A Study of Guselkumab in Participants With Familial Adenomatous Polyposis

Adenomatous Polyposis Coli Clinical Trial

Official title:

A Phase 1b, Multicenter, Randomized, Blinded, Placebo-controlled Study to Evaluate the Efficacy of Guselkumab in Subjects With Familial Adenomatous Polyposis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03649971
• Other study ID #: CR108515
• Secondary ID: CNTO1959COR10012
• Status: Completed
• Phase: Phase 1
• Start date: November 19, 2018
• Est. completion date: March 23, 2022

Study information

• Verified date: June 2023
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the effect of treatment with guselkumab in participants with familial adenomatous polyposis (FAP) on rectal/pouch polyp burden.

Description:

Familial adenomatous polyposis (FAP) is the most common polyposis syndrome. It is autosomal dominant inherited disorder characterized by early onset of hundreds to thousands of adenomatous polyps throughout colon. If left untreated, this syndrome may develop colorectal cancer (CRC). Polyps from individuals with FAP display inflammatory features associated with activation of interleukin (IL) 23/IL 17/JAK/STAT3 pathway. This inflammation is thought to contribute to further mutagenesis, culminating in tumor development. Specifically, IL-23 is linked to tumor growth and progression in CRC. Guselkumab is a human immunoglobulin monoclonal antibody directed against p19 subunit of IL-23, specifically targets IL-23 and inhibits its interaction with IL-23 receptor, inhibiting IL 23 specific intracellular signaling and subsequent cell activation and cytokine production, which result in less inflammation and reduce tumor development. The clinical hypothesis of this study is that treatment with guselkumab will reduce rectal/pouch polyp burden compared with baseline in active arms compared with placebo. The study is designed to determine if guselkumab has clinical activity in colorectum and duodenum, by reducing number of polyps over a period of 24 weeks. Participants will be randomized to 1 of 3 treatment arms (Guselkumab 100 mg [milligram] SC [subcutaneous], Guselkumab 300 mg SC, and placebo SC). Efficacy evaluations include rectal/pouch polyp burden assessment, biomarker analysis include discrete IL-23 signaling effector proteins (IL-23R, pSTAT3, Il-17A) and safety evaluations will include monitoring of adverse events, laboratory tests, vital sign measurements, and physical examination. Safety will be monitored throughout study (up to Week 60).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 77
• Est. completion date: March 23, 2022
• Est. primary completion date: September 13, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Phenotypic familial adenomatous polyposis (FAP) with disease involvement of the colorectum by either genetic or clinical diagnosis: Adenomatous polyposis coli (APC) germline mutation with or without family history, or with greater than (>)100 adenomas in large intestine and a family history of FAP, attenuated FAP is allowed. FAP phenotype post colectomy for polyposis with a family history of FAP may be allowed
• Post-colectomy or subtotal colectomy
• Polyps with a sum of diameters greater than or equal to (>=)10 millimeter (mm) in the rectum or pouch on biopsy at screening
• A woman of childbearing potential must agree not to get pregnant during the study and at least 12 weeks after the last dose of study administration
• A woman must agree not to breast feed or donate eggs (ova, oocytes) during the study and for a period of 12 weeks after the last administration of study drug

Exclusion Criteria:

• Prior use of any biologic therapy targeting interleukin (IL)-12/23, IL-17, or IL-23 receptor
• Use of non-steroidal anti-inflammatory drugs other than aspirin during the study. The use 100 milligram (mg) of aspirin a day or 700 mg of aspirin per week is allowed
• Treatment with other FAP-directed drug therapy (including NSAID [Nonsteroidal anti-inflammatory drug] drugs), unless completes a 4-week washout period prior to randomization
• High grade dysplasia or cancer on biopsy at screening in GI tract (including stomach, duodenum, and colon/rectum/pouch)
• Duodenal, colorectal, or pouch polyp: >2 centimeter (cm) unless excised at the screening evaluation; and 1 to 2 cm with evidence of high-grade dysplasia upon biopsy unless excised

Related Conditions & MeSH terms

• Adenomatous Polyposis Coli
• Colorectal Neoplasms
• Nasopharyngeal Neoplasms

Intervention

Drug:
• Guselkumab
Guselkumab SC will be administered every 4 weeks.
• Placebo
Placebo SC will be administered every 4 weeks.

Locations

Country	Name	City	State
France	Hopital Edouard Herriot - CHU Lyon	Lyon
France	APHM Hopital Timone	Marseille
Germany	Universitatsklinikum Bonn	Bonn
Germany	Universitätsklinikum Ulm	Ulm
Israel	Sourasky MC	Tel Aviv
Netherlands	Academisch Medisch Centrum Universiteit van Amsterdam	Amsterdam
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Erasmus MC	Rotterdam
Poland	Szpital Kliniczny im. Heliodora Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Po	Poznan
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa
Puerto Rico	Pan American Center for Oncology Trials LLC	Río Piedras
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Clinic I Provincial de Barcelona	Madrid
Sweden	Karolinska Universitetssjukhuset	Stockholm
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	Wexner Medical Center at the Ohio State University	Columbus	Ohio
United States	City of Hope	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of Miami	Miami	Florida
United States	Yale University	New Haven	Connecticut
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania - Perelman School of Medicine	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of Washington	Seattle	Washington
United States	University of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  France,  Germany,  Israel,  Netherlands,  Poland,  Puerto Rico,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Change from Baseline in Rectal/pouch Polyp Burden at Week 24	Percentage change from baseline in rectal/pouch polyp burden (sum of the polyp diameters) at Week 24 will be determined through endoscopy.	Baseline, Week 24
Secondary	Percentage Change from Baseline in Number of Colorectal Polyps	Percentage change from baseline in number of colorectal polyps will be determined.	Baseline, Weeks 24 and 52
Secondary	Percentage Change from Baseline in Number of J-pouch Polyps	Percentage change from baseline in number of J-pouch polyps will be determined.	Baseline, Weeks 24 and 52
Secondary	Percentage Change from Baseline in J-pouch Polyp Burden	Percentage change from baseline in J-pouch polyp burden (sum of polyp diameters) will be determined.	Baseline, Weeks 24 and 52
Secondary	Percentage Change from Baseline in Number of Duodenal Polyps	Percentage change from baseline in number of duodenal polyps will be determined.	Baseline, Weeks 24 and 52
Secondary	Percentage Change from Baseline in Duodenal Polyp Burden	Percentage change from baseline in duodenal polyp burden (sum of polyp diameters) will be determined.	Baseline, Weeks 24 and 52
Secondary	Change in International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Stage	Change in InSiGHT stage will be determined. Various stages of InSiGHT staging system are defined as: Stage 0: 0-10 polyps, all less than (<)5 millimeter (mm); Stage 1: 10-25 polyps, most < 5 mm, none greater than (>) 1 centimeter (cm); Stage 2: 10-25 polyps, any > 1 cm, amenable to complete removal; Stage 3: > 25 polyps amenable to complete removal, or any incompletely removed sessile polyp, or any evidence of High-Grade Dysplasia (HGD), even if completely excised; and Stage 4: > 25 polyps amenable to complete removal, or any incompletely excised sessile polyp showing HGD, any invasive cancer).	Baseline, Weeks 24 and 52
Secondary	Change in Spigelman Stage Score	Change in Spigelman stage score will be determined. Spigelman classification system measures risk of developing duodenal cancer in familial adenomatous polyposis (FAP). It has been classified in following stages- Stage 0 (0 points); Stage 1 (1-4 points); Stage 2 (5-6 points); Stage 3 (7-8 points); and Stage 4 (9-12 points). The total score ranges from 0 to 12. Points are accumulated for polyps' number, size, histology and severity of dysplasia. Stage 1 indicates mild disease, whereas stage 3-4 indicates severe duodenal polyposis.	Baseline, Weeks 24 and 52
Secondary	Trough Concentration of Guselkumab	Serum samples will be analyzed to determine trough concentrations of guselkumab using a validated specific, and sensitive method.	Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
Secondary	Number of Participants with Anti-guselkumab Antibodies	Number of participants with Anti-guselkumab antibodies will be determined.	Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
Secondary	Anti-guselkumab Antibodies Serum Titers	Serum samples will be screened for antibodies binding to guselkumab and the titer of confirmed positive samples will be reported.	Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
Secondary	Number of Participants with Adverse Events as a Measure of Safety	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.	From Screening up to 60 Weeks
Secondary	Number of Participants with Vital Sign Abnormalities as a Measure of Safety and Tolerability	Number of participants with vital sign abnormalities will be reported. Vital signs includes temperature, pulse/heart rate, respiratory rate and blood pressure.	From Screening up to 52 Weeks
Secondary	Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability	Number of participants with clinical laboratory abnormalities will be reported. Blood samples for serum chemistry and hematology will be collected at predefined time points for clinical laboratory testing.	From Screening up to 52 Weeks
Secondary	Relative Changes to Baseline in Levels of Interleukin (IL)-23 Effector Proteins in Biopsy Tissue	Relative Changes to Baseline in levels of IL-23 effector proteins in biopsy tissue will be measured.	Baseline, Weeks 12, 24, and 52