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

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

study id #: NCT02961374

condition: Attenuated Familial Adenomatous Polyposis, Familial Adenomatous Polyposis

status: Not yet recruiting

purpose:

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.

intervention: Drug: Erlotinib Hydrochloride
Other: Laboratory Biomarker Analysis

start date: July 31, 2017

estimated completion: June 1, 2019

last updated: April 20, 2017

phase of development: Phase 2

size / enrollment: 70

study design:
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention

study description: 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. V. Gene expression profiles in duodenal adenomas and uninvolved tissue will be compared between baseline and endpoint samples using negative binomial statistics (DESeq2). VI. Identify differentially expressed genes between duodenal polyps and uninvolved tissue at endpoint compared to baseline. VII. Evaluate the effect of weekly erlotinib on EGFR and Wnt target gene expression in duodenal adenomas. VIII. 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.

primary outcomes:

  • Incidence of grade 2/3 adverse event (AE) rate assessed according to National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 2.5 years ] [ Designated as safety issue: Yes ] Mean percent change in duodenal polyp burden assessed by EGD [ Time Frame: Baseline to 6 months post-intervention ] [ Designated as safety issue: No ] For all measurements of response, the 95% confidence intervals will be provided.

secondary outcomes:

  • Absolute and percent change in desmoid tumor size [ Time Frame: Baseline to 2.5 years ] [ Designated as safety issue: No ] 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 ex Absolute and percent change in duodenal polyp number [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ] 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 ex Absolute and percent changes in lower gastrointestinal polyp burden [ Time Frame: Baseline to 2.5 years ] [ Designated as safety issue: No ] 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 ex Absolute and percent changes in number for the subset of participants with IPAA or ileo-rectal anastomosis with rectal stump [ Time Frame: Baseline to 2.5 years ] [ Designated as safety issue: No ] 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 ex Change in differentially expressed genes of duodenal polyps and uninvolved tissue [ Time Frame: Baseline to 2.5 years ] [ Designated as safety issue: No ] 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 ex EGFR and Wnt gene expression [ Time Frame: Up to 2.5 years ] [ Designated as safety issue: No ] 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 ex Immune response signaling in duodenal adenomas and uninvolved tissue [ Time Frame: Up to 2.5 years ] [ Designated as safety issue: No ] 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 ex Incidence of all adverse events assessed according to NCI CTCAE version 4.0 [ Time Frame: Up to 2.5 years ] [ Designated as safety issue: Yes ] 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 and severity of adverse events will be tabulated and summarized across all grades. Grade 2+ adverse events will be similarly described and summarized separately. Overall toxicity incidence, as well as toxicity profiles will be explored and summarized.

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 Spigelman 2-3 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 Ability to understand and the willingness to sign a written informed consent document Willingness 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 Willingness to discontinue smoking for the duration of study intervention
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 within institutional limits of normal Urinary protein and urinary casts within institutional limits of normal Not pregnant or breast feeding; 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 Willingness to use adequate contraception to avoid pregnancy or impregnation until 2 weeks after discontinuing study agent Willingness to provide mandatory biospecimens as specified in the protocol

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, such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice Use of CYP3A4 inducers such as rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's wort Use of any other investigational agents =< 12 weeks prior to pre-registration 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 Use of anticoagulation medications, including but not limited to coumadin, warfarin, plavix
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 discontinue for the duration of clinical trial participation may be enrolled; an alternate drug to control gastroesophageal reflux disease (GERD)/peptic ulcer disease (PUD) symptoms will be suggested 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

sponsor: National Cancer Institute (NCI)

contacts: Elena M. Stoffel 617-724-5200 estoffel@partners.org
Paul J. Limburg 507-538-7623 Limburg.paul@mayo.edu
Carol Burke 216-444-7000 burkec1@ccf.org
Robert E. Schoen 412-647-2811
Eduardo Vilar-Sanchez 713-792-3245 evilar@mdanderson.org
Jewel Samadder jewel.samadder@hsc.utah.edu
Marcia R. Cruz-Correa 787-765-2363 marcia.cruz1@upr.edu

investigators: Elena M. Stoffel, Paul J. Limburg, Carol Burke, Robert E. Schoen, Eduardo Vilar-Sanchez, Jewel Samadder, Marcia R. Cruz-Correa

locations: United States, Puerto Rico