ZH9 for Bladder Cancer
(PARADIGM-1 Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Prokarium Ltd
Must not be taking: Antineoplastics
Disqualifiers: Urinary tract infection, Polyuria, Malignancy, others
No Placebo Group
Approved in 1 Jurisdiction
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.12345
Is the treatment ZH9 generally safe for humans?
How is the treatment ZH9 different from other bladder cancer treatments?
Research Team
JH
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 18 years old or older.
I am fully active or can carry out light work.
My bladder cancer has come back and was confirmed by a biopsy.
See 4 more
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
See 5 more
Trial 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 (Other)
Trial OverviewThe 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
4Treatment groups
Experimental Treatment
Group I: Dose Level 4 - ZH9Experimental Treatment1 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 - ZH9Experimental Treatment1 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 - ZH9Experimental Treatment1 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 - ZH9Experimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Michael G. Oefelein Clinical TrialsBakersfield, CA
Duke Health-Duke Cancer CenterDurham, NC
Chesapeake UrologyHanover, MD
Urology San Antonio Medical CenterSan Antonio, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Prokarium Ltd
Lead Sponsor
Trials
2
Patients Recruited
70+
References
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]We investigated the use of a live, attenuated Salmonella enterica serovar Typhi vaccine strain as an antitumor immunotherapy. Mice bearing a subcutaneous tumor (LM3 mammary adenocarcinoma) were immunized on three occasions with S. Typhi strain CVD 915 by injection into the tumor, the peritumoral tissue and the draining lymph node areas; this procedure was termed Salmonella multiple treatment (Salmonella MT). Tumor-bearing mice subjected to the Salmonella MT exhibited reduced tumor growth, prolonged survival and reduced incidence of lung metastases, compared to untreated mice. We examined the mechanisms mediating this effect and found that Salmonella MT promoted an antitumor Th1-type response characterized by increased frequencies of IFN-γ-secreting CD4(+) T and CD8(+) T cells with reduction of regulatory T cells in tumor draining lymph nodes. The main cells infiltrating bacteria-treated tumors were activated neutrophils, which can exert an antitumor effect through the secretion of TNF-α. These results demonstrate for the first time the efficacy of an attenuated S. Typhi vaccine strain as a cancer immunotherapeutic agent. By potentiating the host antitumor immune response, this approach could be a powerful adjunct tool for cancer therapy.
Oral attenuated Salmonella typhimurium vaccine against MG7-Ag mimotope of gastric cancer. [2019]To develop an oral attenuated Salmonella typhimurium vaccine against gastric cancer and to evaluate its efficacy in mice.
Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. [2021]A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer.
Immunotherapy of a plasmacytoma with attenuated salmonella. [2019]An attenuated strain of Salmonella typhimurium, SL3235, developed as a prototypic typhoid vaccine, is shown to retard growth of a murine plasmacytoma, TEPC-183, and to prolong survival of tumor-bearing mice. Live salmonella, but not acetone-killed organisms, had antitumor activity. The immunotherapeutic effect was demonstrable when the tumor was injected intralesionally or intraperitoneally. Increased survival, longer mean time to death, and retardation of tumor growth were found when the salmonella were given intralesionally as late as the sixth day post-tumor injection. Timing of salmonella inoculation, as well as the salmonella dose, had an effect on treatment efficacy. Injection of salmonella intraperitoneally exerted a strong antitumor effect when given as late as the third day post-tumor inoculation. The highest dose (2 x 10(6)) of salmonella was less effective than doses 10- or 100-fold lower. TEPC-183 plasmacytoma is rapidly growing and highly immunosuppressive, so the ability of the salmonella to exert therapeutic activity against it is a measure of the potency of the vaccine. These observations are of interest, as they show that a genetically engineered, avirulent strain of Salmonella has immunotherapeutic properties similar to those of BCG and other biological response modifiers, and might have clinical potential as an antitumor agent.
Attenuated Salmonella typhimurium carrying shRNA-expressing vectors elicit RNA interference in murine bladder tumors. [2021]To examine whether attenuated Salmonella typhimurium (S typhimurium) could be used as an anti-cancer agent or a tumor-targeting vehicle for delivering shRNA-expressing pDNA into cancer cells in a mouse tumor model.
Therapeutic effects of Salmonella typhi in a mouse model of T-cell lymphoma. [2013]In this study, we assessed the effectiveness of a live, attenuated Salmonella enterica serovar Typhi (S. Typhi) vaccine strain as a cancer immunotherapy in a mouse model of metastatic T-cell lymphoma. EL4 tumor-bearing C57BL/6J mice immunized with S. Typhi strain CVD 915, by injection into the tumor and the draining lymph node areas, displayed a significant decrease in tumor growth, a reduction in the mitotic index (MI) of tumors, a delayed development of palpable lymph node metastases and most importantly improved survival, compared to untreated mice. Besides, complete tumor regression was achieved in a small number of bacteria-treated mice. A successful therapeutic response associated with a significant reduction of tumor mass was evident as early as 5 days after treatment. The administration of Salmonella to tumor-bearing mice promoted early cellular infiltration (mainly neutrophils) within the tumor, and was accompanied by a decreased intratumoral interleukin 10 production as well as by leukocyte expansion in tumor draining lymph nodes. A tumor-specific memory immune response was induced in most of cured animals, as evidenced by the lack of tumor growth after a rechallenge with the same tumor. EL4 cells cultured with live Salmonella failed to proliferate and underwent apoptosis in a dose-dependent, time-dependent, and contact-dependent manner. To our knowledge, these results demonstrate for the first time the efficacy of a S. Typhi vaccine strain as an oncolytic and immunotherapeutic agent against a highly malignant tumor and support the use of S. Typhi-based vaccine strains in cancer therapy.
Attenuated Salmonella VNP20009 mutant (ΔhtrA) is a promising candidate for bacteria-mediated tumour therapy in hosts with TNFR1 deficiency. [2018]VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anticancer effect wildly used in tumour therapy on animal models. For its clinical application, an accurate bio-safety assessment on sensitive models is necessary. In this study, we use TNFR1 KO mice as a susceptive model to assess the virulence of bacterial VNP20009 and its derivative ΔhtrA. By intraperitoneal administration of Salmonella, the increased lethality was observed in TNFR1 KO mice infected with VNP20009, but not with ΔhtrA. We performed a systemically comparative analysis of their toxicity, and ΔhtrA shows a better bio-safety for TNFR1 KO mice. Since the macrophages with TNFR1 deficiency exhibit a reduced ability of bacteria clearance, ΔhtrA with lower survival ability in normal macrophages restores its viability in TNFR1 KO macrophages. Thus, ΔhtrA was further tested for its antitumour effect in TNFR1 KO mice bearing a B16F10 melanoma model. It displays a moderate antitumour effect, suggesting ΔhtrA instead of VNP20009 might be a promising candidate for bacteria-mediated tumour therapy specific to those with low immunity.
Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice. [2023]We have developed the genetically-modified Salmonella typhimurium A1-R strain that selectively targets tumors. S. typhimurium A1-R is auxotrophic for Leu and Arg, which precludes it from growing continuously in normal tissues but allows high tumor virulence. We report here the efficacy and safety of three different routes of S. typhimurium A1-R administration: oral (p.o.), intravenous (i.v.), and intra-tumoral (i.t.) in nude mice with orthotopic human breast cancer. Nude mice with MDA-MB-435 human breast cancer, expressing red fluorescent protein (RFP), were administered S. typhimurium A1-R by one of the three routes: [p.o.: 2×10(8) colony forming units (CFU)/200 μl; i.v.: 2.5×10(7) CFU/100 μl; i.t.: 2.5×10(7) CFU/50 μl] twice a week. Tumor growth was monitored by fluorescence imaging and caliper measurement in two dimensions. S. typhimurium A1-R targeted tumors at much higher levels than normal organs after all three routes of administration. The fewest bacteria were detected in normal organs after p.o. administration, which suggests that p.o. administration has the highest safety. The i.v. route had the greatest antitumor efficacy. There were no obvious toxic effects on the host with any of the routes of administration. The results of this study suggest that p.o. administration was the most safe to the host and the i.v. route was most effective for tumor targeting with S. typhimurium A1-R.
Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development. [2021]Typhoid (Salmonella typhi and paratyphi) carriers and gall bladder cancer (GBC) are endemic in northern India. Results of previous studies about association of typhoid carriers with GBC are inconsistent. We studied antibodies against Salmonella typhi and paratyphi in serum samples of patients with GBC.
[Anti-tumor effect and impact on tumor immune microenvironment of tumor-targeted Salmonella VNP20009]. [2018]Salmonella is a gram-negative bacterium that has an ability of tumor-targeting growth and proliferation. Attenuated Salmonella VNP20009 is a virulence genes-knockout bacterial strain based on Salmonella typhimurium, and it has an advantage of good therapeutic effect and low toxicity. One of the mechanisms of anti-tumor effect of VNP20009 is the induction of inflammatory reaction within tumor tissues. We used B16F10 melanoma model to investigate the mechanism of the anti-tumor effect of VNP20009. VNP20009 treatment effectively inhibited tumor growth and promoted the apoptosis and necrosis of tumor cells. VNP20009 increased the accumulation or infiltration of CD8(+) T cells and CD11b(+) monocytes within tumor tissue by raising the level of immune response and thus, induce the production of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) to kill tumor cells by breaking the immuno-evasion barrier in the tumor microenvironment.
Attenuated mutant strain of Salmonella Typhimurium lacking the ZnuABC transporter contrasts tumor growth promoting anti-cancer immune response. [2018]Salmonella Typhimurium has been shown to be highly effective as antitumor agent. The aim of this study was to investigate the tumor targeting efficacy and the mechanism of action of a specific attenuated mutant strain of Salmonella Typhimurium (STM) devoid of the whole operon coding for the high-affinity zinc transporter ZnuABC, which is required for bacterial growth in environments poor in zinc and for conferring full virulence to different Gram-negative pathogens.We showed that STM is able to penetrate and replicate into tumor cells in in vitro and in vivo models. The subcutaneous administration of STM in mammary adenocarcinoma mouse model led to both reduction of tumor growth and increase in life expectancy of STM treated mice. Moreover, investigating the potential mechanism behind the favorable clinical outcomes, we provide evidence that STM stimulates a potent inflammatory response and a specific immune pattern, recruiting a large number of innate and adaptive immune cells capable to contrast the immunosuppressive environment generated by tumors.