A Phase 1 Dose-escalation Study of UGN-501 Administered Intravesically in Adult Participants With Recurrent NMIBC

Prior treatment

• Current or previous evidence of muscle invasive, locally advanced nonresectable, or metastatic urothelial carcinoma, including T2, T3, T4, and/or stage IV disease.
• Prior treatment with any human adenovirus-based therapy, such as nadofaragene firadenovec-vncg or cretostimogene grenadenorepvec.
• Intravesical therapy within 4 weeks before starting study intervention, including but not limited to BCG, chemotherapy, and nogapendekin alfa inbakicept.
• Participation in a study of an investigational agent with receipt of study therapy, or receipt of an investigational device, within 4 weeks before the first dose of study intervention.
• Receipt of immune modulator therapy within 5 half-lives of starting study intervention, including but not limited to pembrolizumab, BCG, and nogapendekin alfa inbakicept.
• Receipt of a vaccine or anti-viral agent within 2 weeks before starting study intervention.
• Immunocompromised state, including but not limited to HIV infection or any condition that required systemic immunosuppressive treatment in the past 2 years, such as active systemic autoimmune disease or solid organ or stem cell transplant. Short courses (≤14 days) of steroids for medical reasons without anticancer intent, such as atopic dermatitis, psoriasis, infection, or allergic reaction, are permitted if the last dose was at least 4 weeks before the first dose of study intervention.
• Cannot tolerate intravesical dosing or intravesical surgical manipulation.

Other illness

• Current systemic therapy for bladder cancer.
• Active infection requiring systemic therapy, including urinary tract infection. Participants may enter the study once the infection is satisfactorily treated.
• Any medical, psychological, familial, sociological, or geographical condition that, in the opinion of the investigator, would preclude participation in the study.
• History of malignancy of another organ system within the past 5 years, except previously treated UTUC, basal cell carcinoma or squamous cell carcinoma of the skin, and/or prostate cancer meeting protocol-specified criteria.
• Known allergy or hypersensitivity to any of the study interventions or any study intervention excipients.

• Participant must be 18 years of age or older at the time of signing informed consent.
• Has confirmed recurrent non-muscle invasive bladder cancer (NMIBC) with high-grade Ta and/or T1 disease and/or carcinoma in situ (CIS), or recurrent low-grade Ta and/or T1 disease.
• Participants with high-grade Ta and/or T1 disease and/or CIS must meet one of the following criteria:
  • Has BCG-unresponsive disease, defined as:
  • persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy; or
  • recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; or
  • high-grade T1 disease at the first evaluation following a BCG induction course.
  • Adequate BCG therapy is defined as at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course. Participants with BCG-unresponsive disease also must be unwilling or unfit to undergo radical cystectomy.
  • Is BCG-exposed, defined as high-grade persistent or recurrent NMIBC within 24 months of the last dose of BCG but not meeting the definition of BCG-unresponsive disease, and received at least 5 of 6 doses of an initial induction course of BCG.
  • Is BCG intolerant, defined as the inability to tolerate at least 1 full induction course of BCG.
  • Has a high-grade Ta tumor ≤3 cm and failed at least 1 previous course of therapy, such as TURBT plus an adjuvant induction course of intravesical chemotherapy.
• Participants with low-grade disease must meet one of the following criteria:
  • Ta tumors recurring within 1 year.
  • Ta solitary tumor \>3 cm.
  • Ta multifocal tumors.
  • T1 tumors.
• All visible papillary tumors must be resected and obvious areas of CIS fulgurated during Screening or within 6 weeks before Screening. Participants with T1 disease should have a re-staging TURBT during Screening or within 6 weeks before Screening. Enhanced cystoscopy, such as blue light cystoscopy or other locally accepted modalities, is permitted, but the same modality must be used for all subsequent disease assessments.
• Has Eastern Cooperative Oncology Group performance status score ≤2.
• Has no concomitant upper tract urothelial carcinoma (UTUC) or urothelial carcinoma within the prostatic stroma. Freedom from upper tract disease, if clinically indicated, must be demonstrated by no evidence of upper tract tumor by either IV pyelogram, retrograde pyelogram, CT urogram with or without contrast, MRI urogram with or without contrast, or ureteroscopy with ureteral washing for cytology, performed within 6 months of enrollment. Participants with urothelial carcinoma involving the prostatic urethra, where carcinoma is confined to the ducts and/or epithelium, may be included after a restaging TURBT is performed to rule out more extensive disease involving the prostatic stroma.
• Participants with prostate cancer may be eligible if, after surgery or radiation, they do not meet criteria for biochemical recurrence, or if they are on active surveillance at very low, low, or favorable risk for progression, defined as Gleason Grade Group 1 or 2, Gleason score ≤7, prostate-specific antigen \<20 ng/dL, and cT1-cT2b, at the discretion of the investigator.
• Has adequate organ and bone marrow function within 14 days of treatment initiation, as determined by routine laboratory tests:
  • Leukocytes ≥3000/μL.
  • Absolute neutrophil count ≥1500/μL.
  • Platelets ≥100,000/μL.
  • Hemoglobin ≥9.0 g/dL.
  • Total bilirubin ≤1.5 × upper limit of normal (ULN).
  • Aspartate aminotransferase (AST) ≤2.5 × ULN.
  • Alanine aminotrasferase (ALT) ≤2.5 × ULN.
  • Alkaline phosphatase ≤2.5 × ULN.
  • Estimated creatinine clearance ≥30 mL/min using the Cockcroft-Gault equation.
• Has a life expectancy \>12 months.
• Participants and participant partners must agree to follow contraception and barrier method requirements consistent with local regulations and the protocol during the study intervention period and for at least 12 weeks after the last study intervention instillation.
• Is willing and able to sign informed consent and comply with the requirements and restrictions listed in the informed consent form and protocol.