A Study of Guselkumab in Participants With Familial Adenomatous Polyposis

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

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.

Study Overview

• Status: Completed
• Conditions: Adenomatous Polyposis Coli
• Intervention / Treatment: Drug: Guselkumab; Drug: Placebo

Detailed 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).

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69437
    • Hopital Edouard Herriot - CHU Lyon
  • Marseille, France, 13385
    • APHM Hopital Timone
• Germany
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Ulm, Germany, 89070
    • Universitätsklinikum Ulm
• Israel
  • Tel Aviv, Israel, 64239
    • Sourasky MC
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum Universiteit van Amsterdam
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• Poland
  • Poznan, Poland, 60 355
    • Szpital Kliniczny im Heliodora Swiecickiego Uniwersytetu Medycznego im Karola Marcinkowskiego w Po
  • Warszawa, Poland, 02-781
    • Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy
• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • Pan American Center for Oncology Trials LLC
• Spain
  • Barcelona, Spain, 8036
    • Hosp Clinic de Barcelona
  • Barcelona, Spain, 8035
    • Hosp Univ Vall D Hebron
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center Columbia University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Wexner Medical Center at the Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania - Perelman School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Guselkumab Dose 1; Participants will receive guselkumab Dose 1 subcutaneous (SC), 6 doses every 4 weeks from Week 0 to Week 20. Participants who respond to guselkumab may continue treatment at the same dose level through Week 48.	Drug: Guselkumab; Guselkumab SC will be administered every 4 weeks.; Other Names: Tremfya
Experimental: Guselkumab Dose 2; Participants will receive guselkumab Dose 2 SC, 6 doses every 4 weeks from Week 0 to Week 20. Participants who respond to guselkumab may continue treatment at the same dose level through Week 48.	Drug: Guselkumab; Guselkumab SC will be administered every 4 weeks.; Other Names: Tremfya
Placebo Comparator: Placebo; Participants will receive placebo SC, 6 doses every 4 weeks from Week 0 to Week 20.	Drug: Placebo; Placebo SC will be administered every 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2018
• Primary Completion (Actual): September 13, 2021
• Study Completion (Actual): March 23, 2022

Study Registration Dates

• First Submitted: August 27, 2018
• First Submitted That Met QC Criteria: August 27, 2018
• First Posted (Actual): August 28, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Colonic Diseases; Adenoma; Otorhinolaryngologic Diseases; Neoplastic Syndromes, Hereditary; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Adenomatous Polyps; Intestinal Polyposis; Colorectal Neoplasms; Nasopharyngeal Neoplasms; Adenomatous Polyposis Coli
• Other Study ID Numbers: CR108515; CNTO1959COR1001 (Other Identifier: Janssen Research & Development, LLC); 2019-001980-57 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No