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

Each potential subject must satisfy all of the following criteria to be
enrolled in the study:
1. Males and females >=18 years of age.
2. Diagnosis of phenotypic FAP with disease involvement of the colorectum with
either:
a. Genetic diagnosis: APC germline mutation (with or without family history) or
obligate
carrier.
b. Clinical diagnosis: FAP phenotype with >100 adenomas in large intestine
and subject has a family history of FAP.
c. Clinical diagnosis: FAP phenotype who are status post colectomy for
polyposis, subject has a family history of FAP, and 2 FAP experts agree to the
diagnosis.
d. Attenuated FAP diagnosis: APC germline mutation required.
3. Criterion modified per Amendment 3.
3.1. Post-colectomy or subtotal colectomy with ileocolonic anastomosis, IRA, or
IPAA.
4. Polyps with a sum of diameters >=10 mm in the rectum or pouch post screening
biopsies.
5. Screening laboratory test results within the following parameters (if 1 or
more of the laboratory parameters is out of range, a single retest of
laboratory values is permitted during the approximately 4-week screening
period):
a. White blood cells (WBCs) >=3.5 x 103/µL
b. Absolute neutrophil count (ANC) >=1.5 x 103/µL
c. Hemoglobin >= 10.0 g/dL
d. Platelets >=100 x 103/µL.
e. Total bilirubin <=1.5 times the upper limit of normal (ULN).
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2 times
the ULN
g. Creatinine clearance (calculated if measured is not available) >=60
mL/min/1.73m2
6. A woman must meet one of the following criteria:
o premenarchal;
o postmenopausal (>45 years of age with amenorrhea for at least 12 months or
any age with amenorrhea for at least 6 months and a serum follicle-stimulating
hormone [FSH] level >40 IU/L);
o permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral
salpingectomy);
o otherwise incapable of pregnancy;
o have a negative pregnancy test result at screening and baseline.
7. Before randomization, a female subject of childbearing potential must be
practicing a highly effective method of contraception and agrees to remain on a
highly effective method while receiving study drug and until 12 weeks after
last dose
8. Criterion modified per Amendment 4
8.1 A woman must agree not to breast feed, or to donate eggs (ova, oocytes) or
freeze for future use, for the purposes of assisted reproduction during the
study and for a period of 12 weeks after the last administration of study drug.
9. Criterion modified per Amendment 4
9.1 A man must agree not to father a child, or to donate sperm or freeze for
future use, for the purposes of reproduction during the study and for a period
of 12 weeks after the last administration of study drug.
10. Are considered eligible according to the following tuberculosis (TB)
screening criteria:
a. Have no history of latent or active TB prior to screening.
b. Have no signs or symptoms suggestive of active TB upon medical history
and/or physical examination.
c. Have had no recent close contact with a person with active TB.
d. Within 8 weeks prior to the first administration of study intervention, have
a negative QuantiFERON®-TB test result.
e. Have a chest x-ray (both posterior-anterior and lateral views, or per
country regulations where applicable), taken <=12 weeks before the first
administration of study intervention and read by a qualified radiologist, with
no evidence of current, active TB or old,
inactive TB.
11. Sign an informed consent form.
12. Willing and able to adhere to the prohibitions and restrictions specified
in this protocol.

Any potential subject who meets any of the following criteria will be excluded
from participating in the study.
1. Prior use of any biologic therapy targeting IL-12/23, IL-17, or IL-23
receptor antagonists.
2. Criterion modified per Amendment 4: Use of non-steroidal anti-inflammatory
drugs other than aspirin exceeding 5 days per month, unless completes a 4-week
washout period prior to randomization. The use 100 mg of aspirin a day or 700
mg of aspirin per week is allowed.
3. Treatment with other FAP-directed drug therapy, unless completes a 4-week
washout period prior to randomization.
Criterion modified per Amendment 3.
4.1 High grade dysplasia or cancer on biopsy at screening in GI tract
(including stomach,
duodenum, and colon/rectum/pouch).
5. Criterion modified per Amendment 4.
5.2 Duodenal, colorectal, or pouch polyp:
• >2 cm unless excised at the screening evaluation.
• 1 to 2 cm with evidence of high-grade dysplasia upon biopsy unless excised.
6. Tests positive for hepatitis B virus (HBV) infection or is seropositive for
antibodies to hepatitis C virus (HCV).
7. Has a history of, or ongoing, chronic or recurrent infectious disease,
including but not limited to, chronic renal infection, chronic chest infection,
recurrent urinary tract infection, or open, draining, or infected skin wounds
or ulcers.
8. Has current signs or symptoms of a clinically significant infection.
Established non-serious infections need not be considered exclusionary at the
discretion of the investigator.
9. Has a history of serious infection, including any infection requiring
hospitalization or IV antibiotics, for 8 weeks before baseline.
10. Has evidence of a herpes zoster infection within 8 weeks before baseline.
11. Has a history of latent or active granulomatous infection, including
histoplasmosis or coccidioidomycosis. Participants with radiographic evidence
of possible prior histoplasmosis or coccidioidomycosis will be excluded.
12. Has a chest x-ray within 12 weeks prior to the first administration of
study intervention that shows an abnormality suggestive of a malignancy or
current active infection, including TB.
13. Has or has had a nontuberculous mycobacterial infection or clinically
significant opportunistic infection (eg, cytomegalovirus colitis,
pneumocystosis, invasive aspergillosis).
14. History of human immunodeficiency virus (HIV) antibody positive, or tests
positive for HIV.
15. Any serious underlying medical or psychiatric condition, dementia or
altered mental status or any issue that would impair the ability of the subject
to receive or tolerate the planned treatment at the investigational site, to
understand informed consent or that in the opinion of the investigator would
contraindicate the subject*s participation in the study or confound the results
of the study.
16. 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.
17.Criterion modified per Amendment 4.: Received, or is expected to receive,
any live virus or live bacterial vaccination within 12 weeks before the first
administration of study intervention.
18. Has had a BCG vaccination within 12 months of screening
Criterion modified per Amendment 3.
19.1 Currently has a malignancy or has a history of malignancy within 5 years
before
screening (with the exception of a nonmelanoma skin cancer that has been
adequately
treated with no evidence of recurrence for at least 12 weeks before the first
study
intervention administration or cervical carcinoma in situ that has been treated
with no
evidence of recurrence for at least 12 weeks before the first study intervention
administration or localized papillary thyroid carcinoma that has been treated
with no
evidence of recurrence for at least 12 weeks before the first study intervention
administration).
20. Has a known history of lymphoproliferative disease, including monoclonal
gammopathy of unknown significance, lymphoma, or signs and symptoms suggestive
of possible lymphoproliferative disease, such as lymphadenopathy, hepatomegaly,
or splenomegaly, or monoclonal gammopathy of undetermined significance.
21. Has a transplanted organ (with exception of a corneal transplant >12
weeks before screening).
22. Known hypersensitivity, allergies, or intolerance to any excipient
contained in the study drug (see guselkumab IB).
23. Has received an experimental antibody or biologic therapy within the
previous 6 months, or received any other experimental therapy or new
investigational agent within 30 days or 5 half-lives (whichever is longer) of
any administration of study intervention or is currently enrolled in, or
intends to participate in any other study using an investigational agent or
procedure during participation in this study.
24. Has any condition for which, in the opinion of the investigator,
participation would not be in the best interest of the subject (e.g.,
compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments.
25. Is an employee of the investigator or study site, with direct involvement
in the proposed study or other studies under the direction of that investigator
or study site, as well as family members of the employees or the investigator.