ZH9 for Bladder Cancer

(PARADIGM-1 Trial)

Recruiting at 4 trial locations

Overseen By Melinda Snyder

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Prokarium Ltd

Must not be taking: Antineoplastics

Disqualifiers: Urinary tract infection, Polyuria, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop any local or systemic cancer treatments at least 3 weeks before starting the study drug. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment ZH9 for bladder cancer?

Research shows that similar treatments using live, weakened strains of Salmonella have been effective in slowing tumor growth and boosting the body's immune response against cancer in animal models. This suggests that ZH9 might also help in treating bladder cancer by enhancing the immune system's ability to fight tumors. ^{1 2 3 4 5}

Is the treatment ZH9 generally safe for humans?

Research on similar Salmonella strains used in cancer therapy shows they can be safe, with no obvious toxic effects observed in animal studies. However, safety in humans would need to be confirmed through clinical trials. ^{1 4 6 7 8}

How is the treatment ZH9 different from other bladder cancer treatments?

ZH9 is unique because it uses a live, weakened strain of Salmonella bacteria to stimulate the body's immune system to attack cancer cells, which is different from traditional treatments like chemotherapy or radiation that directly target cancer cells. ^{1 4 9 10 11}

Research Team

Josefin-Beate Holz, MD

Principal Investigator

Prokarium Ltd

Eligibility Criteria

This trial is for patients with recurrent non-muscle invasive bladder cancer (NMIBC) who are suitable for intravesical therapy. Specific details about inclusion and exclusion criteria were not provided, but typically participants must meet certain health standards and may be excluded based on factors like other medical conditions or treatments that could interfere with the study.

Inclusion Criteria

I am fully active or can carry out light work.

My bladder cancer has come back and was confirmed by a biopsy.

I have bladder cancer and either can't use BCG treatment or it didn't work for me.

Exclusion Criteria

I haven't had cancer treatment within the last 3 weeks or 5 times the half-life before starting ZH9.

I have not had an infection in the last 2 weeks.

Significant 12-lead electrocardiogram abnormalities

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1: Single Ascending Dose (SAD)

Evaluation of safety, tolerability, and pharmacology of ZH9 IVI in a single ascending dose patient cohort using a 3+3 escalation design

4 weeks

Part 2: Oral Prime and IVI

Evaluation of safety, tolerability, and pharmacology of ZH9 oral prime followed by ZH9 IVI in 2 patient cohorts

8 weeks

Part 3: Expansion Cohorts

Further evaluation of safety, pharmacology, and clinical efficacy of ZH9 in 2 expansion cohorts of patients with recurrent intermediate- and high-risk NMIBC

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• ZH9

Trial Overview The study tests ZH9, a new treatment administered first through IVI (intravenous infusion) then orally. It's divided into three parts: assessing safety and dosage in Part 1, evaluating combined oral and IVI administration in Part 2, and further examining safety, dosing effects, and how well it works in Part 3.

Participant Groups

Group I: Dose Level 4 - ZH9 Experimental Treatment 1 Intervention

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

Group II: Dose Level 3 - ZH9 Experimental Treatment 1 Intervention

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

Group III: Dose Level 2 - ZH9 Experimental Treatment 1 Intervention

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

Group IV: Dose Level 1 - ZH9 Experimental Treatment 1 Intervention

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

ZH9 is already approved in United States for the following indications:

Approved in United States as ZH9 for:

• None - Currently in Phase 1/1b clinical trial for Non-Muscle Invasive Bladder Cancer

Who Is Running the Clinical Trial?

Prokarium Ltd

Lead Sponsor

Trials

2

Recruited

70+

Findings from Research

The use of a live, attenuated Salmonella enterica serovar Typhi vaccine strain (CVD 915) as an immunotherapy in mice with tumors led to reduced tumor growth, prolonged survival, and fewer lung metastases, indicating its potential efficacy as a cancer treatment.

The treatment promoted a strong antitumor immune response characterized by increased levels of specific T cells and activated neutrophils, suggesting that this approach enhances the body's natural defenses against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel Salmonella Typhi-based immunotherapy promotes tumor killing via an antitumor Th1-type cellular immune response and neutrophil activation in a mouse model of breast cancer. Vendrell, A., Gravisaco, MJ., Pasetti, MF., et al.[2018]

The oral attenuated Salmonella typhimurium vaccine developed against the MG7-Ag mimotope of gastric cancer successfully induced a significant antibody response in mice, indicating its immunogenic potential.

In a tumor challenge model, the vaccine provided some protective effects, with 1 out of 5 immunized mice remaining tumor-free, while all control mice developed tumors, suggesting its efficacy in preventing gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral attenuated Salmonella typhimurium vaccine against MG7-Ag mimotope of gastric cancer. Meng, FP., Ding, J., Yu, ZC., et al.[2019]

The VNP20009 strain of Salmonella typhimurium can be safely administered to patients with metastatic cancer, with a maximum-tolerated dose identified at 3 x 10(8) cfu/m2, although higher doses led to significant toxicities.

While some tumor colonization was observed in a few patients, there were no objective tumor regressions, indicating that while the treatment is safe, its efficacy in reducing tumor size needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. Toso, JF., Gill, VJ., Hwu, P., et al.[2021]

The attenuated strain of Salmonella typhimurium, SL3235, demonstrated significant antitumor activity against a rapidly growing murine plasmacytoma, TEPC-183, leading to prolonged survival in tumor-bearing mice when administered intralesionally or intraperitoneally.

The effectiveness of the Salmonella treatment was influenced by the timing of administration and the dosage, with lower doses proving more effective than higher doses, suggesting a potential for this genetically engineered strain as a novel immunotherapeutic agent in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of a plasmacytoma with attenuated salmonella. Eisenstein, TK., Bushnell, B., Meissler, JJ., et al.[2019]

Attenuated Salmonella typhimurium can effectively target tumors in mice, accumulating in tumor tissue for up to 40 days and achieving a tumor-to-normal tissue ratio greater than 1000/1.

The bacteria not only delivered shRNA that inhibited GFP expression in tumor cells by 73.4%, but also significantly delayed tumor growth and improved survival rates in the treated mice, suggesting a promising new approach for solid tumor treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Attenuated Salmonella typhimurium carrying shRNA-expressing vectors elicit RNA interference in murine bladder tumors. Yang, N., Li, SH., Lü, YZ., et al.[2021]

The live, attenuated Salmonella enterica serovar Typhi (S. Typhi) vaccine strain CVD 915 significantly reduced tumor growth and improved survival in a mouse model of metastatic T-cell lymphoma, with some mice achieving complete tumor regression.

Treatment with S. Typhi induced a strong immune response, including early infiltration of neutrophils into tumors and the development of tumor-specific memory immune responses, suggesting its potential as an effective cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effects of Salmonella typhi in a mouse model of T-cell lymphoma. Vendrell, A., Gravisaco, MJ., Goin, JC., et al.[2013]

VNP20009, a genetically modified Salmonella strain, shows increased lethality in TNFR1 knockout mice, indicating its virulence, while its derivative ΔhtrA demonstrates better bio-safety and lower toxicity in the same model.

ΔhtrA exhibits a moderate antitumor effect in TNFR1 KO mice with melanoma, suggesting it may be a safer and effective option for bacterial-mediated tumor therapy in patients with compromised immune systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Attenuated Salmonella VNP20009 mutant (ΔhtrA) is a promising candidate for bacteria-mediated tumour therapy in hosts with TNFR1 deficiency. Xu, W., Zhou, T., Zhou, J., et al.[2018]

The genetically-modified Salmonella typhimurium A1-R strain effectively targets tumors in nude mice with human breast cancer, showing higher levels of bacteria in tumors compared to normal organs regardless of the administration route.

Among the three routes tested (oral, intravenous, and intra-tumoral), oral administration was found to be the safest with the least bacteria in normal tissues, while intravenous administration demonstrated the greatest antitumor efficacy, indicating a balance between safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice. Zhang, Y., Tome, Y., Suetsugu, A., et al.[2023]

In a study of 100 gall bladder cancer (GBC) patients, 22% tested positive for antibodies against Salmonella, indicating a higher prevalence of typhoid carriers among GBC patients compared to healthy controls (0%).

The Vi antibody was particularly prevalent in GBC patients (13%) and was associated with older males (≥50 years), suggesting a potential link between Salmonella infection and gall bladder cancer, especially in this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development. Shukla, R., Shukla, P., Behari, A., et al.[2021]

The attenuated Salmonella strain VNP20009 effectively inhibits tumor growth in a B16F10 melanoma model by promoting tumor cell apoptosis and necrosis, demonstrating its potential as a cancer treatment.

VNP20009 enhances the immune response by increasing the infiltration of CD8(+) T cells and CD11b(+) monocytes in tumor tissues, leading to higher levels of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which help to overcome the tumor's ability to evade the immune system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-tumor effect and impact on tumor immune microenvironment of tumor-targeted Salmonella VNP20009]. Han, YH., Lai, XH., Le, ZW., et al.[2018]

The attenuated mutant strain of Salmonella Typhimurium (STM) effectively targets and replicates within tumor cells, demonstrating its potential as an antitumor agent in both in vitro and in vivo models.

In a mammary adenocarcinoma mouse model, STM treatment not only reduced tumor growth but also increased the life expectancy of the mice, likely by stimulating a strong inflammatory response and enhancing immune cell recruitment to combat the tumor's immunosuppressive environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Attenuated mutant strain of Salmonella Typhimurium lacking the ZnuABC transporter contrasts tumor growth promoting anti-cancer immune response. Chirullo, B., Ammendola, S., Leonardi, L., et al.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A novel Salmonella Typhi-based immunotherapy promotes tumor killing via an antitumor Th1-type cellular immune response and neutrophil activation in a mouse model of breast cancer. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Oral attenuated Salmonella typhimurium vaccine against MG7-Ag mimotope of gastric cancer. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy of a plasmacytoma with attenuated salmonella. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Attenuated Salmonella typhimurium carrying shRNA-expressing vectors elicit RNA interference in murine bladder tumors. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Therapeutic effects of Salmonella typhi in a mouse model of T-cell lymphoma. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Attenuated Salmonella VNP20009 mutant (ΔhtrA) is a promising candidate for bacteria-mediated tumour therapy in hosts with TNFR1 deficiency. [2018]

8. Greece pubmed.ncbi.nlm.nih.gov

Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice. [2023]

9. Thailand pubmed.ncbi.nlm.nih.gov

Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development. [2021]

10. China pubmed.ncbi.nlm.nih.gov

[Anti-tumor effect and impact on tumor immune microenvironment of tumor-targeted Salmonella VNP20009]. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Attenuated mutant strain of Salmonella Typhimurium lacking the ZnuABC transporter contrasts tumor growth promoting anti-cancer immune response. [2018]