start date: October 27, 2017
estimated completion: March 28, 2021
last updated: September 13, 2019
phase of development:
Phase 2
size / enrollment: 70
study design: 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:
Mean percent change in duodenal polyp burden assessed by esophagogastroduodenoscopy [ Time Frame: Baseline to 6 months post-intervention ]
For all measurements of response, the 95% confidence intervals will be provided.
- 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 ]
secondary outcomes:
Incidence of all adverse events assessed according to NCI CTCAE version 4.0 [ Time Frame: Up to 2.5 years ]
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. Frequency distributions, graphical techniques, and other descriptive measures will form the basis of these analyses. In addition, all adverse event data that are graded as 3, 4, or 5 and classified as either "unrelated or unlikely to be related" to the study intervention in the event of an actual relationship developing will be reviewed.
- Absolute and percent change in duodenal polyp number [ Time Frame: Baseline to 6 months ]
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.
- Absolute and percent changes in lower gastrointestinal polyp burden [ Time Frame: Baseline to 2.5 years ]
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.
- Absolute and percent changes in number for the subset of participants with ileal pouch anal anastomosis or ileo-rectal anastomosis with rectal stump [ Time Frame: Baseline to 2.5 years ]
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.
- Absolute and percent change in desmoid tumor size [ Time Frame: Baseline to 2.5 years ]
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.
- Change in differentially expressed genes of duodenal polyps and uninvolved tissue [ Time Frame: Baseline to 2.5 years ]
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.
- EGFR and Wnt gene expression [ Time Frame: Up to 2.5 years ]
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.
- Immune response signaling in duodenal adenomas and uninvolved tissue [ Time Frame: Up to 2.5 years ]
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.
inclusion criteria:
• Eligible Ages: 18 - 69
• Eligible Sexes: all
• 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
• Use of anticoagulation medications, including but not limited to coumadin, warfarin, plavix
• 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
