Phase II Study of Cetuximab With or Without OSI-906 in Head and Neck Squamous Cell Carcinoma (HNSCC)

Cetuximab is designed to prevent or slow down the growth of cancer cells by blocking
proteins on the cancer cell, called the epidermal growth factor receptor (EGFR).

OSI-906 is designed to prevent or slow the growth of cancer cells.

A placebo is not a drug. It looks like the study drug but is not designed to treat any
disease or illness. It is designed to be compared with a study drug to learn if the study
drug has any real effect.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned
(as in the flip of a coin) to 1 of 2 groups.

- If you are in Group 1, you will receive cetuximab and OSI-906.

- If you are in Group 2, you will receive cetuximab and a placebo.

Neither you nor the study doctor will know if you are receiving OSI-906 or the placebo.
However, if needed for your safety, the study doctor will be able to find out which group
you are in.

If the disease gets worse, the study doctor will find out which group you were in and you
will be offered the chance to take OSI-906 alone if you were not already receiving it.

Study Drug Administration:

Each cycle is 21 days.

On Days 1, 8, and 15 of each cycle, you will receive cetuximab by vein. The first dose of
cetuximab will be given over about 120 minutes. If it is well tolerated, each additional
infusion will be given over about 60 minutes.

You will take OSI-906 or placebo by mouth 2 times every day about 12 hours apart (in the
morning and evening).

You should take OSI-906 or placebo with food and a glass (up to 6 ½ ounces) of water. If you
forget to take a dose, you can take it any time up to 6 hours before the next dose. You
must not take the missed dose with the next dose on that same day or with a dose the next
day. If you vomit after taking the tablet(s), the dose should be replaced only if the
tablet(s) can actually be seen and counted. You should store the study drug/placebo at room
temperature below 77°F.

In order to help decrease the risk of infusion reaction, you will receive Benadryl
(diphenhydramine) by vein before the first dose of cetuximab. If the doctor thinks it is
needed, you will receive diphenhydramine before every dose of cetuximab.

On Day 1 of each cycle, you will need to return all unused OSI-906 or placebo and the empty
bottles.

Study Visits:

At every visit, you will be asked if you have had any side effects and to list any drugs you
may be taking.

On Day 1 of each cycle (+/- 7 days):

- You will have a physical exam, including measurement of your weight.

- Blood (about 3 teaspoons) will be drawn for routine tests. You should not eat or drink
anything (fast) for 8 hours before this blood draw.

- If the doctor thinks it is needed and you are able to become pregnant, you will have a
blood (less than 1 teaspoon) or urine pregnancy test.

On Days 1, 8, and 15 of each cycle, your vital signs will be measured before and after you
receive cetuximab.

Every 6 weeks (+/- 14 days):

- You will have an ECG.

- You will have a CT scan and/or MRI scan to check the status of the disease.

Length of Study:

You may continue to receive treatment as long as you are benefitting. You will be taken off
study early if you experience any intolerable side effects, the disease get worse, the
doctor thinks it is your best interest, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-treatment
and follow-up visits.

End-of-Treatment Visit:

Within 30 days after the last dose of study drugs/placebo, you will have an end-of-treatment
visit:

- You will have a physical exam, including measurement of your vital signs and weight

- You will be asked if you have had any side effects and to list any drugs you may be
taking.

- Blood (about 3-4 teaspoons) will be drawn for routine tests.

- If the doctor thinks it is needed, you will have a CT scan or MRI scan to check the
status of the disease.

Long Term Follow-Up:

About every 6 months from then on, you (or your family members or designees) will be asked
about how you are doing and what treatments you may be receiving. This may be by phone,
letter, email, or during clinic visits.

This is an investigational study. OSI-906 is not FDA approved or commercially available. At
this time, OSI-906 is only being used in research. Cetuximab is FDA approved and
commercially available for the treatment of colorectal and head/ neck cancer. The
combination of OSI-906 and cetuximab is investigational.

Up to 66 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed recurrent or metastatic
head and neck squamous cell carcinoma of the oral cavity, oropharynx, larynx or
hypopharynx.

2. Patients must be willing to have a biopsy of tumor tissue for biomarker analysis.

3. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
>/= 20 mm with conventional techniques or as >/= 10 mm with spiral computed
tomography (CT) scan or magnetic resonance imaging (MRI). Measurable lymph nodes are
required to be >/= 15 mm in size (short axis diameter). Measurable disease in
previously radiated areas is acceptable as long as there has been documented
progression.

4. Patients must have disease progression: 1) After platinum-based chemotherapy for
recurrent/metastatic disease OR 2) Within 6 months of receiving definitive
platinum-based combined modality therapy.

5. Previous treatment with cetuximab is allowed, as long as there has been a period >/=
6 months between the last cetuximab treatment and randomization

6. All prior cytotoxic therapy must have been completed at least three weeks prior to
treatment on study.

7. Age >/= 18 years

8. ECOG performance status /= 60%

9. Patients must have normal liver function as defined below: total bilirubin institutional upper limit of normal and aspartate aminotransferase (AST or
SGOT)/alanine aminotransferase (ALT or SGPT) normal.

10. Patients - both males and females - with reproductive potential (ie, menopausal for
less than 1 year and not surgically sterilized) must practice effective contraceptive
measures throughout the study. Women of childbearing potential must provide a
negative pregnancy test (serum or urine) within 14 days prior to registration.

11. Patients must provide verbal and written informed consent to participate in this
study

12. Prior radiation treatment is acceptable as long as it has been completed one week
prior to treatment on protocol.

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents with anti-cancer
activity.

2. Patients with known, untreated brain metastases. Patients with treated (irradiated or
resected) brain metastases are eligible if treatment was completed >/= 28 days prior
to study entry and if clinical neurologic function is stable.

3. History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition to OSI-906 or other agents used in the study.

4. QTc interval > 450 msec at baseline.

5. Concomitant drugs with a generally accepted risk of causing Torsades de Pointes

6. Congestive heart failure, New York Heart Association (NYHA) Class III or IV

7. History of arrhythmia which is symptomatic and requires treatment, or asymptomatic
sustained ventricular tachycardia. Patients with atrial fibrillation controlled on
medication are not excluded.

8. Fasting blood sugar > 150 mg/dl at baseline

9. Serious underlying medical condition which would impair the ability of the patient to
receive protocol treatment, in the opinion of the treating physician.

10. Pregnant or breast-feeding females.