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
Overview
- Phase
- Phase 1
- Intervention
- UGN-301
- Conditions
- Not specified
- Sponsor
- UroGen Pharma Ltd.
- Enrollment
- 51
- Locations
- 13
- Primary Endpoint
- Recurrence-free survival (RFS) rate
- Status
- Completed
- Last Updated
- 3 months ago
Overview
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 * UGN-301 + gemcitabine 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. Patients with noninvasive papillary carcinoma and/or tumor that invades the lamina propria (Ta and/or T1) who do not have disease recurrence and patients with carcinoma in situ (CIS) who have a 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/T1 patients without disease recurrence and CIS patients with CR at 6 months may enter an Optional Maintenance Period of up to 9 months.
Investigators
Caretha L. Creasy
Scientific
Urogen Pharma Ltd.
Eligibility Criteria
Inclusion Criteria
- •Able to give informed consent.
- •Arm A: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS or recurrent IR LG Ta and/or T1 disease.
- •Arm B: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS. Arm C: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS.
- •Patients with HG Ta and/or T1 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/T1 disease within 12 months of completion of adequate BCG therapy, or 2) recurrent HG Ta/T1 disease within 6 months of completion of adequate BCG therapy, or 3) HG T1 disease at the first evaluation following a BCG induction course.
- •Notes: Adequate BCG therapy is defined as at least 5 of 6 doses of an initial induction course plus 1) at least 2 of 3 doses of maintenance therapy or 2) 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 during Screening or within 6 weeks before Screening. Note: Blue light cystoscopy is not permitted.
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.
- •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 previously treated UTUC, basal cell carcinoma or squamous cell carcinoma of the skin, and/or prostate cancer under active surveillance (see inclusion criterion 8).
- •Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation.
- •Intravesical therapy within 4 weeks before starting study treatment.
Arms & Interventions
UGN-301 monotherapy dose escalation (Arm A)
Dose escalation of UGN-301 monotherapy in patients with recurrent NMIBC with high grade (HG) Ta and/or T1 disease and/or CIS or recurrent intermediate risk (IR) low grade (LG) Ta and/or T1 disease.
Intervention: UGN-301
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 and/or T1 disease and/or CIS.
Intervention: UGN-301
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 and/or T1 disease and/or CIS.
Intervention: UGN-201
UGN-301 dose escalation + gemcitabine combination (Arm C)
Dose escalation of UGN-301 in combination with a fixed dose of gemcitabine in patients with recurrent NMIBC with HG Ta and/or T1 disease and/or CIS.
Intervention: UGN-301
UGN-301 dose escalation + gemcitabine combination (Arm C)
Dose escalation of UGN-301 in combination with a fixed dose of gemcitabine in patients with recurrent NMIBC with HG Ta and/or T1 disease and/or CIS.
Intervention: Gemcitabine
Outcomes
Primary Outcomes
Recurrence-free survival (RFS) rate
Time Frame: 3 months
RFS rate is defined as the proportion of patients with Ta/T1 disease who are recurrence-free at the Week 12 (3-month) Visit.
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.
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.
Concentration of UGN-301 in blood and urine
Time Frame: 6 weeks
Data will be summarized using descriptive statistics.
Secondary Outcomes
- UGN-301 concentration in serum at the end of a dosing interval (Ctau) following single and repeat dose administration(6 weeks)
- UGN-201 t1/2 following single and repeat dose administration(6 weeks)
- UGN-301 area under the concentration-time curve (AUC) following single and repeat dose administration(6 weeks)
- UGN-301 terminal half-life (t1/2) following single and repeat dose administration(6 weeks)
- Concentration of UGN-201 and its metabolites in blood and urine(6 weeks)
- UGN-201 Cmax following single and repeat dose administration(6 weeks)
- UGN-301 maximum serum concentration (Cmax) following single and repeat dose administration(6 weeks)
- Presence of anti-drug antibodies (ADA) in serum(3 months)
- UGN-301 time to maximum serum concentration (tmax) following single and repeat dose administration(6 weeks)
- UGN-201 Ctau following single and repeat dose administration(6 weeks)
- UGN-201 AUC following single and repeat dose administration(6 weeks)
- UGN-201 tmax following single and repeat dose administration(6 weeks)