Intravesical PPM Therapy for Bladder Cancer

Overseen By Lori Lerner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: VA Office of Research and Development

Must not be taking: Blood thinners

Disqualifiers: Upper urinary tract cancer, Metastasis, Heart failure, CNS disease, others

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

Compensation: Varies

Number of Visits: 8

Duration: 6 weeks

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new bladder cancer treatment called PPM, which uses tiny particles to deliver a chemotherapy drug directly to cancer cells. It targets patients whose bladder cancer has not spread into the muscle and who did not respond to a previous treatment. The goal is to find the right dose and check for side effects and effectiveness.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use other investigational agents or certain medications that affect blood clotting, like aspirin (except low-dose), Coumadin, or heparin. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug PLZ4-coated paclitaxel-loaded micelles (PPM) for bladder cancer?

Research shows that paclitaxel, when delivered using micelles (tiny particles that help carry drugs), can penetrate bladder tissues more effectively than traditional methods. This suggests that using PLZ4-coated paclitaxel-loaded micelles could improve drug delivery to bladder cancer cells, potentially making the treatment more effective. ^{1 2 3 4 5}

Is PLZ4-coated paclitaxel-loaded micelles (PPM) safe for humans?

Research on paclitaxel-loaded polymeric micelles (PPM) in combination with cisplatin for lung cancer showed significant antitumor activity and improved tolerability compared to standard paclitaxel formulations, suggesting a favorable safety profile. However, specific safety data for PLZ4-coated PPM in humans is not available, and further research is needed to confirm its safety in clinical trials. ^{1 3 5 6 7}

How is the drug PLZ4-coated paclitaxel-loaded micelles (PPM) unique for bladder cancer treatment?

PLZ4-coated paclitaxel-loaded micelles (PPM) are unique because they use a special coating to improve the delivery of paclitaxel directly into the bladder, enhancing drug uptake and effectiveness compared to traditional formulations. This approach helps the drug penetrate bladder tissues more effectively, potentially leading to better treatment outcomes for bladder cancer. ^{1 2 3 4 6}

Research Team

Chong-Xian Pan, MD PhD

Principal Investigator

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Eligibility Criteria

This trial is for adults with bladder cancer that hasn't spread into the muscle and didn't respond to BCG treatment. Participants need good lung function, can't have severe heart issues or other serious illnesses, must not be pregnant or nursing, and should agree to use birth control. They should also have a life expectancy of more than 24 months.

Inclusion Criteria

I cannot or will not undergo major bladder surgery as advised.

I cannot or will not undergo major bladder surgery as advised.

I am 18 years old or older.

Exclusion Criteria

Other illness that in the opinion of the investigator would exclude the patient from participating in this study

Psychiatric illness/social situations that would limit compliance with study requirements

I am not pregnant or nursing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

PPM is administered as intravesical instillation once weekly for six weeks to determine the recommended Phase II dose and assess toxicity and preliminary efficacy

6 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including urine cytology and cystoscopy

6 weeks

2 visits (in-person)

Treatment Details

Interventions

• PLZ4-coated paclitaxel-loaded micelles (PPM)

Trial Overview The trial tests PLZ4-coated paclitaxel-loaded micelles (PPM), designed to target bladder cancer cells specifically. PPM will be placed directly into the bladder in patients who haven’t responded well to prior treatments. The study aims to find the right dose for future trials and check its safety and early effectiveness.

Participant Groups

Group I: Phase I dose-escalation and expansion cohort Experimental Treatment 1 Intervention

There are three doses at the dose escalation stage: Dose level I: paclitaxel (PTX) 25 mg or 0.5 mg/ml; Dose Level II: PTX 50 mg or 1.0 mg/ml; Dose Level III: PTX 75 mg or 1.5 mg/ml. At the expansion cohort, up to 12 patients will be recruited and treated with PPM at the PTX dose of 50 mg or 1.0 mg/ml to determine the efficacy.

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

University of California, Davis

Collaborator

Trials

958

Recruited

4,816,000+

Findings from Research

Diblock copolymer micelles (MePEG-PDLLA and MePEG-PCL) significantly enhance the delivery of anticancer drugs paclitaxel (PTX) and docetaxel (DTX) into bladder tissues compared to traditional commercial formulations, leading to higher tissue levels and better drug exposure.

This study utilized freshly excised pig bladder sections and demonstrated that these micellar formulations improve drug penetration, suggesting a more effective treatment option for superficial bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The uptake of paclitaxel and docetaxel into ex vivo porcine bladder tissue from polymeric micelle formulations. Tsallas, A., Jackson, J., Burt, H.[2018]

Paclitaxel-loaded gelatin nanoparticles were developed for treating superficial bladder cancer, showing a rapid drug release profile with approximately 90% of the drug released within 2 hours, making them a promising option for intravesical therapy.

In a study involving dogs, these nanoparticles achieved drug concentrations in bladder tissues that were 2.6 times higher than those obtained with the conventional Cremophor formulation, indicating improved delivery and potential efficacy against bladder tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy. Lu, Z., Yeh, TK., Tsai, M., et al.[2018]

Intravesical administration of paclitaxel formulated with the PMB30W polymer (PTX-30W) showed no cytotoxicity in cell cultures, unlike the conventional solubilizer Cremophor, which was toxic to bladder cancer cells.

In an orthotopic bladder cancer model, PTX-30W significantly reduced tumor weight and achieved higher paclitaxel concentrations in tumors compared to the Cremophor formulation, suggesting better efficacy and penetration for treating non-muscle invasive bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model. Tamura, K., Kikuchi, E., Konno, T., et al.[2018]

The study developed mucoadhesive nanoparticles using hydrophobically derivatized hyperbranched polyglycerols (dHPGs) to deliver paclitaxel, showing that the HPG-C10-PEG formulation released up to 80% of the drug and remained stable in acidic urine, which is important for bladder cancer treatment.

In vivo tests demonstrated that the paclitaxel/HPG-C10-PEG formulation significantly reduced tumor growth in mice compared to standard Taxol, indicating its potential as a more effective and well-tolerated treatment for non-muscle-invasive bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel incorporated in hydrophobically derivatized hyperbranched polyglycerols for intravesical bladder cancer therapy. Mugabe, C., Hadaschik, BA., Kainthan, RK., et al.[2018]

The study developed a novel bladder cancer-targeting nanomicelle (DC-PNM) that effectively delivers the chemotherapy drug paclitaxel (PTX), showing a significant improvement in survival rates in mice with bladder cancer xenografts, increasing median survival from 55 days to 69.5 days.

DC-PNM demonstrated specific targeting to bladder cancer cells while showing minimal interaction with lung cancer cells, indicating its potential for reducing toxicity and enhancing the efficacy of chemotherapy in treating bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer. Pan, A., Zhang, H., Li, Y., et al.[2020]

Intravesical docetaxel (DTX) formulations, particularly those loaded in hyperbranched polyglycerols (HPGs), were well tolerated in a mouse model of bladder cancer, showing no significant local or systemic toxicities.

The HPG-loaded DTX formulation (0.5 mg/mL) was significantly more effective in reducing tumor growth compared to the commercial formulation (Taxotere), indicating a potential for improved efficacy in bladder cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer. Mugabe, C., Matsui, Y., So, AI., et al.[2018]

In a phase IIB study involving 276 patients with advanced non-small-cell lung cancer, paclitaxel-loaded polymeric micelles (PPM) combined with cisplatin demonstrated a response rate of 43.6%, which was noninferior to the 41.9% response rate of standard paclitaxel plus cisplatin.

While PPM plus cisplatin had a higher incidence of grade 3 neutropenia, the overall safety profile was comparable to that of the standard treatment, indicating that PPM is a well-tolerated alternative for chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-loaded polymeric micelle (230 mg/m(2)) and cisplatin (60 mg/m(2)) vs. paclitaxel (175 mg/m(2)) and cisplatin (60 mg/m(2)) in advanced non-small-cell lung cancer: a multicenter randomized phase IIB trial. Lee, SY., Park, HS., Lee, KY., et al.[2015]

References

1. Germany pubmed.ncbi.nlm.nih.gov

The uptake of paclitaxel and docetaxel into ex vivo porcine bladder tissue from polymeric micelle formulations. [2018]

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

Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Paclitaxel incorporated in hydrophobically derivatized hyperbranched polyglycerols for intravesical bladder cancer therapy. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer. [2020]

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

In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer. [2018]

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

Paclitaxel-loaded polymeric micelle (230 mg/m(2)) and cisplatin (60 mg/m(2)) vs. paclitaxel (175 mg/m(2)) and cisplatin (60 mg/m(2)) in advanced non-small-cell lung cancer: a multicenter randomized phase IIB trial. [2015]