A Phase 1/2 Study of HS-410 in Patients With Non-Muscle Invasive Bladder Cancer After TURBT

Study Overview
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Brief Summary
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Phase I/II study: Phase 1 is an open-label, safety study, patients who previously received 3-6 instillations of weekly intravesical Bacillus Calmette-Guerin (BCG) induction therapy (as standard of care) followed by low dose intradermal (1*10^6 cells) HS-410 monotherapy. Phase 2, patients will be randomized to one of three blinded (physician-patient), placebo-controlled groups and receive either intradermal placebo or low dose (1*10^6 cells) or high dose (1*10^7 cells) vesigenurtacel-L in combination with induction and maintenance intravesical BCG. Patients who do not receive BCG will be enrolled into an open-label, non-randomized group receiving high dose (1*10^7 cells) intradermal HS-410 monotherapy.

Detailed Description
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This study is a two part study: Phase I and Phase II. The Phase 1 portion is an open-label, safety study. Patients will have previously received 3-6 instillations of weekly intravesical Bacillus Calmette-Guerin (BCG) induction therapy (as standard of care) followed by low dose intradermal (1*10^6 cells) HS-410 monotherapy. In Phase 2, patients will be assigned to treatment groups based on whether they will receive induction BCG in the typical post-TURBT window. If the investigator plans to administer BCG, patients will be randomized to one of three blinded (physician-patient), placebo-controlled groups and receive either intradermal placebo or low dose (1*10^6 cells) or high dose (1*10^7 cells) vesigenurtacel-L in combination with induction and maintenance intravesical BCG. If patients will not receive BCG, they will be enrolled into an open-label, non-randomized group and receive high dose (1*10^7 cells) intradermal HS-410 monotherapy.

Official Title
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Phase 1/2, Placebo-Controlled, Randomized Study to Evaluate the Safety, Immune Response & Clinical Activity of HS-410 in Patients With Non-Muscle Invasive Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT)

Conditions
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Bladder Cancer

Intervention / Treatment
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* Biological: HS-410
* Biological: Placebo
* Biological: BCG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non-muscle invasive bladder cancer [Ta, T1 or Tis (CIS)] that has been removed by transurethral resection Either: (i) high-risk disease, defined as T1 and/or high-grade and/or CIS or (ii) intermediate-risk disease, defined as Ta low-grade with at least 3 of the following 4 risk factors: multiple tumors, tumor size > 3cm, early recurrence (<1 year from previous staging procedure), or recurrence with a frequency of more than once in any 12 month period Not have received bacillus Calmette-Guérin (BCG) or have completed previous BCG treatment > 12 months prior to the baseline staging procedure. Phase 2 Arms 1-3: Suitable to receive a 6-week course of BCG in the adjuvant setting within 6 weeks following TURBT. Phase 2 Arm 4: Suitable for monotherapy vaccine administration post-TURBT. For Phase 1 only: Has previously received 3-6 weekly doses of BCG. Adequate laboratory parameters Exclusion Criteria: Human immunodeficiency virus (HIV) infection or immunodeficiency disorders, either primary or acquired Infections or intercurrent illness requiring active therapy Any condition requiring active steroid or other immunosuppressive therapy Active malignancies within the past 12 months except negligible risk of metastasis or death treated with expected curative outcome. Prostate pelvic radiation within the past 12 months Significant cardiac impairment Current alcohol or chemical abuse, or mental or psychiatric condition precluding protocol compliance Pregnant or nursing Allergy to soy, egg, or peanut products Receiving another investigational agent (30 day wash-out required prior to first dose) Neo-adjuvant therapy prior to baseline staging procedures for the current occurrence of non-muscle invasive bladder cancer Prior treatment with a cancer vaccine for this indication Prior vaccination with BCG for tuberculosis disease Prior splenectomy

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: HS-410 Low Dose<br>In the open label Phase 1 portion, HS-410 is given as 1*10^6 cells per dose for 12 weekly injections followed by 3 monthly injections. | Biological: HS-410<br>* Vaccine derived from irradiated cancer cells genetically engineered to continually secrete gp96<br>|
| Experimental: Phase II: HS-410 Low-Dose Plus BCG<br>In the Phase 2 portion, HS-410 is given as 1*10^6 cells per dose weekly for 6 weeks in combination with BCG, followed by 6 weeks of HS-410 alone, and then 3 courses of three once-weekly doses of HS-410 in combination with BCG. | Biological: HS-410<br>* Vaccine derived from irradiated cancer cells genetically engineered to continually secrete gp96<br>Biological: BCG<br>* Vaccine derived from a live bacterium<br>* Other names: Bacillus Calmette-Guerin;|
| Experimental: Phase II: High-Dose HS-410 Plus BCG<br>In the Phase 2 portion, HS-410 is given as 1*10^7 cells per dose weekly for 6 weeks in combination with BCG, followed by 6 weeks of HS-410 alone, and then 3 courses of three once-weekly doses of HS-410 in combination with BCG. | Biological: HS-410<br>* Vaccine derived from irradiated cancer cells genetically engineered to continually secrete gp96<br>Biological: BCG<br>* Vaccine derived from a live bacterium<br>* Other names: Bacillus Calmette-Guerin;|
| Placebo Comparator: Phase II: Placebo Plus BCG<br>In the Phase 2 portion, a placebo is given weekly for 6 weeks in combination with BCG, followed by 6 weeks of placebo alone, and then 3 courses of three once-weekly doses of placebo in combination with BCG. | Biological: Placebo<br>* Injection containing sterile solution but no cells<br>Biological: BCG<br>* Vaccine derived from a live bacterium<br>* Other names: Bacillus Calmette-Guerin;|
| Experimental: Phase II: High-Dose HS-410<br>In the Phase II portion, if patients will not receive BCG, HS-410 is given as 1*10^7 cells per dose weekly for 12 weeks, and then 3 courses of three once-weekly doses of HS-410. | Biological: HS-410<br>* Vaccine derived from irradiated cancer cells genetically engineered to continually secrete gp96<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Safety and Tolerability | To evaluate the safety and tolerability of vesigenurtacel-L | Up to 3 years. | 
| Phase 2: 1-year Disease-Free Survival | Arm 1, 2, 3: 1-year DFS in patients with NMIBC treated with BCG in combination with blinded study product (one of two doses of vesigenurtacel-L or placebo) Arm 4: 1-year DFS in patients with NMIBC treat1fv 9 with high dose vesigenurtacel-L monotherapy One-year disease-free survival will be defined as the proportion of patients who are free from recurrent disease, progressive disease, and alive one year after the date of randomization/treatment assignment | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Recurrence at 3, 6, 12, 18, and 24 Months | Evaluate the proportion of patients with recurrence at 3, 6, 12, 18, and 24 months | Up to 2 years | 
| Proportion of Patients With Progressive Disease at 3, 6, 12, 18, and 24 Months | Evaluate the proportion of patients with progressive disease at 3, 6, 12, 18, and 24 | Up to 2 years | 
| Disease-free Survival at 3, 6, 18, and 24 Months | Evaluate Disease Free Survival at 3, 6, 18 and 24 months | Up to 2 years | 
| Overall Disease-free Survival | Evaluate overall Disease Free Survival | Up to 3 years | 
| Overall Survival, Expressed as the Number of Participants Alive | Evaluate overall survival (OS) | Up to 3 years | 
| Proportion of Patients Undergoing Repeat Transurethral Resection of Bladder Tumor (TURBT) by 12 and 24 Months |  | Up to 2 years | 
| Proportion of Patients Undergoing Cystectomy by 12 and 24 Months | Evaluate the proportion of patients undergoing cystectomy by 12 and 24 months from randomization | Up to 2 years | 
| Immunologic Response of PBMCs Via Intracellular Cytokine Staining (ICS) by Flow Cytometry and/or Enzyme-linked Immunosorbent Spot (ELISPOT) on CD8+ Cells After HS-410 Vaccination as Compared to Baseline. | Evaluate the proportion of patients with immunologic response of peripheral blood mononuclear cells (PBMCs) via intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells following vesigenurtacel-L vaccination | Up to 2 years | 
| Immunologic Response of Peripheral Blood Mononuclear Cells (PBMCs) and Stimulation Analysis Via ICS in Baseline and Post-treatment Biopsies, if Clinically Indicated | Evaluate immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of interferon gamma (IFNγ) and granzyme B (gzB) | Up to 3 years | 
| Total PBMC Counts by Flow Cytometry | Evaluate total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, helper T-cells, cytotoxic T-cells, natural killer (NK) cells and T-reg) | Up to 3 years | 
| Tumor Antigen Expression | Evaluation of pre-treatment tumor tissue for antigen expression | At screening | 
| Tumor Infiltrating Lymphocytes (TILs) | Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for presence of TILs | Up to 3 years | 
| T Cell Receptor Sequencing of Peripheral Blood T Cells Before and During Treatment | Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for presence of TILs, T cell receptor sequencing of peripheral blood T cells before and during the course of treatment. | Up to 2 years | 
| Safety of the Combination of the HS-410 and BCG | Phase 2 only Evaluate the safety of the combination of vesigenurtacel-L and BCG | Up to 1 year | 
| Safety of the High Dose HS-410 Monotherapy | Phase 2 only Evaluate the safety of high dose vesigenurtacel-L monotherapy | Up to 3 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TURBT, Bladder, Cancer, GP96, Vaccine, Immunotherapy, Heat Biologics, BCG, Bacillus Calmette-Guerin, Bacillus Calmette-Guérin