start date: November 19, 2018
estimated completion: March 28, 2022
last updated: December 4, 2020
phase of development:
Phase 1
size / enrollment: 72
study 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).
primary outcomes:
- Percentage Change from Baseline in Rectal/pouch Polyp Burden at Week 24 [ Time Frame: Baseline, Week 24 ]
Percentage change from baseline in rectal/pouch polyp burden (sum of the polyp diameters) at Week 24 will be determined through endoscopy.
secondary outcomes:
- Percentage Change from Baseline in Number of Colorectal Polyps [ Time Frame: Baseline, Weeks 24 and 52 ]
Percentage change from baseline in number of colorectal polyps will be determined.
- Percentage Change from Baseline in Number of J-pouch Polyps [ Time Frame: Baseline, Weeks 24 and 52 ]
Percentage change from baseline in number of J-pouch polyps will be determined.
- Percentage Change from Baseline in J-pouch Polyp Burden [ Time Frame: Baseline, Weeks 24 and 52 ]
Percentage change from baseline in J-pouch polyp burden (sum of polyp diameters) will be determined.
- Percentage Change from Baseline in Number of Duodenal Polyps [ Time Frame: Baseline, Weeks 24 and 52 ]
Percentage change from baseline in number of duodenal polyps will be determined.
- Percentage Change from Baseline in Duodenal Polyp Burden [ Time Frame: Baseline, Weeks 24 and 52 ]
Percentage change from baseline in duodenal polyp burden (sum of polyp diameters) will be determined.
- Change in International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Stage [ Time Frame: Baseline, Weeks 24 and 52 ]
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).
- Change in Spigelman Stage Score [ Time Frame: Baseline, Weeks 24 and 52 ]
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.
- Trough Concentration of Guselkumab [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, and 24 ]
Serum samples will be analyzed to determine trough concentrations of guselkumab using a validated specific, and sensitive method.
- Number of Participants with Anti-guselkumab Antibodies [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, and 24 ]
Number of participants with Anti-guselkumab antibodies will be determined.
- Anti-guselkumab Antibodies Serum Titers [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, and 24 ]
Serum samples will be screened for antibodies binding to guselkumab and the titer of confirmed positive samples will be reported.
- Number of Participants with Adverse Events as a Measure of Safety [ Time Frame: From Screening up to 52 Weeks ]
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.
- Number of Participants with Vital Sign Abnormalities as a Measure of Safety and Tolerability [ Time Frame: From Screening up to 24 Weeks ]
Number of participants with vital sign abnormalities will be reported. Vital signs includes temperature, pulse/heart rate, respiratory rate and blood pressure.
- Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability [ Time Frame: From Screening up to 24 Weeks ]
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.
- Relative Changes to Baseline in Levels of Interleukin (IL)-23 Effector Proteins in Biopsy Tissue [ Time Frame: Baseline, Weeks 12 and 24 ]
Relative Changes to Baseline in levels of IL-23 effector proteins in biopsy tissue will be measured.
inclusion criteria:
• Eligible Ages: 18 - 120
• Eligible Sexes: all
• 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 81 milligram (mg) of aspirin a day or 650 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
• Duodenum or colon/rectum/pouch with high grade dysplasia or cancer on biopsy at screening
• 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.
