Clinical trial NCT03649971: A Study of Guselkumab in Participants With Familial Adenomatous Polyposis
Official title: A Phase 1b, Multicenter, Randomized, Blinded, Placebo-controlled Study to Evaluate the Efficacy of Guselkumab in Subjects With Familial Adenomatous Polyposis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adenomatous Polyposis Coli
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2018-08-28
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Percentage Change from Baseline in Rectal/pouch Polyp Burden at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Percentage Change from Baseline in Number of Colorectal Polyps
timeFrame: Baseline, Weeks 24 and 52
measure: Percentage Change from Baseline in Number of J-pouch Polyps
timeFrame: Baseline, Weeks 24 and 52
measure: Percentage Change from Baseline in J-pouch Polyp Burden
timeFrame: Baseline, Weeks 24 and 52
measure: Percentage Change from Baseline in Number of Duodenal Polyps
timeFrame: Baseline, Weeks 24 and 52
measure: Percentage Change from Baseline in Duodenal Polyp Burden
timeFrame: Baseline, Weeks 24 and 52
measure: Change in International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Stage
timeFrame: Baseline, Weeks 24 and 52
measure: Change in Spigelman Stage Score
timeFrame: Baseline, Weeks 24 and 52
measure: Trough Concentration of Guselkumab
timeFrame: Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
measure: Number of Participants with Anti-guselkumab Antibodies
timeFrame: Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
measure: Anti-guselkumab Antibodies Serum Titers
timeFrame: Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48
measure: Number of Participants with Adverse Events as a Measure of Safety
timeFrame: From Screening up to 60 Weeks
measure: Number of Participants with Vital Sign Abnormalities as a Measure of Safety and Tolerability
timeFrame: From Screening up to 52 Weeks
measure: Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability
timeFrame: From Screening up to 52 Weeks
measure: Relative Changes to Baseline in Levels of Interleukin (IL)-23 Effector Proteins in Biopsy Tissue
timeFrame: Baseline, Weeks 12, 24, and 52
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School Of Medicine
state: Missouri
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Wexner Medical Center at the Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania - Perelman School of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Lyon
country: France
facility: Hopital Edouard Herriot - CHU Lyon
city: Marseille
country: France
facility: APHM Hopital Timone
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Tel Aviv
country: Israel
facility: Sourasky MC
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum Universiteit van Amsterdam
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Poznan
country: Poland
facility: Szpital Kliniczny im Heliodora Swiecickiego Uniwersytetu Medycznego im Karola Marcinkowskiego w Po
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy
city: Rio Piedras
country: Puerto Rico
facility: Pan American Center for Oncology Trials LLC
city: Barcelona
country: Spain
facility: Hosp Univ Vall D Hebron
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: