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).

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.

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)

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu