A Study of Guselkumab in Participants With Familial Adenomatous Polyposis

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Adenomatous Polyposis Coli

Intervention / Treatment
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* Drug: Guselkumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Guselkumab Dose 1<br>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<br>* Guselkumab SC will be administered every 4 weeks.<br>* Other names: Tremfya;|
| Experimental: Guselkumab Dose 2<br>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<br>* Guselkumab SC will be administered every 4 weeks.<br>* Other names: Tremfya;|
| Placebo Comparator: Placebo<br>Participants will receive placebo SC, 6 doses every 4 weeks from Week 0 to Week 20. | Drug: Placebo<br>* Placebo SC will be administered every 4 weeks.<br>|

What is the study measuring?
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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 |