CASCADE 2002: PROTECT Study, "PRObiotics to TrEat Anal preCancer Trial

Prior treatment

• Receipt of chemotherapy, radiotherapy or immunosuppressive medication in three months preceding enrollment in ULACNet-101 or at the screening visit for ULACNet-102.
• Participant initiated a new treatment with antibiotics within the 2 weeks prior to screening or plans to start antibiotic therapy during the study period.
• Use of probiotics other than EXE-346 during the study and for a period of two weeks prior to screening.
• Participant has participated in any clinical study of an approved or unapproved investigational medicinal product within the 30 days prior to screening.

Other illness

• History of any anogenital cancer.
• History of inflammatory bowel disease
• Presence of untreated cervical HSIL or cervical cancer.
• Anal HSIL on clinical examination or biopsy that clinicians are concerned for cancer.
• Immunosuppression as a result of underlying illness or treatment including:
  • Use of high dose corticosteroids (\>10 mg/day prednisone or equivalent) for \>=7 days (inhaled, otic, topical and ophthalmic corticosteroids are permitted).
  • Primary immune deficiency disease.
  • Use of synthetic or biologic disease-modifying anti-rheumatic drugs.
  • History of bone marrow or solid organ transplant.
  • History of any other clinically significant autoimmune or immunosuppressive disease.
• Participant has known hypersensitivity to EXE-346 or any product components.
• Current known infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• History of significant thrombocytopenia, history of thrombosis with thrombocytopenia (TTS) syndrome or heparin-induced thrombocytopenia.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.

Other

• Participant is taking NSAIDs as a long-term treatment (ie, consistent use for at least 4 days/week each month). Acute use of NSAIDs is allowed.
• Warts so extensive that they preclude the clinician from determining the extent and location of HSIL.
• Sustained, manually confirmed, sitting systolic blood pressure \>150 mm Hg or \<90 mm Hg or a diastolic blood pressure \>95 mm Hg as measured by 3 readings taken 15 minutes apart at screening or Visit 1.
• Any other finding that, in the opinion of the Investigator deems the participant unsuitable for the study.

• Signed informed consent
• Biopsy-proven anal HSIL (men or women) at a screening visit for C2002, or clinic patients with known untreated HSIL diagnosed within the previous 3 months.
  • 4\. At least one focus of anal HSIL must be large enough to be monitored for response, i.e.,not completely removed after the screening biopsy.
  • 5\. Total volume of HSIL is less than 50% of the anal canal or perianal region. 6.Must be actively on treatment with effective antiretroviral therapy (ART) regimen for at least three months preceding enrollment (Visit 1, Day 1) at screening for C2002.
  • 7.HIV RNA \<200 copies/ml at baseline. 9.Eastern Cooperative Oncology Group (ECOG) performance status \<=1 (Karnofsky \>= 70%).
  • 10\. Participants must meet the following laboratory parameters within 3 months before enrollment:
• Leukocytes: ≥3,000/mm\^3. b. Absolute neutrophil count: ≥1,500/mm\^3. c. Platelets: ≥100,000/mm\^3. d. Elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin \<=2 times the upper limit of normal.
  • 11\. Not pregnant or breast feeding and one of the following:
• Of non-childbearing potential (i.e. persons aged 60 years or older or who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses for at least 12 months and without an alternative medical cause).
• Persons aged less than 60 years of childbearing potential and agree to practice highly effective contraception from initiation of taking EXE-346 or placebo through 14 days after taking the last dose of EXE-346 or placebo. Highly effective methods of contraception include one or more of the following:
  • i.Male partner who is sterile (medically effective vasectomy) prior to the female participant's entry into the study and is the sole sexual partner for the female participant.
  • ii.Hormonal (oral, intravaginal, transdermal, implantable or injectable); Progestogen-only hormonal contraceptives without inhibition of ovulation are not considered to be highly effective.
• An intrauterine hormone-releasing system. iv. An intrauterine device. v. Bilateral tubal occlusion or removal. vi. Sexual abstinence, only if the participant refrains from heterosexual intercourse from initiation taking EXE-346 or placebo through 14 days after taking the last dose of EXE-346 or placebo and it is the usual lifestyle of the participant.