Radiation Therapy and Bortezomib and Cetuximab With or Without Cisplatin to Treat Head and Neck Cancer

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Brief Title

Radiation Therapy and Bortezomib and Cetuximab With or Without Cisplatin to Treat Head and Neck Cancer

Official Title

Phase I Study of Bortezomib and Cetuximab Without or With Cisplatin in Combination With Radiation Therapy for Advanced Head and Neck Cancer

Brief 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Evaluate feasibility/toxicities of combining proteasome inhibitor bortezomib with cetuximab without/with cisplatin concurrent with radiation for therapy of Pts with advanced SCCHN, and identify MTD for bortezomib for further clinical phase 2 dev...

Secondary Outcome

 1) Evaluate objective response rate, progression-free survival/overall survival with the above regimen. 2) Determine effects of bortezomib with cetuximab or with cetuximab/ cisplatin to inhibit activation of NF-kB, EGFR, MAPK, and STAT3 signal p...

Condition

Carcinoma, Squamous

Intervention

Bortezomib (Velcade, PS-341)


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

3

Start Date

February 5, 2008

Completion Date

August 27, 2010

Primary Completion Date

August 27, 2010

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Histologically or cytologically confirmed squamous cell carcinoma, including variants,
             or undifferentiated/poorly differentiated carcinoma of the head and neck (any site,
             except nasopharynx).

          2. Previously untreated stage IV disease (AJCC staging system, 6th edition), or,

          3. Patients with residual disease or regional recurrence of head and neck cancer after
             surgery and/or chemotherapy, but with no prior bortezomib, EGFR inhibitor therapy or
             head and neck radiotherapy. All such patients should be eligible to receive full dose
             radiation therapy, and must be evaluated and accepted for treatment by a Radiation
             Oncologist. Prior cisplatin is allowed if administered greater than 3 months earlier.

          4. Patients with no clinically measurable distant disease, or those with asymptomatic
             small distant lesions outside the radiation field of less than or equal to 3cm
             individual or aggregate diameter, but for whom palliation of local and regional
             disease is clinically warranted will be eligible.

          5. Any number of other prior systemic therapies is allowed. Patients must have fully
             recovered from the effects of any prior surgery, or chemotherapy. A minimum time
             period of 4 weeks (6 weeks for nitrosoureas or mitomycin C) should elapse between the
             completion of prior chemotherapy and enrollment in the study.

          6. Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of bortezomib in combination with cetuximab or
             cisplatin and radiation in patients <18 years of age, and head and neck cancer in
             children is exceedingly rare, except for those with disorders of DNA damage repair,
             bone marrow or transplant immunosuppression likely to have lower tolerance to these
             drugs and RT, children are excluded from this study.

          7. ECOG performance status 0-1 (Karnofsky greater than or equal to 70 percent).

          8. Patients must have normal organ and marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  total bilirubin within normal institutional limits, except for patients with
                  Gilberts syndrome, with increased indirect bilirubin less than or equal to 3
                  mg/dL

               -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
                  normal

               -  creatinine within normal institutional limits

             OR

             -creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
             creatinine levels above institutional normal.

          9. The effects of bortezomib on the developing human fetus are unknown. For this reason
             and because other therapeutic agents used in this trial are known to be teratogenic,
             women of child-bearing potential and men must have agreed to use adequate
             contraception (hormonal or barrier method of birth control; prior vasectomy; tubal
             ligation or abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

         10. Adequate cognitive and neurologic function to protect against and detect and report
             toxicities experienced, and to understand and to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          1. Patients with previously untreated nasopharyngeal cancer (any stage) will be excluded,
             but patients with recurrent nasopharyngeal carcinoma will be eligible.

          2. Prior treatment with radiation to the head and neck, or systemic EGFR inhibitors or
             bortezomib is not allowed.

          3. Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
             mitomycin C) prior to entering the study or those who have not recovered from adverse
             events due to agents administered more than 4 weeks earlier.

          4. Patients may not be receiving any other investigational agents.

          5. Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          6. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to bortezomib, cetuximab, cisplatin or other agents used in study.

          7. Patients with greater than or equal to grade 2 peripheral sensory neuropathy because
             bortezomib can cause irreversible worsening and a painful type of chemotherapy
             associated peripheral neuropathy.

          8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          9. Pregnant women are excluded from this study because bortezomib, cetuximab and
             cisplatin 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 bortezomib, cetuximab and cisplatin, breastfeeding should
             be discontinued if the mother is treated with bortezomib, cetuximab and cisplatin.
             These potential risks may also apply to other agents used in this study.

         10. HIV-positive patients or patients on any antiretroviral therapy are ineligible because
             of the potential for possible pharmacodynamic interactions with bortezomib, cetuximab
             and cisplatin, particularly bone marrow and mucosal toxicity, which could affect the
             MTD. These patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy.
      

Gender

All

Ages

18 Years - 90 Years

Accepts Healthy Volunteers

No

Contacts

Carter Van Waes, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01445405

Organization ID

080071

Secondary IDs

08-C-0071


Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Carter Van Waes, M.D., Principal Investigator, National Institute on Deafness and Other Communication Disorders (NIDCD)


Verification Date

February 8, 2013