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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05375903
Recruitment Status : Recruiting
First Posted : May 17, 2022
Last Update Posted : December 21, 2022
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Non-muscle Invasive Bladder Cancer NMIBC Carcinoma in Situ of Bladder Bladder Cancer Urothelial Carcinoma Bladder Urothelial Carcinoma Recurrent Drug: UGN-301 Drug: UGN-201 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 1, 2022
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: UGN-301 monotherapy dose escalation (Arm A)
Dose escalation of UGN-301 monotherapy in patients with recurrent NMIBC with high grade (HG) Ta disease and/or CIS or recurrent intermediate risk (IR) low grade (LG) Ta disease.
Drug: UGN-301

Induction Period: Intravesical administration once weekly for 6 weeks.

Optional Maintenance Period: Intravesical administration once every 3 months (at 6, 9, and 12 months after the start of treatment).

Other Name: UGN-301 (zalifrelimab) intravesical solution

Experimental: UGN-301 dose escalation + UGN-201 combination (Arm B)
Dose escalation of UGN-301 in combination with a fixed dose of UGN-201 in patients with recurrent NMIBC with HG Ta disease and/or CIS.
Drug: UGN-301

Induction Period: Intravesical administration once weekly for 6 weeks.

Optional Maintenance Period: Intravesical administration once every 3 months (at 6, 9, and 12 months after the start of treatment).

Other Name: UGN-301 (zalifrelimab) intravesical solution

Drug: UGN-201

Induction Period: Intravesical administration once weekly for 6 weeks.

Optional Maintenance Period: Intravesical administration once every 3 months (at 6, 9, and 12 months after the start of treatment).

Other Name: UGN-201 (imiquimod) intravesical solution




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 15 months ]
    The number of patients with each type of event will be summarized.

  2. Concentration of UGN-301 in blood and urine [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  3. Complete response rate (CRR) [ Time Frame: 3 months ]
    CRR is defined as the proportion of CIS patients who achieved CR at the Week 12 (3-month) Visit.

  4. Recurrence-free survival (RFS) rate [ Time Frame: 3 months ]
    RFS rate is defined as the proportion of patients with Ta papillary disease who are recurrence-free at the Week 12 (3-month) Visit.


Secondary Outcome Measures :
  1. Presence of anti-drug antibodies (ADA) in serum [ Time Frame: 3 months ]
    The number of patients with ADA will be summarized.

  2. UGN-301 maximum serum concentration (Cmax) following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  3. UGN-301 area under the concentration-time curve (AUC) following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  4. UGN-301 time to maximum serum concentration (tmax) following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  5. UGN-301 terminal half-life (t1/2) following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  6. UGN-301 concentration in serum at the end of a dosing interval (Ctau) following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  7. Concentration of UGN-201 and its metabolites in blood and urine [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  8. UGN-201 Cmax following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  9. UGN-201 AUC following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  10. UGN-201 tmax following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  11. UGN-201 t1/2 following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.

  12. UGN-201 Ctau following single and repeat dose administration [ Time Frame: 6 weeks ]
    Data will be summarized using descriptive statistics.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able to give informed consent.
  2. 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.

  3. 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).
  4. Have all papillary tumors visible by white light resected, and obvious areas of CIS fulgurated during Screening or within 6 weeks before Screening. Note: Blue light cystoscopy is not permitted.
  5. Eastern Cooperative Oncology Group (ECOG) status ≤ 2.
  6. 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.
  7. 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).
  8. 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.
  9. 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.
  10. 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.
  11. Has a life expectancy > 12 months.

Exclusion Criteria:

  1. Current or previous evidence of muscle invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (ie, T2, T3, T4 and/or stage IV).
  2. Current systemic therapy for bladder cancer.
  3. High or low grade T1 disease.
  4. 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.
  5. Active infection requiring systemic therapy including urinary tract infection (once satisfactorily treated, patients can enter the study).
  6. 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.
  7. Women who are pregnant or nursing.
  8. Any medical psychological, familial, sociological, or geographical condition that, in the opinion of the Investigator, would preclude participation in the study.
  9. 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).
  10. Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation.
  11. Intravesical therapy within 4 weeks before starting study treatment.
  12. 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.
  13. Has received an immune modulator therapy within 5 half-lives of starting study treatment.
  14. Has received a vaccine within 2 weeks before starting study treatment.
  15. Has a known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05375903


Contacts
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Contact: Heather Lansford 646-844-6091 heather.lansford@urogen.com
Contact: Christine Lentowski 646-809-2657 christine.lentowski@urogen.com

Locations
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United States, Arkansas
Arkansas Urology Recruiting
Little Rock, Arkansas, United States, 72211
Contact: Katie O'Brien    501-219-8900 ext 2002    katie@arkansasurology.com   
Principal Investigator: R. Jonathan Henderson, MD         
United States, California
UCLA - University of California Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Karim Chamie, MD    310-794-5929    kchamie@mednet.ucla.edu   
Principal Investigator: Karim Chamie, MD         
United States, Florida
Florida Urology Partners, LLC Recruiting
Tampa, Florida, United States, 33615
Contact: Linda Seibert    239-223-4488    linda@gulfcoastcta.com   
Principal Investigator: Osvaldo Padron, MD         
United States, New York
Manhattan Medical Research Recruiting
New York, New York, United States, 10016
Contact: Luis Leanez    917-409-3919    lleanez@manhattanmedicalresearch.com   
Principal Investigator: Jed Kaminetsky, MD         
United States, Ohio
Clinical Research Solutions Recruiting
Middleburg Heights, Ohio, United States, 44130
Contact: Jennifer Simpkins    440-340-9010    JSimpkins@crssites.com   
Principal Investigator: Lawrence Gervasi, MD         
Spain
NEXT Oncology IOB- Hospital Quironsalud Barcelona Recruiting
Barcelona, Spain, 08023
Contact: Fabricio Racca, MD    (+34) 932 381 661    fracca@nextoncology.eu   
Hospital Clinic de Barcelona Instituto Clinic de Nefrologia y Urologia (ICNU) Recruiting
Barcelona, Spain, 08036
Contact: Maria Jose Ribal, MD    (+34) 932 279 346    mjribal@clinic.cat   
NEXT Oncology- Hospital Quironsalud Mardrid Recruiting
Madrid, Spain, 28223
Contact: Valentina Boni, MD    (+34) 914 521 900    vboni@nextoncology.eu   
Sponsors and Collaborators
UroGen Pharma Ltd.
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Responsible Party: UroGen Pharma Ltd.
ClinicalTrials.gov Identifier: NCT05375903    
Other Study ID Numbers: UR001
First Posted: May 17, 2022    Key Record Dates
Last Update Posted: December 21, 2022
Last Verified: December 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Carcinoma in Situ
Recurrence
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
Pathologic Processes
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Imiquimod
Pharmaceutical Solutions
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Interferon Inducers