Age greater or equal to 18 years

          -  Absolute neutrophil count greater or equal to 1500/µl, Platelet count greater or equal
             to 100,000/µl

          -  Creatinine clearance 45 ml/min or higher calculated using the Cockcroft-Gault formula

          -  Total bilirubin within normal limits and AST/ALT less than 3 times the upper limit of
             normal

          -  Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
             ratio. For UPC ratio >0.5, 24-hour urine protein should be obtained and the level must
             be <1000mg for patients to be eligible

          -  Informed consent must be obtained from all patients prior to beginning therapy.
             Patients should have the ability to understand and the willingness to sign a written
             informed consent document

          -  Patients should be willing and able to take folic acid and vitamin B12 supplementation
             and should interrupt aspirin or other non-steroidal anti-inflammatory agents for a
             5-day period

          -  The use of anti-platelet agents(e.g. dipyridamole (Persatine), ticlopidine (Ticlid),
             clopidogrel (Plavix)) is allowed only if patient is not receiving aspirin or NSAID's
             known to inhibit platelet function.

          -  Patients who meet the following criteria will be excluded due to the possibility of
             increased risk for tumor bleeding with bevacizumab therapy:

               -  active bleeding due to head and neck cancer of more than ½ teaspoon of bright red
                  blood per episode or history of persistent bleeding due to SCCHN that required
                  major intervention (surgery or embolization) to be controlled.

               -  history of gross hemoptysis (bright red blood of .05 teaspoon or more per episode
                  of coughing) less than or equal to 3 months prior to enrollment

               -  history of coagulopathy or hemorrhagic disorders

          -  Patients should not be on therapeutic anticoagulation (prophylactic use of warfarin 1
             mg per day is allowed) and INR should be < 1.5 at registration.

          -  Patients with a prior history of squamous cell or basal carcinoma of the skin or in
             situ cervical cancer must have been curatively treated. Patients with a history of
             other prior malignancy must have been treated with curative intent and must have
             remained disease-free for 5 years post diagnosis

          -  Patients with history of hypertension must be well-controlled upon study entry
             (≤150/90) on a stable regimen of anti-hypertensive therapy. Patients should not have
             any prior history of hypertensive crisis or hypertensive encephalopathy.

          -  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. Prior surgical therapy will consist only of incisional
             or excisional biopsy and organ sparing procedures such as debulking of airway
             compromising tumors or neck dissection in a patient with an existing primary tumor.
             Any non-biopsy procedure must have taken place >4 weeks but <3 months of initiating
             protocol treatment. No history of abdominal fistula, gastrointestinal perforation, or
             intra-abdominal abscess within 6 months prior to registration. No serious non-healing
             wound, ulcer, or bone fracture.

          -  No unstable angina or myocardial infarction within the previous 6 months; no
             symptomatic congestive heart failure; no serious cardiac arrhythmia requiring
             medication; no clinically significant peripheral vascular disease; no history of
             aortic dissection; no history of any CNS cerebrovascular ischemia or stroke within the
             last 6 months; no active serious infection. All patients will have a baseline EKG. If
             abnormalities consistent with active coronary artery disease are detected, the patient
             will be referred to a cardiologist for appropriate evaluation and management prior to
             treatment on study

          -  For patients who have baseline clinically significant pleural or peritoneal effusions
             (on the basis of symptoms or clinical examination) before initiation of protocol
             therapy, consideration should be given to draining the effusion prior to starting
             therapy due the potential of increased toxicity with pemetrexed in that setting

          -  Submission of archival tumor samples, unstained slides or blocks, for correlative
             studies is strongly encouraged, but not required for subject participation if tissue
             is not readily available or quantity is not sufficient for release per submitting
             pathologist.

        Exclusion Criteria:

          -  Patients who are receiving any other investigational agents.

          -  Ineligible will be patients with uncontrolled intercurrent illness including, but not
             limited to,ongoing or active infection or psychiatric illness/social situations that
             would limit compliance with study requirements.

          -  Patients should not have prior history of a serious reaction to a monoclonal antibody.
             Patients with known hypersensitivity to Chinese hamster ovary cell products or other
             recombinant human antibodies are not eligible.

          -  Women must not be pregnant or breast feeding because chemotherapy may be harmful to
             the fetus or the nursing infant. Pregnant women are excluded from this study because
             chemotherapy and/or bevacizumab have the potential for teratogenic or abortifacient
             effects.

          -  HIV-positive patients receiving combination anti-retroviral therapy are excluded from
             the study because of possible drug interactions with study drugs. Appropriate studies
             will be undertaken in patients receiving combination anti-retroviral therapy when
             indicated.