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

Information source: University of Utah
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Adenomatous Polyposis Coli

Intervention: Erlotinib (Drug); Sulindac (Drug); Placebo A (Drug); Placebo B (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Utah

Official(s) and/or principal investigator(s):
Randall Burt, MD, Principal Investigator, Affiliation: University of Utah at Huntsman Cancer Institute

Overall contact:
Therese Berry, Phone: 801-581-3917, Email: therese.berry@hci.utah.edu

Summary

The purpose of this study is to determine in a randomized, placebo-controlled, phase II trial if the combination of sulindac and erlotinib causes a significant regression of duodenal and colorectal adenomas in familial adenomatous polyposis (FAP) and attenuated FAP patients.

Clinical Details

Official title: Genetic Events Leading to APC-Dependent Colon Cancer in High-Risk Families; a Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Primary outcome: Compare the change in total duodenal and colorectal polyp burden at 6 months

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: 69 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Therese Berry, Phone: 801-581-3917, Email: therese.berry@hci.utah.edu

Huntsman Cancer Institute, Salt Lake City, Utah 84112, United States; Recruiting
Therese Berry, BS, Phone: 801-581-3917, Email: therese.berry@hci.utah.edu
Michelle Done, BS, Phone: 801-581-4066, Email: michelle.done@hci.utah.edu
Randall Burt, MD, Principal Investigator
Additional Information

Starting date: April 2010
Last updated: June 14, 2012

Page last updated: February 07, 2013

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