Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis

A Phase 3, Multi-Site, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of eRapa to Improve Clinical Outcomes in Patients With Familial Adenomatous Polyposis

The main goal of this clinical trial is to learn if the drug eRapa works to slow down the progression of disease in patients diagnosed with Familial Adenomatous Polyposis (FAP). Researchers will compare eRapa to Placebo. The questions to be answered by this trial are:

• Does taking eRapa help to slow down the progression of the disease in patients with FAP?
• Is eRapa a safe treatment for patients diagnosed with FAP?
• What is the effect of eRapa on the number of polyps found in GI tract of patients diagnosed with FAP?
• How does treatment with eRapa affect a patient's quality of life?

Participants will:

• Take eRapa or placebo once per day every other week until disease progresses (gets worse), stops taking part in the trial or dies.
• Visit the clinic once every 3 months for check ups and tests.
• Have an endoscopy at the start of the trial and then every 6 months to check on whether the disease is getting better or worse.

This is a Phase 3, multi-site, prospective, randomized, double-blind, placebo-controlled trial of eRapa administered to patients with FAP who are at high risk of disease progression. 168 patients with FAP will be enrolled in the trial and randomized 2:1 to receive 0.5 mg eRapa or matching placebo orally, once a day (QD) every other week. There is no minimum treatment duration as this is an event-driven trial; however, the intervention period will continue until disease progression, participant withdrawal from treatment, or until the overall trial endpoint is reached. Participant eligibility is restricted to patients under active surveillance for genetic or clinically diagnosed FAP and who have an intact colon; who are postcolectomy/subtotal colectomy and have documented residual polyps in the rectum/sigmoid or who are post-proctocolectomy with ileal-pouch anal anastomosis and documented polyps in the pouch. Eligible participants will undergo a baseline endoscopy and subsequent endoscopic procedures performed every 6 months to monitor for disease progression.

Randomized patients will be stratified based on the following disease characteristics:

• Intact colon versus post-surgical resection with retained rectum/sigmoid or pouch, and
• Duodenal polyposis (current Spigelman stage score ≤2 versus Spigelman stage score ≥3) For the purposes of this trial, high-risk for disease progression is defined as meeting one of the following:
• Patients who have intact colons and have >100 polyps but ≤500 polyps
• Patients who have retained rectum/sigmoid or ileal-pouch-anal anastomosis and have ≥10 polyps that are ≥3 mm in diameter, or
• Patients who have a history of duodenal polyposis Spigelman stage score of 3 or 4 with at least 1 duodenal polyp that has been removed within 18 months of screening.

Trial assessments should be conducted as per the Schedule of Activities with a visit occurring about once every 3 months.

Assessment of Spigelman stage will not require a biopsy unless the lesion has an abnormal appearance and/or is ≥10 mm.

Inclusion Criteria:

1. Participant must be ≥18 years of age inclusive.
2. Participant must have documented FAP, confirmed by adenomatous polyposis coli genotype mutation testing.
3. Participant must have at least 1 of the following high-risk features: >100 polyps but ≤500 polyps in the colon, or ≥10 polyps in the retained rectum/sigmoid or ileal pouch (≥3 mm in size), or Spigelman stage 3 or 4 with at least 1 polyp ≥10 mm to be removed at baseline or on endoscopy performed within 18 months of screening.
4. Contraceptive use by participants or participant partners until at at least 12 weeks after stopping study treatment.
5. Agree not to donate gametes for the purpose of reproduction until at at least 12 weeks after stopping study treatment.
6. Willing to undergo endoscopic evaluation.

Exclusion Criteria:

1. Participant has unresected or incompletely resected high-grade dysplasia or cancer within the duodenum, colon, rectum, or ileal pouch at screening endoscopy.
2. Participant has any polyps ≥8 mm in the duodenum, colon, rectum, or ileal pouch remaining after screening endoscopy (polyps ≥8 mm are to be resected during screening endoscopy).
3. Participant has had surgery within 6 weeks of the trial.
4. Participant has active malignancy or history of malignancy diagnosed within 24 months of first dose of trial intervention.
5. Participant has a history of, or currently has, an acquired or primary (congenital) immunodeficiency.
6. Participant has active and clinically significant tuberculosis (positive Quantiferon Gold test), bacterial, fungal, or viral infection, including human immunodeficiency virus (HIV).
7. Participant has any medical or social condition that, in the opinion of the Investigator, might increase participant risk if enrolled, prevent participant compliance to trial procedures, or present an unacceptable confound to safety or clinical trial data.