Phase I Study of Bortezomib and Cetuximab Without or With Cisplatin in Combination With Radiation Therapy for Advanced Head and Neck Cancer
- 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,
- 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.
-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.
-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.
-Patients with advanced Stage IV SCCHN, without history prior neck radiation, for whom
concurrent chemo-RT is an option.
- 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
- 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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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...
Alan S Wayne, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|