Radiation and Cetuximab Plus Intratumoral EGFR Antisense DNA in Locally Advanced Head and Neck Squamous Cell Carcinoma

The Epidermal Growth Factor Receptor (EGFR) is highly expressed in SCCHN and its
overexpression is associated with poor patient outcome. EGFR is a promising target of
anticancer therapy. The investigators have developed EGFR antisense DNA as a safe and
potentially efficacious treatment for SCCHN as shown in a previous phase I study conducted at
the University of Pittsburgh. Cetuximab (Erbitux or C225) is a chimerized EGFR monoclonal
antibody that has produced positive results in a phase III trial in SCCHN when added to
radiation therapy and was approved by the FDA for the treatment of locally advanced SCCHN.
Radiation plus cetuximab is considered a standard treatment, especially for patients who are
not good candidates for chemotherapy. In the current study, the investigators plan to
evaluate the addition of intratumoral EGFR antisense DNA (EGFR AS) to standard radiation with
concurrent cetuximab in patients.

Objectives

- To evaluate the safety of the combination of intratumoral EGFS AS DNA with standard
cetuximab and radiation.

- To evaluate the locoregional progression-free survival in selected patients with locally
advanced SCCHN treated with intratumoral EGFR AS DNA combined with standard radiation
plus cetuximab.

- To evaluate other efficacy parameters, including the objective response rate, distant
control and overall progression-free survival, and overall survival.

- To determine the effect of EGFR antisense therapy on EGFR-related biomarkers. The
investigators will use reverse phase protein microarrays (RPPA) and immunohistochemical
(IHC) analysis of tissue microarrays (TMA) on baseline and post-treatment tumor tissue
to determine the expression level and modulation of a panel of EGFR and EGFR-pathway
related biomarkers, including (but not necessarily limited to) EGFR, pEGFR, Src, pMAPK,
STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E-cadherin, p-ErbB3, and Ki67.

- To examine the transfection of the EGFR antisense gene therapy in vivo.

Subject population

The investigators will enroll patients with SCCHN who are suitable for intratumoral
injections of EGFR antisense.

Treatment plan

EGFR AS will be administered by direct intratumoral injection using direct visualization,
endoscopy, or imaging-guidance (ultrasound) as clinically determined (see protocol). Patients
will receive a total of up to 4 weekly intratumoral injections of EGFR antisense (or less if
there is no identifiable tumor) starting 2 weeks prior to radiation (study schema in
protocol). Patients will receive standard radiation 70 Gy/200 cGy/daily, 5 days/week, with
concurrent cetuximab 250 mg/m2, after a loading dose of 400 mg/m2 2 weeks prior to starting
radiation.

Statistical Design and Sample Size

The study will be conducted in two-stages. In the first stage, 11 patients with stage IVA-C
or recurrent disease will be evaluated for safety. If the regimen is deemed safe, a total of
31 patients with stage III or IVA-B, previously untreated SCCHN will be enrolled in the
second stage of the study.

Inclusion Criteria:

- First stage Patients with AJCC 7th edition stage IVA-IVC or recurrent or metastatic
head and neck cancer will be eligible. Patients with M1 disease must have asymptomatic
or low volume distant metastasis and require palliation for local and regional
disease.

- Second stage (phase II part) Patients with AJCC 7th edition stage III-IVB (T1-T4,
N1-3M0) head and neck cancer, except WHO type II and III nasopharyngeal cancer,
including unknown primary tumors.

- Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or
variants or poorly differentiated carcinoma.

- Unidimensionally measurable disease (RECIST criteria).

- ECOG performance status of 0-2

- In the second stage of the study, therapy will be administered with a curative intent
and patients should not have recurrent disease or distant metastasis.

- Primary tumor and/or lymphadenopathy should be technically suitable for intratumoral
injections. The Otolaryngologist specialist on the head and neck team will determine
this feasibility.

- Participating patients should agree to undergo a tumor biopsy at baseline as well as
approximately 2 weeks later as specified in study schema.

- Prior treatment

- First stage: any prior treatment, except prior therapy, which specifically and
directly targets the EGFR pathway, administered within the last 6 months. No prior
radiation therapy to the head and neck.

- Second stage: no prior chemotherapy, biologic/molecular targeted therapy (including
any prior therapy which specifically and directly targets the EGFR pathway), or
radiotherapy for head and neck cancer.

- Prior surgical therapy will consist only of incisional or excisional biopsy, including
tonsillectomy, and organ sparing procedures, including neck dissection. Any non-biopsy
surgical procedure for head and neck cancer must have taken place at least one month
before initiating protocol treatment, at the treating physician's discretion.

- Patients must have organ and marrow function as defined below:

Absolute neutrophil count above/equal to 1,000/µL Platelets above/equal to 75,000/µL
Hemoglobin above/ equal to 10 g/dL Total bilirubin <2 x upper normal institutional limits
Creatinine clearance > 20 mL/min

- Age 18 years or older

- Because radiation therapy is known to be teratogenic and EFGR inhibitors may have
teratogenic potential, women of childbearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control) prior to study
entry and for the duration of study participation, and for 3 months after completing
study treatment. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.

- Informed consent must be obtained from all patients prior to beginning therapy.
Patients should have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Severe renal insufficiency (creatinine clearance < 20 mL/min)

- Treatment with anticoagulants, except when used to maintain the patency of a central
venous line, or INR >1.5, or PTT ratio >1.5.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements. Significant history of uncontrolled cardiac disease; i.e.,
uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure.

- Patients may not be receiving any other investigational agents.

- No history of prior malignancy, with the exception of curatively treated squamous cell
or basal carcinoma of the skin or in situ cervical cancer, DCIS or LCIS of the breast,
localized early stage prostate cancer, or malignancy that has been treated with a
curative intent with a 3-year disease-free survival.

- Pregnant women are excluded from this study because cetuximab, EGFR AS, and radiation
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 cetuximab and EGFR AS, breastfeeding should be
discontinued if the mother is treated with cetuximab. The effects of cetuximab and
EGFR AS on the developing human fetus at the recommended therapeutic dose are unknown.
For this reason women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect she
is pregnant while in this study, she should inform her treating physician immediately.

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible drug interactions with cetuximab. Appropriate studies
will be undertaken in patients receiving combination anti-retroviral therapy when
indicated. HIV status of the patient will be obtained from the patient's history via
discussion with the investigator. HIV testing is not required.

- Prior severe infusion reaction to a monoclonal antibody.

- Patients who are not informed of and are not willing to comply with the
investigational nature of the study and have not signed a written informed consent in
accordance with institutional and good clinical practice guidelines.

- Phase 2 ONLY (second stage) - Subjects M1 disease will be excluded.