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

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.

-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.