Radiation Therapy and Bortezomib and Cetuximab With or Without Cisplatin to Treat Head and Neck Cancer
Condition: Carcinoma, Squamous; Head and Neck Cancer; Oral Cancer; Laryngeal Cancer; Pharyngeal Cancer
MeSH terms: Head and Neck Neoplasms; Mouth Neoplasms; Laryngeal Neoplasms; Carcinoma, Squamous Cell; Pharyngeal Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Bortezomib acts on molecules in head and neck cancer cells that are important for the cells
      growth and survival. The drug may help make the cancer more sensitive to radiation and other
      chemotherapy drugs.

      Cetuximab is a monoclonal antibody that has increased the effectiveness of radiation
      treatment in patients with head and neck cancer in clinical trials.

      Cisplatin has shrunk head and neck cancers and improved treatment response and survival when
      combined with radiation treatment.

      Objectives:

      To determine the highest safe dose of bortezomib when combined with cetuximab without or with
      cisplatin and with radiation in patients with advanced head and neck cancer.

      To examine the benefits and side effects of these drug combinations with radiation in
      patients with advanced head and neck cancer.

      Eligibility:

      Patients 18 years of age and older with advanced Stage IV head and neck cancer who have not
      previously had neck radiation.

      Design:

      Patients will be assigned sequentially to one of two treatment groups: Group A receives
      bortezomib and cetuximab beginning the week before, and for the duration of, radiation
      therapy; Group B receives bortezomib, cetuximab and cisplatin beginning the week before, and
      for the duration of, radiation therapy.

        -  Cetuximab is given as a 2-hour infusion through a vein (intravenously, IV) for the first
           dose and then over 1 hour for subsequent weekly doses.

        -  Bortezomib is given as an injection into a vein over about 5 seconds, twice a week for 2
           weeks, followed by a 1-week rest for a total of three 3-week treatment cycles during
           radiation.

        -  Cisplatin is given in once a week as a 1-hour IV infusion

        -  Radiation therapy is given 5 days a week for 7 to 8 weeks.

      Post-treatment follow-up:

        -  Until 2 weeks after treatment ends, patients are followed once a week including a
           physical examination, review of treatment side effects, and blood tests.

        -  For 2 months after treatment ends, patients may need to return to the hospital for
           medical evaluation and supportive care, depending on their condition.

        -  8-weeks after treatment ends, patients return for evaluation with a history and physical
           examination; blood tests; ear, nose and throat evaluation and endoscopy; CT or MRI scan,
           or both, of the neck and chest; and, if indicated, a PET scan....
    

Detailed description: 
      Background:

        -  Advanced squamous cell carcinoma involving the head and neck (SCCHN) has a mortality
           exceeding 50 percent and significant impact on function and quality of life.

        -  Treatment of locally advanced SCCHN with anti-Epidermal Growth Factor Receptor (EGFR)
           antibody cetuximab (Erbitux or C225) or DNA damaging agent cisplatin concurrent with
           radiation therapy (RT) have shown improvements in response, survival, and organ
           preservation, of approximately10-20 percent over RT alone. The combination of cetuximab,
           cisplatin and RT is currently under investigation as the next standard for concurrent
           chemo-RT for patients with SCCHN.

        -  Cetuximab inhibits EGFR, which is overexpressed by approximately 90 percent of SCCHN and
           is associated with decreased patient survival. EGFR contributes to activation of the
           Mitogen Activated Protein Kinase (MAPK) and Signal Transduction and Activating
           Transcription Factor (STAT3) pathways, which promote induction of genes involved in cell
           proliferation and survival.

        -  Recently, the Nuclear Factor-kappaB (NF-kB) pathway has been shown to be an independent
           pathway important for altered expression of prosurvival genes, the malignant phenotype,
           and prognosis.

        -  Proteasome inhibitor bortezomib (Velcade, PS-341) can inhibit NF-kB and target genes, as
           well as increase expression of tumor suppressor genes such as p53 in SCCHN. Bortezomib
           in combination with RT, cetuximab or cisplatin induces greater cytotoxic effects in
           cancer cells than these treatments individually in preclinical studies.

        -  In this phase I trial we will determine the feasibility of administering bortezomib
           concurrently with cetuximab and RT, and cetuximab, cisplatin and RT. We hypothesize that
           bortezomib can be given with these combinations with an acceptable toxicity profile and
           a maximum tolerated dose (MTD) that demonstrates clinical activity and effects on NF-kB,
           MAPK and STAT3 pathway signaling and apoptosis in SCCHN.

      Specific Objectives:

      Primary Objectives

      -To evaluate the feasibility and toxicities of combining the proteasome inhibitor bortezomib
      with cetuximab, or cetuximab and cisplatin concurrent with radiation for therapy of patients
      with advanced squamous cell carcinoma of the head and neck (SCCHN), and to identify the MTD
      for bortezomib for further clinical phase 2 development.

      Secondary Objectives

      -To evaluate the objective response rate, progression-free survival and overall survival with
      the above regimen.

      To determine the effects of bortezomib with cetuximab, or bortezomib, cetuximab with
      cisplatin to inhibit activation of the NF-kB, EGFR, MAPK, and STAT3 signal pathways,
      expression of pro-survival and pro-angiogenesis genes regulated by these pathways, and
      effects on proliferation, apoptosis and angiogenesis.

      Eligibility:

      -Patients with advanced Stage IV SCCHN, without history prior neck radiation, for whom
      concurrent chemo-RT is an option.

      Design:

        -  All patients will receive standard RT to a total dose of 70 Gy, in 2 Gy/day fractions, 5
           days/week, concurrent with either bortezomib and cetuximab, or bortezomib, cetuximab and
           cisplatin.

        -  Bortezomib will be given following a dose escalation schema (3 dose levels of 0.7, 1 and
           1.3 mg/m2/dose) IV twice weekly for the first two weeks of three 21-day cycles which
           each include a 1 week break, starting the week prior to RT initiation and for a total of
           7-8 weeks.

        -  In group A, patients with receive bortezomib, cetuximab and RT, and in group B,
           bortezomib, cetuximab, cisplatin and RT.

        -  Previously established MTDs will be used for weekly administration of cetuximab
           (400mg/m2 initially and then 250 mg/m(2) IV weekly), and cisplatin (30mg/m(2) IV
           weekly).

        -  Cetuximab or cetuximab and cisplatin will be given with the first dose of bortezomib the
           week prior to RT and continue weekly during RT (7-8 weekly doses). Drug therapy will not
           be given after RT completion.

        -  Groups A will accrue before group B, to identify the MTD for the combination of
           bortezomib, cetuximab and RT, and then bortezomib, cetuximab, cisplatin and RT, for
           expansion and phase 2 development.

        -  Serum and blood will be collected for study of potential proteomic and genetic markers
           of drug sensitivity and effects, and tumor response and recurrence, within 2 weeks
           pretreatment and days 5, 12 of bortezomib cycle 1, and day 12 of cycles 2 and 3. Serum
           will be collected thereafter every 3 months up to 24 months.

        -  Optional tumor and/or skin biopsies will be performed within 2 weeks before start of
           treatment and on day 5 of the first week during treatment with drugs alone, and on day
           12 after start of RT for correlative studies of the combined effects of bortezomib with
           cetuximab, or bortezomib cetuximab and cisplatin on signal pathway activation, apoptosis
           and other markers, without and with RT. (Details of correlative studies). Patients will
           be evaluated by CT and FDG-PET pre-treatment and for response 8 weeks post-RT using WHO
           RECIST criteria.

        -  The study design and sample size is Phase 1, 3-6 patients per dose level to establish
           the MTD. An additional 6-10 patients (in each group) will be treated at the MTD in order
           further assess toxicity, response and molecular correlatives. The anticipated sample
           size is between 6 and 46.
    

Intervention name(s): Bortezomib (Velcade, PS-341); Cetuximab; Cisplatin; Radiation Therapy
Intervention type(s): Drug; Drug; Drug; Procedure
Intervention MeSH terms: Cetuximab; Bortezomib
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Proteasome; Bortezomib; NF-kappaB; Cetuximab; Epidermal Growth Factor; Head and Neck Cancer; Squamous Cell Carcinoma; Oral Cancer