A Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients

This will be a single-center, phase-II, six-month-long, placebo-controlled, double blinded,
randomized trial of the epidermal growth factor receptor (EGFR) inhibitor, erlotinib
(Tarceva) and the cyclooxygenase (COX-2) inhibitor, sulindac in patients with familial
adenomatous polyposis (FAP) or attenuated FAP. FAP is an autosomal dominant inherited colon
cancer predisposition with a 100% risk of colon cancer in the absence of preventive care
(endoscopy and surgery). Efficacious chemoprevention for duodenal adenomas is an unmet
clinical need in FAP patients that would reduce the morbidity from duodenectomy and risk of
duodenal adenocarcinoma. Currently the only Food and Drug Administration (FDA)-approved
chemopreventive agent is celecoxib which results in a modest reduction of duodenal and
colorectal polyps and is associated with cardiac toxicity at effective doses. If it can be
shown that combinatorial inhibition of COX-2 and EGFR activity leads to successful
regression in duodenal adenomatous polyps in FAP, it could be used as an effective
chemopreventive regimen in FAP patients with duodenal adenomas or who have undergone
surgical resection of duodenal adenomas or have many rectal adenomas. FAP and AFAP patients
will be screened by endoscopy for presence of 5 or more duodenal polyps, then randomized to
either A) erlotinib at 75 mg/day and sulindac at 150 mg/day or B) placebo for 6 months. The
endpoint will be endoscopy at 6 months.

Primary Aim : To determine if the combination of sulindac and erlotinib causes a significant
regression of duodenal adenomas in FAP and attenuated FAP patients.

Secondary :

1. Measure if combination of sulindac and erlotinib cause a reduction in duodenal
polyposis based on Spigelman classification.

2. Determine if the combination of sulindac and erlotinib causes a significant regression
of colorectal adenomas.

3. Measure changes in COX-2 expression, EGFR phosphorylation, MEK1 phosphorylation, AKT
phosphorylation, Ki-67 expression and/or cyclin D1 expression in intestinal polyps and
normal intestinal mucosa with treatment.

4. Determine ß-catenin localization in adenomatous intestinal polyps with or without
oncogenic KRAS mutations.

Inclusion Criteria:

- Patients who are 18 years or older with a clinical or genetic diagnosis of FAP or
attenuated FAP.

- Presence of duodenal polyps with a sum of diameters ≥ 5mm.

- Minimum of two weeks since any major surgery

- WHO performance status ≤1

- Adequate bone marrow function as show by: normal leukocyte count, platelet count ≥
120 x 109/L, Hgb > 12 g/dL

- Adequate liver function as shown by: normal serum bilirubin(≤ 1.5 Upper Limit Normal
{ULN}) and serum transaminases (≤ 2.0 ULN)

- Patient must discontinue taking any Nonsteroidal anti-inflammatory drugs (NSAIDS)
within one month of treatment initiation.

- Patients must be able to provide written informed consent.

Exclusion Criteria:

- Prior treatment with any investigational drug within the preceding 4 weeks.

- Malignancies within the past 3 years except for adequately treated carcinoma of the
cervix or basal or squamous cell carcinomas of the skins.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study as determined by the
Principle Investigator such as:

1. Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤ 6 months prior to first study treatment, serious uncontrolled
cardiac arrhythmia

2. Severely impaired lung function

3. Any active (acute or chronic) or uncontrolled infection/ disorders.

4. Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

5. Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- Screening clinical laboratory values that indicate any of the following:

1. anemia

2. thrombocytopenia

3. leucopenia

4. elevations of transaminases greater than 2X ULN

5. elevation of bilirubin > 1.5 X ULN

6. alkaline phosphatase elevation > 1.5 X ULN

7. increased creatinine, urinary protein, or urinary casts outside the clinically
normal range.

- Gastrointestinal bleeding (symptoms including dyspnea, fatigue, angina, weakness,
malaise, melena, hematochezia, hematemesis, anemia or abdominal pain will require
clinical assessment to rule out gastrointestinal bleeding).

- Patient who is currently taking any anti-coagulation medication.

- Women who are pregnant or breast feeding.

- Patients with a known hypersensitivity to sulindac or erlotinib or to their
excipients