A Phase 1/1b Study of ZH9 Treatment in Patients With Non-Muscle Invasive Bladder Cancer (PARADIGM-1)

A Phase 1/1b Study Evaluating the Safety, Pharmacology, and Clinical Effect of ZH9 Treatment in Patients With Non-Muscle Invasive Bladder Cancer

This is a first-in-human, multicenter, Phase 1/1b, 3-part, double-blind study of ZH9 in patients with recurrent NMIBC who are eligible for intravesical therapy. In Part 1, the safety, tolerability, and pharmacology of ZH9 IVI will be evaluated in a single ascending dose (SAD) patient cohort. In Part 2, the safety, tolerability, and pharmacology of ZH9 oral prime followed by ZH9 IVI will be evaluated in 2 patient cohorts at the doses and schedule established in Part 1. In Part 3, the safety, pharmacology, and clinical efficacy of ZH9 will be further evaluated in 2 expansion cohorts of patients with recurrent intermediate- and high-risk NMIBC.

Study Overview

• Status: Active, not recruiting
• Conditions: NMIBC; Non Muscle Invasive Bladder Cancer; High Risk NMIBC
• Intervention / Treatment: Drug: ZH9

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Bakersfield, California, United States, 93301
      • Michael G. Oefelein Clinical Trials
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Health-Duke Cancer Center
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center, LLC
  • Texas
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Histologically documented recurrence of NMIBC
• BCG unresponsive (BCG naïve patients may be enrolled if they have received at least 1 line of adequate intravesical standard of care (SOC) treatment and are either not candidates for BCG or do not have access to BCG (e.g., BCG shortage))
• Eastern Cooperative Oncology Group Performance Status 0-1
• Adequate organ and marrow function
• Highly effective contraception if risk of conception exists.
• A female participant is eligible if not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) or is a WOCBP that uses highly effective contraception.

Exclusion Criteria:

• Received treatment with any local or systemic antineoplastic therapy within 3 weeks or 5× the plasma half-life prior to first dose of ZH9
• Major surgery or radiation within the 3 weeks prior to Screening (TURBT is not considered major surgery)
• Concurrent urinary tract infection or history of clinically significant polyuria
• Symptoms consistent with typhoid
• Evidence of infection within 2 weeks of the first dose of ZH9
• Significant 12-lead electrocardiogram abnormalities
• History of malignancy within the previous 12 months
• History of allogeneic tissue/solid organ transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1 - ZH9; Part 1 will evaluate SAD of ZH9 administered as an IVI in patients with recurrent NMIBC. A standard 3+3 escalation design will be employed with the dose levels	Drug: ZH9; ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.
Experimental: Dose Level 2 - ZH9; Part 1 will evaluate SAD of ZH9 administered as an IVI in patients with recurrent NMIBC. A standard 3+3 escalation design will be employed with the dose levels	Drug: ZH9; ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.
Experimental: Dose Level 3 - ZH9; Part 1 will evaluate SAD of ZH9 administered as an IVI in patients with recurrent NMIBC. A standard 3+3 escalation design will be employed with the dose levels	Drug: ZH9; ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.
Experimental: Dose Level 4 - ZH9; Part 1 will evaluate SAD of ZH9 administered as an IVI in patients with recurrent NMIBC. A standard 3+3 escalation design will be employed with the dose levels	Drug: ZH9; ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicities	Toxicity will be evaluated according to the NCI CTCAE Version 5.0	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete pathologic response	Rate of complete pathologic response at determined timepoints by cystoscopy, urine cytology, and if needed for pathological confirmation, biopsy	3, 6, and 12 months
Rate of recurrence-free survival and duration or response	Rate of recurrence-free survival and duration of response as determined by cystoscopy and urine cytology	3, 6, and 12 months
Rate of CR	Rate of CR as determined by biopsy in patients with CIS at baseline	6 and 12 months
Proportion of patients with cystectomy-free survival	Proportion of patients with cystectomy-free survival as determined by cystoscopy and urine cytology	6 and 12 months
Rate of progression-free survival	Rate of progression-free survival, including disease progression and all-cause death	12 months
Overall response rate and recurrence-free rate	Overall response rate and recurrence-free rate in the bladder following IVI	6 and 12 months
Change from baseline in systemic and local inflammatory markers in the bladder	Change from baseline in systemic and local inflammatory markers in the bladder as defined by clinical laboratory safety assessments (serum chemistry, hematology, urinalysis)	12 months

Collaborators and Investigators

• Sponsor: Prokarium Ltd
• Investigators: Study Director: Josefin-Beate Holz, MD, Prokarium Ltd

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2024
• Primary Completion (Estimated): August 30, 2025
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: December 12, 2023
• First Submitted That Met QC Criteria: December 12, 2023
• First Posted (Actual): December 26, 2023

Study Record Updates

• Last Update Posted (Actual): August 19, 2025
• Last Update Submitted That Met QC Criteria: August 16, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Urologic Neoplasms; Carcinoma; Urinary Bladder Diseases; Non-Muscle Invasive Bladder Neoplasms; Urinary Bladder Neoplasms
• Other Study ID Numbers: PRK-23101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No