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A Study of Guselkumab in Participants With Familial Adenomatous Polyposis

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT03649971
Collaborator
(none)
77
Enrollment
32
Locations
3
Arms
40.1
Actual Duration (Months)
2.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

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 Design

Study Type:
Interventional
Actual Enrollment :
77 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 1b, Multicenter, Randomized, Blinded, Placebo-controlled Study to Evaluate the Efficacy of Guselkumab in Subjects With Familial Adenomatous Polyposis
Actual Study Start Date :
Nov 19, 2018
Actual Primary Completion Date :
Sep 13, 2021
Actual Study Completion Date :
Mar 23, 2022

Arms and Interventions

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.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage Change from Baseline in Rectal/pouch Polyp Burden at Week 24 [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 Outcome Measures

    1. Percentage Change from Baseline in Number of Colorectal Polyps [Baseline, Weeks 24 and 52]

      Percentage change from baseline in number of colorectal polyps will be determined.

    2. Percentage Change from Baseline in Number of J-pouch Polyps [Baseline, Weeks 24 and 52]

      Percentage change from baseline in number of J-pouch polyps will be determined.

    3. Percentage Change from Baseline in J-pouch Polyp Burden [Baseline, Weeks 24 and 52]

      Percentage change from baseline in J-pouch polyp burden (sum of polyp diameters) will be determined.

    4. Percentage Change from Baseline in Number of Duodenal Polyps [Baseline, Weeks 24 and 52]

      Percentage change from baseline in number of duodenal polyps will be determined.

    5. Percentage Change from Baseline in Duodenal Polyp Burden [Baseline, Weeks 24 and 52]

      Percentage change from baseline in duodenal polyp burden (sum of polyp diameters) will be determined.

    6. Change in International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Stage [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).

    7. Change in Spigelman Stage Score [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.

    8. Trough Concentration of Guselkumab [Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48]

      Serum samples will be analyzed to determine trough concentrations of guselkumab using a validated specific, and sensitive method.

    9. Number of Participants with Anti-guselkumab Antibodies [Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48]

      Number of participants with Anti-guselkumab antibodies will be determined.

    10. Anti-guselkumab Antibodies Serum Titers [Weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48]

      Serum samples will be screened for antibodies binding to guselkumab and the titer of confirmed positive samples will be reported.

    11. Number of Participants with Adverse Events as a Measure of Safety [From Screening up to 60 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.

    12. Number of Participants with Vital Sign Abnormalities as a Measure of Safety and Tolerability [From Screening up to 52 Weeks]

      Number of participants with vital sign abnormalities will be reported. Vital signs includes temperature, pulse/heart rate, respiratory rate and blood pressure.

    13. Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability [From Screening up to 52 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.

    14. Relative Changes to Baseline in Levels of Interleukin (IL)-23 Effector Proteins in Biopsy Tissue [Baseline, Weeks 12, 24, and 52]

      Relative Changes to Baseline in levels of IL-23 effector proteins in biopsy tissue will be measured.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

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

    Sponsors and Collaborators

    • Janssen Research & Development, LLC

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Janssen Research & Development, LLC
    ClinicalTrials.gov Identifier:
    NCT03649971
    Other Study ID Numbers:
    • CR108515
    • CNTO1959COR1001
    • 2019-001980-57
    First Posted:
    Aug 28, 2018
    Last Update Posted:
    Jul 15, 2022
    Last Verified:
    Jul 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Colorectal Neoplasms
    Nasopharyngeal Neoplasms
    Adenomatous Polyposis Coli

    Study Results

    No Results Posted as of Jul 15, 2022