Bevacizumab/Ph 2 for Locally Advanced Head and Neck Cancer
Condition: Carcinoma, Squamous Cell of Head and Neck
MeSH terms: Head and Neck Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
Intervention: Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, Cisplatin, Cetuximab and Bevacizumab (XPE-A), surgery
Intervention description: Induction therapy consists of 3 cycles of bevacizumab 15mg/kg on day 1, cetuximab weekly days 1,8,15 (loading dose of cetuximab 400mg/m2 on cycle 1, day 1, then 250 mg/m2 on all subsequent administrations), cisplatin 75mg/m2 on day 1, docetaxel 75mg/m2 on day 1, repeated every 21 days. After 3 cycles of induction therapy, patients will receive standard radiation 70-74 Gy/ 200 cGy/ daily, 5 days/ week with concurrent weekly cisplatin 30mg/m2, cetuximab 250mg/m2 and bevacizumab 15mg/kg every 3 weeks x 3. There is optional surgery for non-responders in the primary (stable disease) after TPE-A.
Intervention MeSH terms: Bevacizumab; Cetuximab; Cisplatin; Docetaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Locally advanced head and neck cancer; Squamous cell carcinoma of the head and neck

Summary:

      Locally advanced squamous cell carcinoma of the head and neck (SCCHN) is treated with various
      combinations of radiation and chemotherapy. This study aims to evaluate the rate of complete
      responses with induction therapy (primary endpoint) and progression-free survival, overall
      survival and objective response rates of docetaxel, cisplatin, cetuximab, and bevacizumab
      (TPE-A) followed by radiation therapy, cisplatin, cetuximab, and bevacizumab (XPE-A). Also,
      the investigators plan to investigate a panel of EGFR and angiogenesis biomarkers in pre-and
      post- treatment tumor biopsies. Finally, the investigators will evaluate the associated
      treatment toxicities and the quality of life.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with AJCC 7th edition stage III-IVB head and neck cancer, all sites,
             including unknown primary tumors.

          -  Prior to entry in the study the resectability and alternative treatment options for
             each patient will be determined by a team composed of an Ear, Nose, and Throat
             Surgeon, a Radiation Oncologist and a Medical Oncologist. Stage determination, optimal
             local treatment, and its timing according to this protocol will be determined at this
             evaluation. The unequivocal demonstration of distant metastasis (M1) confers
             ineligibility.

          -  Histologically or cytologically confirmed diagnosis of squamous cell or poorly
             differentiated carcinomas, or WHO types I-III of the nasopharynx.

          -  Unidimensionally measurable disease is required (RECIST 1.1).

          -  No prior chemotherapy, biologic/molecular targeted therapy (including any prior
             therapy which specifically and directly targets the EGFR pathway), or radiotherapy for
             head and neck cancer.

          -  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.

          -  ECOG performance status 0-1.

          -  Age 18 years or older.

          -  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.

          -  All patients should have their tumor tissue tested for HPV (in situ hybridization
             and/or p16 staining by immunohistochemistry), and results must be known prior to study
             entry, and will consent to have available archival tumor samples, unstained slides or
             blocks from previous diagnostic or therapeutic procedures submitted for correlative
             studies, including assessment of target molecules EGFR, VEGF and related biomarkers.
             Also, patients must agree to submit blood samples for correlative studies at least at
             baseline.

          -  Absolute neutrophil count at or above 1500/µl, Platelet count at or above 100,000/µl

          -  Creatinine clearance 60 ml/min or higher calculated using the Cockcroft-Gault formula:

        Calculated Creatinine Clearance = (140-age) X actual body wt (kg)/ 72 X serum creatinine
        Multiply this number by 0.85 if the patient is female

          -  Total bilirubin within normal limits and AST/ALT less than 3 times the upper limit of
             normal.

          -  Urine dipstick must be < 0-1+ within 2 weeks (14 days) of randomization. If urine
             dipstick result is > 1+, a calculation of Urine Protein Creatinine (UPC) ratio is
             required. Patients must have a UPC ratio < 1.0 to participate in the study.

        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 1gm. UPC ratio is calculated
        using one of the following formula:

          -  [urine protein]/[urine creatinine] - if both protein and creatinine are reported in
             mg/DI

          -  [(urine protein) × 0.088]/[urine creatinine] - if urine creatinine is reported in
             mmol/L

               -  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 3 years post diagnosis.

               -  Patients may not be receiving any other investigational agents.

        Exclusion Criteria:

          -  History of severe allergic reactions attributed to docetaxel or compounds of similar
             chemical or biologic composition to docetaxel, or other drugs formulated with
             polysorbate 80.

          -  Prior severe infusion reaction to a monoclonal antibody or known hypersensitivity to
             any component of bevacizumab

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  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

          -  No patients with significant baseline sensory or motor neurologic deficits (> grade I
             neuropathy) will be treated on this study.

          -  Because patients with immune deficiency are at increased risk of lethal Infections
             when treated with marrow-suppressive therapy, HIV-positive patients are excluded from
             the study. Appropriate studies will be undertaken in patients with HIV and those
             receiving combination anti- retroviral therapies when indicated.

          -  Patients with HPV positive tumors (P16+ by immunohistochemistry and/or HPV+ by in situ
             hybridization) AND smoking history =<10 pack-years

          -  Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
             and/or diastolic blood pressure >100 mmHg)

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  New York Heart Association (NYHA) Grade II or greater congestive heart failure

          -  History of myocardial infarction or unstable angina within 12 months prior to Day 1

          -  No history of stroke or transient ischemic attack within 6 months prior to Day 1

          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Day 1

          -  History of hemoptysis (> or = to 1/2 teaspoon of bright red blood per episode) within
             1 month prior to Day 1

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

          -  Patients should not be on therapeutic anticoagulation therapy (prophylactic use of
             warfarin 1mg per day is allowed) and INR should be <1.5 at registration

          -  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.

          -  Major surgical procedure (including neck dissection), open biopsy, or significant
             traumatic injury within 28 days prior to Day 1 or anticipation of need for major
             surgical procedure during the course of the study

          -  Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device, within 7 days prior to Day 1

          -  History of abdominal fistula or gastrointestinal perforation within 6 months prior to
             Day 1

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture

          -  Pregnant or breast-feeding women will be excluded.