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Brief Title: A Phase 1 Dose-escalation Study of UGN-301 in Patients With Recurrent Non-muscle Invasive Bladder Cancer (NMIBC)

A Phase 1, Open-label, Dose-escalation Study to Investigate the Safety, Tolerability, and Pharmacokinetics of UGN-301 (Zalifrelimab) Administered Intravesically as Monotherapy and in Combination With Other Agents in Patients With Recurrent NMIBC

INTRODUCTION

  • Org Study ID: UR001
  • Secondary ID: N/A
  • NTC ID: NCT05375903
  • Sponsor: UroGen Pharma Ltd.

BRIEF SUMMARY

This study is being conducted to evaluate the safety and determine the recommended Phase 2 dose (RP2D) of UGN-301 (zalifrelimab) administered intravesically as monotherapy and in combination with other agents in patients with recurrent NMIBC.

DETAILED DESCRIPTION

This master protocol will comprise multiple treatment arms designed to independently investigate intravesical delivery of UGN-301 either as monotherapy or in combination with other agents. Initial study treatment arms will include:

UGN-301 monotherapy
UGN-301 + UGN-201 (imiquimod) in combination

Additional study treatment arms investigating UGN-301 in combination with other agents may be added in the future.

The study will evaluate escalating doses of UGN-301 to determine the biologically effective dose (BED) and maximum tolerated dose (MTD) of UGN-301 either as monotherapy or in combination with other agents.

When evaluated in combination with other agents, the UGN-301 dose will begin at least 1 dose level lower than the highest dose level cleared in the monotherapy arm, or 1 dose level lower than the RP2D.

Eligible patients in each study treatment arm will enter a 12-week Induction Period.

Noninvasive papillary carcinoma (Ta) patients without disease recurrence and carcinoma in situ (CIS) patients with complete response (CR) at 3 months after the start of treatment will return to the clinic for a Safety Follow-up Visit at 6 months after the start of treatment.

Ta patients without disease recurrence and CIS patients with CR at 6 months may enter an Optional Maintenance Period of up to 9 months.

  • Overall Status
    Recruiting
  • Start Date
    June 2022
  • Phase
    Phase 1
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs)

Primary Outcome 1 - Timeframe: Up to 15 months

Primary Outcome 2 - Measure: Concentration of UGN-301 in blood and urine

Primary Outcome 2 - Timeframe: 6 weeks

Primary Outcome 3 - Measure: Complete response rate (CRR)

Primary Outcome 3 - Timeframe: 3 months

Primary Outcome 4 - Measure: Recurrence-free survival (RFS) rate

Primary Outcome 4 - Timeframe: 3 months

CONDITION

  • Non-muscle Invasive Bladder Cancer
  • NMIBC
  • Carcinoma in Situ of Bladder
  • Bladder Cancer
  • Urothelial Carcinoma Bladder
  • Urothelial Carcinoma Recurrent

ELIGIBILITY

Inclusion Criteria:
Able to give informed consent.
Arm A: Have confirmed recurrent NMIBC with HG Ta disease and/or CIS or recurrent IR LG Ta disease.
Arm B: Have confirmed recurrent NMIBC with HG Ta disease and/or CIS.
Patients with HG Ta disease and/or CIS must meet one of the following criteria:
Have Bacillus Calmette-Guérin (BCG)-unresponsive disease, defined as 1) persistent or recurrent CIS alone or with recurrent Ta disease within 12 months of completion of adequate BCG therapy, or 2) recurrent HG Ta disease within 6 months of completion of adequate BCG therapy. Notes: Adequate BCG therapy is defined as at least 5 of 6 doses of an initial induction course plus at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course. Patients with BCG-unresponsive disease also must be unwilling or unfit to undergo radical cystectomy.

- Have otherwise failed adequate BCG therapy (eg, recurrence > 6 months [papillary] or > 12 months [CIS] after last BCG exposure).

- Are BCG intolerant, defined as the inability to tolerate at least one full induction course of BCG.

- Have HG Ta disease with tumors ≤ 3 cm and failed at least one previous course of therapy (eg, adjuvant intravesical chemotherapy).

- Have all papillary tumors visible by white light resected, and obvious areas of CIS fulgurated. Note: Blue light cystoscopy is not permitted.

- Eastern Cooperative Oncology Group (ECOG) status ≤ 2.

- Absence of concomitant upper tract urothelial carcinoma (UTUC) or urothelial carcinoma (UC) within the prostatic urethra. Freedom from upper tract disease (if clinically indicated) as indicated by no evidence of upper tract tumor by either intravenous pyelogram, retrograde pyelogram, computerized tomography (CT) urogram with or without contrast, or magnetic resonance imaging (MRI) urogram with or without contrast performed within 6 months of enrollment.

- Patients with prostate cancer on active surveillance at low risk for progression, defined as prostate-specific antigen < 10 ng/dL, Gleason score 6 and clinical stage tumor-1 are permitted to be in the study at the discretion of the Investigator (see exclusion criterion 9). - Female patients of childbearing potential must use maximally effective birth control during the period of therapy, must be willing to use contraception for 1 month following the last administration of study drug and must have a negative urine or serum pregnancy test upon entry into this study. Otherwise, female patients must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile. "Maximally effective birth control" means that the patient, if sexually active, should be using a combination of 2 methods of birth control that are approved and recognized to be effective by health authorities. - Male patients must be surgically sterile or willing to use 2 highly effective forms of birth control upon enrollment, during the course of the study, and for 1 month following the last study drug instillation.
Has adequate organ and bone marrow function within 14 days of treatment initiation as determined by routine laboratory tests outlined below:
Leukocytes ≥ 3,000/μL;

- Absolute neutrophil count (ANC) ≥ 1,500/μL;

- Platelets ≥ 100,000/μL;

- Hemoglobin ≥ 9.0 g/dL;

- Total bilirubin ≤ 1.5 × upper limit of normal (ULN);

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN;

- Alkaline phosphatase (ALP) ≤ 2.5 × ULN;

- Estimated creatinine clearance ≥ 30 mL/min calculated using the Cockcroft-Gault equation.

- Has a life expectancy > 12 months.
Exclusion Criteria:
Current or previous evidence of muscle invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (ie, T2, T3, T4 and/or stage IV).

- Current systemic therapy for bladder cancer.

- High or low grade T1 disease.

- Prior therapy with an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1), anti-PD-ligand 1 (L1) agent, or with an agent directed to another co-inhibitory T-cell receptor.

- Active infection requiring systemic therapy including urinary tract infection (once satisfactorily treated, patients can enter the study).

- Active systemic autoimmune disease that required systemic treatment in the past 2 years. Short courses of steroids (≤ 14 days) for medical reasons without anticancer intent (eg, atopic dermatitis, psoriasis, infection, allergic reaction) are permitted if the last dose was ≥ 4 weeks before the first dose of study treatment.

- Women who are pregnant or nursing.

- 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 other organ system within the past 5 years, except treated basal cell carcinoma or squamous cell carcinoma of the skin and ≤ pathological tumor-2 UTUC at least 24 months after nephroureterectomy. Patients with genitourinary cancers other than UC or prostate cancer that are under active surveillance are also excluded (see inclusion criterion 7).

- Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation.

- Intravesical therapy within 4 weeks before starting study treatment.

- Has participated in a study of an investigational agent and received study therapy or received investigational device within 4 weeks before the first dose of study treatment.

- Has received an immune modulator therapy within 5 half-lives of starting study treatment.

- Has received a vaccine within 2 weeks before starting study treatment.

- Has a known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: N/A

Role: N/A

Affiliation: N/A

Overall Contact

Name: N/A

Phone: 646-844-6091, 646-809-2657

Email: heather.lansford@urogen.com, christine.lentowski@urogen.com

LOCATION

Facility Status Contact
Facility: Florida Urology Partners, LLC
Tampa, Florida 33615
United States
Status: Recruiting Contact: Contact
Linda Seibert
239-223-4488
linda@gulfcoastcta.com
Facility: Clinical Research Solutions
Middleburg Heights, Ohio 44130
United States
Status: Recruiting Contact: Principal Investigator
Osvaldo Padron, MD
440-340-9010
JSimpkins@crssites.com