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

Head and Neck Cancer Clinical Trial

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

Status Completed

Clinical Trial 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....

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Carcinoma, Squamous
• Carcinoma, Squamous Cell
• Head and Neck Cancer
• Head and Neck Neoplasms
• Laryngeal Cancer
• Laryngeal Neoplasms
• Mouth Neoplasms
• Oral Cancer
• Pharyngeal Cancer
• Pharyngeal Neoplasms

• NCT number: NCT01445405
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: February 5, 2008
• Completion date: August 27, 2010