Dose Expansion, Safety and Efficacy Study of Intravesical Instillation of TARA-002 in Adults With High-grade Non-muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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TARA-002-101-Ph1b/2 is an open-label Phase 1b/2 dose expansion study to investigate the safety and anti-tumor activity of intravesical treatment of high-grade CIS NMIBC (± Ta/T1) with intravesical instillation of TARA-002 in adults 18 years of age or older. The Phase 1b/2 study (TARA-002-101-Ph1b/2) will be initiated after the RP2D has been established in the Phase 1a dose finding study (TARA-002-101-Ph1a). This Phase 1b/2 (TARA-002-101-Ph1b/2) dose expansion study includes participants with CIS NMIBC (± Ta/T1) with active disease (defined as disease present at last tumor evaluation prior to signing ICF). Participants will be enrolled into one of 2 cohorts: Cohort A: Participants with CIS (± Ta/T1) who are unable to obtain intravesical BCG, or Participants with CIS (± Ta/T1) who have not received intravesical BCG for 24 months prior to CIS diagnosis Cohort B: Participants with CIS (± Ta/T1) who are BCG unresponsive after completion of adequate BCG therapy (minimum 5/6 doses induction and 2/3 doses maintenance or 2/6 doses reinduction)

Official Title
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A Phase 1b/2, Dose Expansion, Open-label Study to Evaluate Safety and Anti-tumor Activity, of Intravesical Instillation of TARA-002 in Adults With High-grade Non-muscle Invasive Bladder Cancer

Conditions
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Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Biological: TARA-002


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years of age or older at the time of signing the informed consent Subjects who have voluntarily given written informed consent after the nature of the study has been explained according to applicable requirements prior to study entry Central histologic confirmation of high-grade non-muscle invasive CIS (± Ta/T1) with active disease Subjects who are unable to obtain intravesical BCG, have not received intravesical BCG for 24 months prior to CIS diagnosis, or have persistent or recurrent CIS (± Ta/T1) within 12 months of completion of adequate BCG Exclusion Criteria: Penicillin allergy (subjects with a questionable history of allergy to penicillin will undergo penicillin blood allergy testing via central laboratory Predominant (defined as > 50%) adenocarcinoma, squamous cell carcinoma, or histological variants including plasmacytoid, sarcomatoid, or squamous components according to central review Concomitant prostatic or upper tract urothelial involvement per Investigator's assessment Nodal and metastatic disease are excluded if they existed at any time (whether present or in the past) Any history of ≥ T2 bladder cancer that existed at any point in time in the subject's history For more information on eligibility criteria, please contact the Sponsor

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: Cohort A: All participants will receive 6 weekly instillations of TARA-002 at the established recommended Phase 2 dose (RP2D). Participants who are eligible for reinduction will receive 6 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. Cohort B: All participants will receive 6 weekly instillations of TARA-002 at the established RP2D. Participants who are eligible for reinduction will receive 6 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. Participants confirmed to have a complete response will receive 3 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. All eligible participants will receive 3 weekly doses of TARA-002 instillation as part of the Third Treatment Period (maintenance) at Months 6, 9, 12, 15, and 18.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TARA-002<br>TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. | Biological: TARA-002<br>* Cohort A: All subjects will receive 6 weekly instillations of TARA-002 at the established recommended Phase 2 dose (RP2D). Subjects who are eligible for reinduction will receive 6 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. Cohort B: All subjects will receive 6 weekly instillations of TARA-002 at the established RP2D. Subjects who are eligible for reinduction will receive 6 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. Subjects confirmed to have a complete response will receive 3 additional weekly doses of TARA-002 instillation as part of the Second Treatment Period. All eligible subjects will receive 3 weekly doses of TARA-002 instillation as part of the Third Treatment Period (maintenance) at Months 6, 9, 12, 15, and 18.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Incidence of high-grade Complete Response at any time after treatment with TARA-002 |  | Month 3 to Month 6 | 
| Cohort A: Incidence of high-grade Complete Response at any time by subgroup (BCG naive and BCG exposed > 24 months) after treatment with TARA-002 |  | Month 3 to Month 6 | 
| Cohort B: Incidence of high-grade Complete Response at any time after treatment with TARA-002 |  | Month 3 to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Incidence and severity of AEs, TEAEs, SAEs and TESAEs after treatment with TARA-002 | AE = adverse event; TEAE = treatment emergent adverse event; SAE = serious adverse event; TESAE = treatment emergent serious adverse event | Day 1 to Month 6 | 
| Cohort A: Change from baseline in inflammatory urine cytokines levels (including IL-6, IL-8, IFN-γ, and TNF-α) after treatment with TARA-002 |  | Day 1 to Month 6 | 
| Cohort A: Quality of Life based on the EORTC questionnaire QLQ-NMIBC24 | EORTC = European Organization for Research and Treatment of Cancer; QLQ-NMIBC24 = Questionnaire for Patients with NMIBC | Day 1 to Month 6 | 
| Cohort A: Quality of Life based on the EORTC questionnaire QLQ-C30 | EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Questionnaire for Patients with Cancer | Day 1 to Month 6 | 
| Cohort B: Duration of high-grade Complete Response after treatment with TARA-002 |  | Month 3 to Month 24 | 
| Cohort B: High-grade Complete Response rate at Months 3, 6, 9, 12, 15, 18, 21, and 24 after treatment with TARA-002 |  | Month 3 to Month 24 | 
| Cohort B: Duration of Complete Response (all recurrent bladder cancer, including low grade Ta) after treatment with TARA-002 |  | Month 3 to Month 24 | 
| Cohort B: Complete Response rate (all recurrent bladder cancer, including low grade Ta) at Months 3, 6, 9, 12, 15, 18, 21, and 24 after treatment with TARA-002 |  | Month 3 to Month 24 | 
| Cohort B: Progression free survival after treatment with TARA-002 |  | 24 months | 
| Cohort B: Disease-specific progression free survival after treatment with TARA-002 |  | 24 months | 
| Cohort B: Overall survival after treatment with TARA-002 |  | 24 months | 
| Cohort B: Disease specific survival after treatment with TARA-002 |  | 24 months | 
| Cohort B: Time to cystectomy after treatment with TARA-002 |  | 24 months | 
| Cohort B: Time to recurrence delayed cystectomy after treatment with TARA-002 |  | 24 months | 
| Cohort B: Time to progression after treatment with TARA-002 |  | 24 months | 
| Cohort B: Time to disease worsening after treatment with TARA-002 |  | 24 months | 
| Cohort B: Incidence and severity of AEs, TEAEs, SAEs and TESAEs after treatment with TARA-002 |  | Day 1 to Month 24 | 
| Cohort B: Change from baseline in inflammatory urine cytokines levels (including IL-6, IL-8, IFN-γ, and TNF-α) after treatment with TARA-002 |  | Day 1 to Month 24 | 
| Cohort B: Quality of Life based on the EORTC questionnaire QLQ-NMIBC24 | EORTC = European Organization for Research and Treatment of Cancer; QLQ-NMIBC24 = Questionnaire for Patients with NMIBC | Day 1 to Month 24 | 
| Cohort B: Quality of Life based on the EORTC questionnaire QLQ-C30 | EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Questionnaire for Patients with Cancer | Day 1 to Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-muscle invasive bladder Cancer, bladder cancer, high grade Ta, high grade NMIBC, carcinoma in situ