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

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ClinicalTrials.gov Identifier: NCT02961374
Recruitment Status : Recruiting
First Posted : November 11, 2016
Last Update Posted : July 17, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
APC Gene Mutation Attenuated Familial Adenomatous Polyposis Familial Adenomatous Polyposis Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Phase 2

Detailed 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Phase II Trial of Weekly Erlotinib Dosing to Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis
Actual Study Start Date : October 27, 2017
Estimated Primary Completion Date : September 1, 2019
Estimated Study Completion Date : September 1, 2019


Arm Intervention/treatment
Experimental: Treatment (erlotinib hydrochloride)
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 Hydrochloride
Given PO
Other Names:
  • Cp-358,774
  • OSI-774
  • Tarceva

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. 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.

  2. 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 Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02961374


Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Jewel Samadder    480-301-8000    Samadder.jewel@mayo.edu   
Principal Investigator: Jewel Samadder         
United States, Michigan
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Elena M. Stoffel    734-647-1417    estoffel@med.umich.edu   
Principal Investigator: Elena M. Stoffel         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Paul J. Limburg    507-284-2511    Limburg.paul@mayo.edu   
Principal Investigator: Paul J. Limburg         
United States, Ohio
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Carol Burke    216-444-6864    burkec@ccf.org   
Principal Investigator: Carol Burke         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Rohit Das    412-864-7091    dasr@upmc.edu   
Principal Investigator: Rohit Das         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Eduardo Vilar-Sanchez    713-745-1836    evilar@mdanderson.org   
Principal Investigator: Eduardo Vilar-Sanchez         
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Priyanka Kanth    801-581-7803    Priyanka.kanth@hsc.utah.edu   
Principal Investigator: Priyanka Kanth         
Puerto Rico
University of Puerto Rico Recruiting
San Juan, Puerto Rico, 00936
Contact: Marcia R. Cruz-Correa    787-772-8300    marcia.cruz1@upr.edu   
Principal Investigator: Marcia R. Cruz-Correa         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Niloy Samadder Mayo Clinic

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02961374     History of Changes
Other Study ID Numbers: NCI-2016-01674
NCI-2016-01674 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00042
MAY2016-07-01 ( Other Identifier: Mayo Clinic )
MAY2016-07-01 ( Other Identifier: DCP )
N01CN00042 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: November 11, 2016    Key Record Dates
Last Update Posted: July 17, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Colorectal Neoplasms
Nasopharyngeal Neoplasms
Adenomatous Polyposis Coli
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Adenomatous Polyps
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Intestinal Polyposis
Genetic Diseases, Inborn
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors