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

Study Overview
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Brief Summary
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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.

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

Conditions
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NMIBC, High Risk NMIBC, Non Muscle Invasive Bladder Cancer

Intervention / Treatment
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* Drug: ZH9


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: In Part 1, the safety, tolerability, and pharmacology of ZH9 administered as an IVI will be evaluated in a single ascending dose cohort in patients with NMIBC. Part 1 may examine up to 4 dose levels. In Part 2, the safety, tolerability, and pharmacology of ZH9 oral prime followed by ZH9 IVI will be evaluated in 2 cohorts in patients with NMIBC at the doses and schedule established in Part 1. In Part 3, the safety, pharmacology, and clinical efficacy of ZH9 (oral prime and IVI) will be further evaluated in 2 expansion cohorts of patients with recurrent intermediate- and high-risk NMIBC.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 - ZH9<br>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<br>* ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.<br>|
| Experimental: Dose Level 2 - ZH9<br>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<br>* ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.<br>|
| Experimental: Dose Level 3 - ZH9<br>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<br>* ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.<br>|
| Experimental: Dose Level 4 - ZH9<br>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<br>* ZH9 is a live attenuated S. enterica serovar Typhi ZH9 [Ty2 ΔaroC ΔssaV]), a differentiated novel microbial immunotherapy.<br>|

What is the study measuring?
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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 |