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Erlotinib Hydrochloride

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Sulindac

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Erlotinib 75 mg per day in combination with sulindac 150 mg twice daily for 6 months.

Placebo capsules matching erlotinib active comparator (Placebo A) once daily and placebo capsules matching sulindac active comparator (Placebo B) twice daily for 6 months

Tarceva oral tablets are conventional, immediate-release tablets containing erlotinib as the hydrochloride salt. Erlotinib(75mg)will be taken once daily for six months in combination with sulindac.

Erlotinib

Sulindac is a non-steroidal, anti-inflammatory indene derivative designed for the treatment of arthritic conditions. For this study, sulindac (150mg) will be taken twice daily in combination with erlotinib

Erlotinib (Tarceva) will provide a 25 mg identical placebo. This will be provided by the Division of Cancer Prevention at the NIH who will receive the drug and placebo from the manufacturer, OSI/Genentech. Dosage for Placebo A will be 75 mg a day for 6 months.

Placebo A

Sulindac will be encapsulated in 150 mg doses along with an identical encapsulated Placebo B. One 150 mg capsules of Placebo B will be taken twice per day with meals (breakfast and supper).

Placebo B

Randall Burt, MD

Niloy J Samadder, MD

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 (AFAP) 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 polyp burden at 6 mohths in FAP and attenuated FAP patients.

Secondary Aim: To measure if combination of sulindac and erlotinib cause a reduction in total duodenal polyp count, and change in duodenal polyp burden or count stratified by genotype and initial polyp burden.

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

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

A comparison between the Sulindac-erlotinib and Placebo arms of the change in polyp burden from a 10-centimeter segment of the duodenum, measured as the sum of the diameters of the polyps, in millimeters (mm), from the duodenal segment (6-month polyp burden minus baseline polyp burden).

A comparison between the Sulindac-erlotinib and Placebo arm Classic FAP subgroups of the change in polyp burden from a 10-centimeter segment of the duodenum, measured as the sum of the diameters of the polyps, in millimeters (mm), from the duodenal segment (6-month polyp burden minus baseline polyp burden).

A comparison between the Sulindac-erlotinib and Placebo arm Attenuated FAP subgroups of the change in polyp burden from a 10-centimeter segment of the duodenum, measured as the sum of the diameters of the polyps, in millimeters (mm), from the duodenal segment (6-month polyp burden minus baseline polyp burden).

A comparison between the Sulindac-erlotinib and Placebo arms of the change in number of polyps in a 10-centimeter segment of the duodenum (6-month polyp count minus baseline polyp count).

A comparison between the Sulindac-erlotinib and Placebo arm Classic FAP subgroups of the change in number of polyps in a 10-centimeter segment of the duodenum (6-month polyp count minus baseline polyp count)

A comparison between the Sulindac-erlotinib and Placebo arm Attenuated FAP subgroups of the change in number of polyps in a 10-centimeter segment of the duodenum (6-month polyp count minus baseline polyp count)

National Cancer Institute (NCI)

University of Utah

Principal Investigator

Sulindac 150 mg twice daily in combination with erlotinib 75 mg per day for 6 months

Sulindac-erlotinib

Placebo

Total

Age, Continuous

Sex: Female, Male

Classic FAP

Attenuated FAP

Familial Adenomatous Polyposis (FAP) Status

N. Jewel Samadder

Change in Duodenal Polyp Burden From Baseline to 6 Months

Classic FAP participants are defined as those presenting with more than 100 colonic adenomas and either (1) multiple family members with a classic FAP phenotype or (2) an adenomatous polyposis coli (APC) mutation in a region of the gene known to correlate with Classic FAP, or (3) both.

Change in Duodenal Polyp Burden From Baseline to 6 Months in Classic Familial Adenomatous Polyposis (FAP) Participants

Attenuated FAP participants are defined with the presence of a mutation in a portion of the adenomatous polyposis coli (APC) gene known to correlate with attenuated FAP and presentation of a milder phenotype in terms of polyp density in the participant and the family. All participants with attenuated FAP had a confirmed mutation in the APC gene.

Change in Duodenal Polyp Burden From Baseline to 6 Months in Attenuated FAP Participants

Change in Number of Duodenal Polyps From Baseline to 6 Months

Classic FAP participants are defined as those presenting with more than 100 colonic adenomas and either (1) multiple family members with a classic FAP phenotype or (2) an adenomatous polyposis coli (APC) mutation in a region of the gene known to correlate with Classic FAP, or (3) both

Change in Number of Duodenal Polyps From Baseline to 6 Months in Classic FAP Participants

Change in Number of Duodenal Polyps From Baseline to 6 Months in Attenuated FAP Participants

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients	NCT01187901	Adenomatous Pol...	Erlotinib Sulindac Placebo A Placebo B	18 Years - 69 Years	University of Utah
A Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients	NCT01187901	Adenomatous Pol...	Erlotinib Sulindac Placebo A Placebo B	18 Years - 69 Years	University of Utah
A Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients	NCT01187901	Adenomatous Pol...	Erlotinib Sulindac Placebo A Placebo B	18 Years - 69 Years	University of Utah

Spots Global Cancer Trial Database for attenuated familial polyposis