Cetuximab in Head and Neck Cancer Patients

This is a window of opportunity trial evaluating the hypothesis that AXL levels correlate
with clinical response to cetuximab in head and neck patients. Patients with head and neck
squamous cell carcinoma who are scheduled to undergo surgical resection of their tumor and
are candidates for cetuximab chemotherapy are eligible to participate.

Primary:

1. To test the hypothesis that low AXL correlates with clinical response to cetuximab in head
and neck cancer patients

Secondary:

1. To further describe the safety of pre-operative administration of cetuximab

Correlative:

1. To correlate AXL expression with change in Ki67 following cetuximab in Head and Neck
Cancer (HNC) patients

2. To examine other putative markers of cetuximab sensitivity such as HER3 and change in
circulating tumor cells

3. To establish the first panel of patient-derived xenografts from patients with known
sensitivity or resistance to cetuximab

Following informed consent, tumor tissue from the research biopsy and a blood draw for
circulating tumor cells will be obtained. The patient will then receive two weekly doses of
pre-operative cetuximab during the interval between diagnostic biopsy and surgery (~14 days),
ensuring that no delay in standard of care (SOC) will occur.

For dose #1, patients will receive cetuximab 400 mg/m2 via intravenous infusion over 2 hours
(maximum infusion rate 10 mg/min) as per the standard of care loading regimen for cetuximab
monotherapy.

For dose #2, patients will receive cetuximab 250 mg/m2 via intravenous infusion over 1 hour
(maximum infusion rate 10 mg/min) as per the standard of care dosing regimen for cetuximab
monotherapy.

At the time of surgery, another blood draw will be obtained for analysis of circulating tumor
cells, and a portion of the resected tumor will be obtained for study analysis.

Correlative studies will include the measurement of proteins hypothesized to be involved in
cetuximab resistance such as AXL, Ki67, EGFR, and HER3 expression from both the biopsy and
the surgical specimen. Blood will be analyzed for correlative analysis of circulating tumor
cells. Tissue from the research biopsy will be utilized for patient-derived xenograft (PDX)
development.

Inclusion Criteria:

Informed consent: patients must be informed of the investigational nature of the study and
must be able to sign a written informed consent.

- Inclusion criteria for research biopsy (screen)

- Patients must have suspected or known clinical presentation of head and neck
squamous cell carcinoma or a recurrence of head and neck squamous cell carcinoma
after initial therapy. For newly suspected head and neck cancer, the procedure
will obtain tissue for both standard of care biopsy and additional tissue for
research.

- Participants must have sufficient tumor volume (approximately 10 cc) to
accommodate at minimum 2-3 core samples for the research biopsy. This will be
approximated based on clinical evidence, such as physician visualization or
palpitation.

- Patients are required to consent to the TSB Biobank protocol (2016-0934) as part
of this study.

- Surgical management must be the chosen modality for management of the head and
neck squamous cell cancer.

- Other therapeutic modalities may follow, but surgery must be the choice for
first therapy rendered.

- Inclusion criteria for cetuximab treatment:

- Patients must have a biopsy proven, squamous cell carcinoma of the head and neck,
excluding advanced cutaneous head and neck squamous cell carcinoma.

- ECOG performance status £ 1

- Women of childbearing potential (WOCP) must not be pregnant (confirmed by a
negative urine/serum pregnancy test within 7 days of cetuximab treatment). In
addition, a medically acceptable method of birth control must be used such as an
oral, implantable, injectable, or transdermal hormonal contraceptive, an
intrauterine device (IUD), use of a double barrier method (condoms, sponge,
diaphragm, or vaginal ring with spermicidal jellies or cream), or total
abstinence during the study participation and for 6 months after last dose of
study drug. Women who are postmenopausal for at least 1 year or surgically
sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are
not considered to be WOCP.

- Men who are not surgically or medically sterile must agree to use an acceptable
method of contraception. Male patients with female sexual partners who are
pregnant, possibly pregnant, or who could become pregnant must agree to use
condoms during the study and for 6 months post study drug. Total abstinence for
the same study period is an acceptable alternative.

Exclusion Criteria:

- Diagnosis of nasopharyngeal carcinoma, advanced cutaneous squamous cell carcinoma of
the head & neck, and salivary gland tumors

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable
safety risks or compromise compliance with the protocol

- Prior chemotherapy, radiotherapy, or major surgery within 8 weeks of study enrollment
or those who have not recovered (to grade ≤ 1 or baseline) from clinically significant
adverse events due to agents administered more than 8 weeks earlier (alopecia and
fatigue excluded). Clinical significance to be determined by the study investigator

- Prior cetuximab therapy is allowed so long as administered ³ 8 weeks ago.

- Evidence of distant metastatic disease

- History of allergic reactions attributed to compounds of chemical or biologic
composition similar to those of cetuximab

- Pregnancy, breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 6 months
after the last dose of trial treatment

- Ongoing or active infection, including active tuberculosis or known infection with the
human immunodeficiency virus (HIV)

- Ongoing treatment with other investigational agents.

- Prior malignancy except for the following:

- adequately treated basal cell or squamous cell skin cancer

- in situ cervical cancer

- adequately treated Stage I or II cancer from which the patient currently has no
evidence of disease

- Synchronous squamous cell carcinomas of the head/neck that are appropriate for
surgical resection as part of the clinical care

- Any of the following cardiac conditions:

- uncontrolled or poorly-controlled arrhythmia or uncontrolled cardiac
insufficiency uncontrolled or poorly-controlled hypertension (>180 mmHg systolic
or > 130 mmHg diastolic)

- Any of the following conditions:

- serious or non-healing wound, ulcer, or bone fracture

- history of abdominal fistula, gastrointestinal perforation, or intraabdominal
abscess within 28 days of study enrollment

- history of cerebrovascular accident (CVA) or transient ischemic attack within 12
months prior to study enrollment

- history of myocardial infarction, ventricular arrhythmia, stable/unstable angina,
symptomatic congestive heart failure, coronary/peripheral artery bypass graft or
stenting or other significant cardiac disease within 6 months prior to study
enrollment

- history of arterial or venous thrombosis/thromboembolic event, including
pulmonary embolism within 6 months of study enrollment

- any condition requiring the use of immunosuppression, excluding rheumatologic
conditions treated with stable doses of corticosteroids

- Use of herbal supplements (St. John's Wort, gingko biloba, etc.) within one week
of cetuximab treatment