Erlotinib Hydrochloride in Reducing Duodenal Polyp Burden in Patients With Familial Adenomatous Polyposis at Risk of Developing Colon Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects of erlotinib hydrochloride and how well it works in reducing duodenal polyp burden in patients with familial adenomatous polyposis at risk of developing colon cancer. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the mean percent change in duodenal polyp burden (sum of diameters from all polyps) from baseline to 6 months post-intervention for familial adenomatous polyposis (FAP) subjects receiving weekly erlotinib hydrochloride (erlotinib). II. To assess the grade 2/3 adverse event rate in this population and compare it to historical data. SECONDARY OBJECTIVES: I. To evaluate all adverse events at least possibly attributed to weekly erlotinib. II. To assess the absolute and percent change in duodenal polyp number from baseline to 6 months. III. To assess the absolute and percent changes in lower gastrointestinal polyp burden and number for the subset of participants with ileal pouch anal anastomosis (IPAA) or ileo-rectal anastomosis with rectal stump. IV. To assess the absolute and percent change in desmoid tumor size in participants who have baseline and follow up computed tomography (CT)s performed as part of their standard of care. CORRELATIVE OBJECTIVES: I. Gene expression profiles in duodenal adenomas and uninvolved tissue will be compared between baseline and endpoint samples using negative binomial statistics (DESeq2). II. Identify differentially expressed genes between duodenal polyps and uninvolved tissue at endpoint compared to baseline. III. Evaluate the effect of weekly erlotinib on EGFR and Wnt target gene expression in duodenal adenomas. IV. Evaluate the effect of weekly erlotinib on immune response signaling in duodenal adenomas and uninvolved tissue. OUTLINE: Patients receive erlotinib hydrochloride orally (PO) once weekly. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

Official Title
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Phase II Trial of Weekly Erlotinib Dosing to Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis

Conditions
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Attenuated Familial Adenomatous Polyposis, Familial Adenomatous Polyposis

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Erlotinib Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION INCLUSION Diagnosis of familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP), defined as at least one of the following: Genetic diagnosis with confirmed APC mutation (Clinical Laboratory Improvement Act [CLIA] certified lab or research testing) Obligate carrier Clinical diagnosis of classic FAP with >= 100 colorectal adenomas status post colectomy and a family history of FAP Clinical diagnosis of FAP, based on personal and family history; Note: This criterion requires documented review and agreement from either the study chair or the Cancer Prevention Network (CPN) lead investigator Ability to understand and the willingness to sign a written informed consent document Willing to discontinue taking nonsteroidal anti-inflammatory drugs (NSAIDS) for 30 days prior to initiation of and during intervention; exception: use of =< 81 mg daily or =< 650 mg weekly aspirin is allowed Willing to discontinue smoking for the duration of study intervention Willing to provide mandatory biospecimens as specified in the protocol REGISTRATION INCLUSION Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Leukocytes (white blood cells [WBC]) >= 3,000/uL (>= 2,500/uL for African-American participants) Platelet count >= 100 x 10^9/L Hemoglobin >= 11.5 g/dL Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) Alkaline phosphatase =< 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =< 2 x institutional upper limit of normal (ULN) Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2 x institutional upper limit of normal (ULN) Creatinine =< institutional upper limits of normal (ULN) Urinary testing results within institutional limits of normal or deemed clinically insignificant Spigelman 2-3 Not pregnant or breast feeding; Note: the effects of erlotinib (Tarceva ) on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately; breastfeeding should be discontinued if the mother is treated with erlotinib Willing to use adequate contraception to avoid pregnancy or impregnation until 2 weeks after discontinuing study agent Exclusion Criteria: PRE-REGISTRATION EXCLUSION Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib Use of potent CYP3A4 inhibitors, including but not limited to ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice Use of potent CYP3A4 inducers, including but not limited to rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's wort Use of any other investigational agents =< 12 weeks prior to pre-registration Uncontrolled intercurrent illness or recent surgical procedure that in the opinion of the investigative team would limit compliance with study requirements, including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure Myocardial infarction =< 6 months prior to intervention Severely impaired lung function Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with study intervention Diagnosed liver disease, such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations History of invasive malignancy =< 3 years prior to pre-registration; exception: adequately treated carcinoma of the cervix, carcinoma in situ, or basal or squamous cell carcinomas of the skin Individuals on anticoagulation medications who cannot safely discontinue the medication for at least 48 hours prior to the study endoscopy, as determined by the study investigator and/or participant's primary healthcare provider History of any upper gastrointestinal (GI) surgery that does not permit access to or evaluation of a 10 cm segment of the duodenum that includes the duodenal bulb, i.e. Whipple procedure or similar REGISTRATION EXCLUSION Histologically-confirmed high grade dysplasia (HGD), cancer, or polyp burden that is not quantifiable Regular (>= 2 times per week) use of drugs that alter the pH of the gastrointestinal tract (GI) tract, such as proton pump inhibitors (PPI) and antacids; exceptions: individuals who use prescription PPIs and have approval from their primary health care provider to replace the PPI with an H2 receptor agonist, i.e. ranitidine, for the duration of the trial will be eligible Gastrointestinal bleeding; note that the presence of any symptoms (dyspnea, fatigue, angina, weakness, malaise, melena, hematochezia, hematemesis, anemia, abdominal pain) will require clinical assessment to rule out gastrointestinal bleeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erlotinib hydrochloride)<br>Patients receive erlotinib hydrochloride PO once weekly. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. | Drug: Erlotinib<br>* Given PO<br>Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change in Duodenal Polyp Burden | Assessed by esophagogastroduodenoscopy, the mean percent change was calculated by subtracting the sum of diameters from all polyps at baseline from the sum of diameters of all polyps at 6 months, then dividing by the sum of diameters from all polyps at baseline and multiplying by 100. | Baseline to 6 months post-intervention | 
| Number of Participants With Grade 2/3 Adverse Event (AE) | Assessed according to National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number of patients reporting a grade 2 or higher event are reported. | Up to 7 months from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Events | Assessed according to NCI CTCAE version 4.0. All registered and treated participants will be evaluable for AEs from the time of their first dose of weekly erlotinib treatment. To evaluate the AE profile for this treatment, the maximum grade for each type of adverse event will be recorded for each participant and frequency tables will be reviewed to determine the overall patterns. The number of patients reporting a grade 1 or higher adverse event at least possibly related to treatment are reported. | Up to 7 months from registration | 
| Change in Duodenal Polyp Number | The number of duodenal polyps at baseline and the number of polyps remaining after 6 months of treatment will collected. The change in duodenal polyp number will be calculated for each patient by subtracting the baseline number of polyps from the 6 month number. Therefore a negative value indicates a decrease in the number of polyps present after 6 months. The median difference and standard deviation is reported. | Baseline to 6 months | 
| Absolute Change in Lower Gastrointestinal Polyp Burden | Lower GI polyp burden was defined using the Pouch Exam form as either 1) the average diameter reported for pouch for participants with ileal pouch-anal anastomosis (IPAA), or 2) the average diameter reported for rectum for participants with ileorectal anastomosis (IRA) + rectal stump. Absolute change from baseline to month 6 are reported here. | Baseline to 6 months | 
| Percent Change in Lower Gastrointestinal Polyp Burden | Lower GI polyp burden was defined using the Pouch Exam form as either 1) the average diameter reported for pouch for participants with ileal pouch-anal anastomosis (IPAA), or 2) the average diameter reported for rectum for participants with ileorectal anastomosis (IRA) + rectal stump. The percent change from baseline to month 6 are reported here. | Baseline to 6 months | 
| Absolute Change in Lower Gastrointestinal Polyp Number | Lower GI polyp number was defined using the Pouch Exam form as either 1) the number of polyps reported for pouch for participants with ileal pouch-anal anastomosis (IPAA), or 2) the number of polyps reported for rectum for participants with ileorectal anastomosis (IRA) + rectal stump. Absolute change from baseline to month 6 are reported here. | Baseline to 6 months | 
| Percent Change in Lower Gastrointestinal Polyp Number | Lower GI polyp number was defined using the Pouch Exam form as either 1) the number of polyps reported for pouch for participants with IPAA, or 2) the number of polyps reported for rectum for participants with IRA + rectal stump. | Baseline to 6 months | 
| Absolute and Percent Change in Desmoid Tumor Size | Laboratory measures will be correlated with participant outcomes (i.e., polyp burden, adverse events) and with each other as well. Cut-points will be determined based on previously defined and accepted standards. Descriptive statistics and simple scatter plots will be generated to review the tissue-based biomarker data. For continuous variables, the actual and % change in the level of each of the biomarkers from pre- to post-intervention will be explored using Wilcoxon signed rank tests, and paired sample t-tests. All categorical variables will be analyzed using chi-square tests or Fisher's exact test. For all translational endpoints, any notable statistical result will be viewed as an impetus for further study rather than as a definitive finding in and of itself. | Baseline to 6 months |