A Study of JNJ-64251330 in Participants With Familial Adenomatous Polyposis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the effect of JNJ-64251330 in participants with Familial Adenomatous Polyposis (FAP) on colorectal polyp burden (sum of the polyp diameters).

Detailed Description
-----------------
Familial adenomatous polyposis (FAP) is the most common polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. JNJ-64251330 (lorpucitinib) is an oral, small molecule, potent pan-janus kinase (JAK) inhibitor that blocks phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. pSTAT induces transcription of multiple genes involved in the progression of inflammatory disease. JNJ-64251330 has chemical properties that limits the amount of drug in the blood while delivering the drug to the tissues of the gut. Local inhibition of JAK in the gut may present a promising method to treat inflammatory diseases of the intestinal tract, such as FAP. The study consists of 3 phases: screening phase (30 days) a treatment phase (24 weeks), and follow-up visit (up to 30 days after last dose of study drug). The total duration of the study will be up to 32 weeks. Study evaluations will include efficacy via endoscopies, safety (monitoring of adverse events (AE), serious adverse events (SAEs), events of infections including tuberculosis (TB), clinical laboratory blood tests (complete blood count and serum chemistries), vital signs, and concomitant medication review), pharmacokinetics, pharmacodynamic and biomarkers evaluations.

Official Title
-----------------
A Phase 1b Study to Evaluate the Efficacy and Safety of JNJ-64251330, a Janus Kinase (JAK) Inhibitor, in Participants With Familial Adenomatous Polyposis

Conditions
-----------------
Adenomatous Polyposis Coli

Intervention / Treatment
-----------------
* Drug: JNJ-64251330


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Genetic diagnosis of classical familial adenomatous polyposis (FAP) (adenomatous polyposis coli [APC] germline mutation or obligate carrier) with disease involvement of the colorectum At least 6 polyps greater than or equal to (>=) 2 millimeters (mm) in diameter in the rectum or colon A female participant of childbearing potential must have a negative highly sensitive pregnancy test at screening and within 72 hours prior to the first dose of study drug and must agree to further pregnancy tests during the study A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study drug Must sign an informed consent form (ICF) indicating he or she understands the purpose of the study and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant's disease Exclusion Criteria: Use of non-steroidal anti-inflammatory drugs (example, aspirin, ibuprofen) exceeding 5 days per month or exceeding the nonprescription dose, unless the participant completes a 4-week washout period prior to the first dose of study drug Treatment with other FAP-directed drug therapy (including sulindac or celecoxib), unless completes a 4-week washout period prior to the first dose of study drug History of human immunodeficiency virus (HIV) History of severe, progressive, or uncontrolled renal, genitourinary, hepatic, hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic, psychiatric, or metabolic disturbances, or signs and symptoms thereof A history of, or ongoing, chronic or recurrent infectious disease including latent or active tuberculosis (TB)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-64251330<br>Participants will receive oral dose of JNJ-64251330 twice daily for 24 Weeks. | Drug: JNJ-64251330<br>* JNJ-64251330 tablets will be administered orally.<br>* Other names: Lorpucitinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change from Baseline in Colorectal Polyp Burden for all Polyps at Week 24 | Percentage change from baseline in colorectal polyp burden for all polyps (the sum of the polyp diameters) at Week 24 will be reported. | Baseline and Week 24 | 
| Percentage Change from Baseline in Colorectal Polyp Burden for Polyps >=2 mm at Week 24 | Percentage change from baseline in colorectal polyp burden (sum of the polyp diameters) for polyps greater than or equal to (>=) 2 millimeters (mm) at Week 24 will be reported. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Number of Colon Polyps | Percentage change in number of colon polyps will be reported. | Baseline and Week 24 | 
| Percentage Change in Number of Rectal Polyps | Percentage change in number of rectal polyps will be reported. | Baseline and Week 24 | 
| Percentage Change in Number of J-pouch Polyps | Percentage change in number of J-pouch polyps (for participants with an ileal pouch-anal anastomosis [IPAA]) will be reported. | Baseline and Week 24 | 
| Percentage Change in Number of Duodenal Polyps | Percentage change in number of duodenal polyps will be reported. | Baseline and Week 24 | 
| Percentage Change in Colon Polyp Burden for all Polyps, Polyps >=2 mm and Polyps >=5 mm | Percentage change in colon polyp burden for all polyps, polyps >=2 mm and polyps >=5 mm will be reported. | Baseline and Week 24 | 
| Percentage Change in Rectal Polyp Burden for all Polyps, Polyps >=2 mm and Polyps >=5 mm | Percentage change in rectal polyp burden for all polyps, polyps >=2 mm and polyps >=5 mm will be reported. | Baseline and Week 24 | 
| Percentage Change in J-Pouch Polyp Burden for all Polyps, Polyps >=2 mm and Polyps >=5 mm | Percentage change in J-Pouch polyp (for participants with an IPAA) burden for all polyps, polyps >=2 mm and polyps >=5 mm will be reported. | Baseline and Week 24 | 
| Percentage Change in Duodenal Polyp Burden for all Polyps, Polyps >=2 mm and Polyps >=5 mm | Percentage change in duodenal polyp burden for all polyps, polyps >=2 mm and polyps >=5 mm will be reported. | Baseline and Week 24 | 
| Change in International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Polyposis Stage (with and Without Colon) | Change in InSiGHT stage will be reported. Various stages are defined as: a) With Colon: Stage 0: 0-10 polyps,all less than [<]5mm); Stage 1: 20-200 polyps,most <5 mm, none, >1 centimeters[cm]; Stage 2: 200-500 polyps,<10 that are >1 cm; Stage 3: 500-1000 polyps or any number if there are 10-50 that are >1 cm and amenable to complete polypectomy; Stage 4: >1000 polyps and/or any polyps grown to confluence and not amenable to simple polypectomy, any invasive cancer; b) Without Colon: Stage 0: 0 -10 polyps, all <5 mm; Stage 1: 10-25 polyps most <5 mm, none >1 cm; Stage 2: 10-25 polyps, any >1 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; Stage 4: >25 polyps not amenable complete removal, or any incompletely excised sessile polyp showing HGD; any invasive cancer. | Baseline and Week 24 | 
| Change in Spigelman Stage Score | Change in Spigelman stage score will be reported. 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. The higher the score, the more severe or advanced the FAP disease in the duodenum. | Baseline and Week 24 | 
| Number of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to 32 weeks | 
| Number of Participants with AEs by Severity | Number of participants with AEs by severity will be reported. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to AE. | Up to 32 weeks | 
| Plasma Concentration of JNJ-64251330 Over Time | Plasma samples will be analyzed to determine plasma concentrations of JNJ-64251330 using a validated specific, and sensitive liquid chromatography coupled to tandem mass spectrometry detection (LC-MS/MS). | Up to Week 24 | 
| Tissue Concentration of JNJ-64251330 Over Time | Tissue biopsy samples will be analyzed to determine tissue concentrations of JNJ-64251330 using a validated specific, and sensitive LC-MS/MS. | Up to Week 24 | 
| Levels of JAK/STAT Pathway Signaling Effector Proteins including pSTAT-3 Relative to Baseline Levels in Colorectal Polyps | Levels of Pan-janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway signaling effector proteins including phosphorylated (p) STAT-3 relative to baseline levels in colorectal polyps will be reported. Polyp and tissue samples will be collected to monitor for changes to the JAK-STAT pathway. | Up to Week 24 |