Gemcitabine vs Water Irrigation for Urothelial Cancer

Overseen By Yair Lotan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Texas Southwestern Medical Center

Disqualifiers: Bladder cancer, Small bladder capacity, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1-3 hours

132 Participants Needed

Trial Summary

What is the purpose of this trial?

There is a high rate of intravesical (bladder) recurrence following extirpative surgery for upper tract urothelial carcinoma. There is no single established standard of care for prevention of intravesical recurrence; however, one protocol in common use involves the use of intravesical gemcitabine instilled into the bladder during surgery and prior to entry into the bladder. There are barriers to the use of gemcitabine, especially at lower volume centers. Some evidence suggests that intravesical irrigation with sterile water has equivalent efficacy to intravesical chemotherapy in prevention of recurrent bladder cancer following transurethral resection of bladder tumors (TURBT). This study is intended to compare recurrence rates using intravesical gemcitabine (as a pseudo-standard of care) and continuous bladder irrigation with sterile water.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Gemcitabine for treating urothelial cancer?

Research shows that Gemcitabine, when used directly in the bladder, can be effective for treating non-muscle invasive bladder cancer, especially after other treatments have failed. It has been found to prevent cancer cell growth in the bladder and is generally well-tolerated by patients. ^{1 2 3 4 5}

Is gemcitabine safe for humans?

Gemcitabine is generally considered to have low toxicities, making it a valid option for patients, including the elderly with other health issues. However, rare cases of lung-related side effects have been reported, ranging from mild breathing issues to severe lung inflammation. ^{1 6 7 8 9}

How is the drug Gemcitabine unique in treating urothelial cancer?

Gemcitabine is unique because it can be administered directly into the bladder (intravesical instillation) to target urothelial cancer, which helps reduce recurrence or progression with fewer systemic side effects compared to traditional chemotherapy that circulates throughout the body. ^{3 4 5 7 8}

Eligibility Criteria

This trial is for adults aged 18-90 with biopsy-proven upper tract urothelial carcinoma (UTUC) who are planning surgery to remove the cancer. Participants must be able to have children and agree to use birth control during the study. They should expect to live more than a year and not have had bladder cancer or bilateral UTUC within the last three years.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent.

I agree to use birth control or abstain from sex during and for 90 days after the study.

I have a confirmed UTUC diagnosis and am scheduled for surgery to remove it.

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or other agents used in study.

3.2.4 Suspicion for small bladder capacity (< 100 mL) based on treating urologist's clinical judgment.

I have cancer in both upper urinary tracts or had it in one with no signs for over 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either intravesical gemcitabine or continuous bladder irrigation with sterile water during surgery

1-3 hours

1 visit (in-person, during surgery)

Follow-up

Participants are monitored for intravesical recurrence and treatment-related adverse events

2 years

Regular follow-up visits as per study protocol

Treatment Details

Interventions

• Gemcitabine
• Sterile Water Irrigation

Trial Overview The study compares two methods of preventing bladder cancer recurrence after UTUC surgery: one uses gemcitabine, a chemotherapy drug, in the bladder; the other uses sterile water irrigation. The goal is to see which method is better at stopping cancer from coming back.

Participant Groups

Group I: sterile water irrigation Experimental Treatment 1 Intervention

intravesical continuous bladder irrigation with sterile water for 1 - 3 hours and a total instilled volume of approximately 4 - 16 liters

Group II: gemcitabine Active Control 1 Intervention

intravesical instillation of gemcitabine (1 g in 50 mL saline) with dwell time of 1 - 3 hours

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

Intravesical gemcitabine instillation may significantly reduce the risk of recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC) compared to saline and mitomycin, based on a review of seven studies involving 1,222 participants.

While gemcitabine shows promise in improving outcomes for NMIBC, the safety profile regarding severe adverse events (grade III to V) compared to other treatments like mitomycin and BCG remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesical gemcitabine for non-muscle invasive bladder cancer: An abridged Cochrane Review. Han, MA., Maisch, P., Jung, JH., et al.[2022]

Intravesical gemcitabine therapy was well-tolerated in 116 patients with intermediate-risk and high-risk bladder cancer, with only 12% reporting mild side effects, indicating a favorable safety profile.

After one year, 74.6% of patients remained disease-free, demonstrating significant efficacy, especially in those with a first occurrence of cancer and no prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a Phase II prospective multicenter study. Bartoletti, R., Cai, T., Gacci, M., et al.[2022]

A single intravesical instillation of 500 microg gemcitabine significantly reduced tumor outgrowth in mice from 90% in the control group to 30%, indicating its efficacy in preventing bladder cancer cell implantation when administered shortly after tumor cell seeding.

Four weekly treatments of gemcitabine also showed effectiveness in reducing tumor outgrowth, with prolonged instillations leading to varying results, suggesting that timing and dosage are critical factors in its therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer. Brocks, CP., Büttner, H., Böhle, A.[2022]

Intravesical gemcitabine treatment after failure of first-line chemotherapy showed a significantly higher 2-year tumor-free survival rate of 70.8% compared to 45.8% for patients receiving original chemotherapy, indicating its efficacy in treating recurrent non-muscle-invasive bladder cancer.

The treatment was generally well tolerated, with only mild adverse effects reported, including one case of renal impairment in each of the gemcitabine groups, suggesting that while effective, renal function should be monitored during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evaluation of the efficacy and safety of intravesical instillation with gemcitabine after first-line intravesical chemotherapy failure in the treatment of non-muscle-invasive bladder cancer]. Cao, M., Ma, CK., Ma, J., et al.[2022]

In a phase I trial involving 44 patients with muscle-invasive bladder cancer who were ineligible for surgery, the maximum-tolerated dose of gemcitabine was determined to be 50 mg/m², with a recommended dose of 40 mg/m² for future studies, indicating a manageable safety profile.

The combination of gemcitabine and radiotherapy resulted in a 2-year locoregional failure rate of 32%, with 38% of patients maintaining an intact bladder and no recurrence, suggesting potential efficacy for this treatment approach in patients who cannot undergo surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined chemoradiotherapy with gemcitabine in patients with locally advanced inoperable transitional cell carcinoma of the urinary bladder and/or in patients ineligible for surgery: a phase I trial. De Santis, M., Bachner, M., Cerveny, M., et al.[2023]

In a study of 10 patients with advanced urothelial carcinoma previously treated with MVAC, the combination of gemcitabine and paclitaxel resulted in significant tumor responses, with 2 complete responses and 5 partial responses after two treatment cycles.

The median overall survival for patients receiving this combination therapy was 10.3 months, with manageable side effects, primarily myelosuppression and hypersensitivity reactions, indicating that this treatment could be a safe and effective second-line option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and paclitaxel chemotherapy as a second-line treatment for advanced or metastatic urothelial carcinoma. Matsumoto, K., Irie, A., Satoh, T., et al.[2022]

A 67-year-old patient developed organizing pneumonia after receiving 30 cycles of intravesical gemcitabine for bladder cancer, highlighting that even rare pulmonary toxicities can occur with this treatment.

Despite the assumption that intravesical gemcitabine is separate from systemic circulation, healthcare professionals should remain vigilant for potential pulmonary side effects, especially in patients with pre-existing risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesically instilled gemcitabine-induced lung injury in a patient with invasive urothelial carcinoma: A case report. Zhou, XM., Wu, C., Gu, X.[2020]

In a study of 13 patients with platinum-resistant advanced urothelial cancer, gemcitabine monotherapy showed limited efficacy, with only one patient achieving a partial response and a median overall survival of 7.3 months.

Despite the low response rates, gemcitabine was well-tolerated, with manageable side effects such as anemia, neutropenia, and thrombocytopenia occurring in 31% of patients, indicating it can be a safe option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Third-line gemcitabine monotherapy for platinum-resistant advanced urothelial cancer. Soga, N., Kise, H., Arima, K., et al.[2022]

In a study of 15 patients with non-muscle-invasive bladder cancer, a single high-concentration intravesical instillation of gemcitabine showed that systemic absorption is proportional to the extent of tumor resection, with peak plasma concentrations being lower than those seen with intravenous administration.

At a mean follow-up of 2 years, 60% of patients remained recurrence-free, and the treatment was well-tolerated, with toxicity not exceeding grade 2, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic absorption and pharmacokinetics of single-dose intravesical gemcitabine after transurethral resection of the bladder in non-muscle-invasive bladder cancer. Maffezzini, M., Campodonico, F., Puntoni, M., et al.[2022]

References

1. Korea (South) pubmed.ncbi.nlm.nih.gov

Intravesical gemcitabine for non-muscle invasive bladder cancer: An abridged Cochrane Review. [2022]

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

Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a Phase II prospective multicenter study. [2022]

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

Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer. [2022]

4. China pubmed.ncbi.nlm.nih.gov

[Evaluation of the efficacy and safety of intravesical instillation with gemcitabine after first-line intravesical chemotherapy failure in the treatment of non-muscle-invasive bladder cancer]. [2022]

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

Combined chemoradiotherapy with gemcitabine in patients with locally advanced inoperable transitional cell carcinoma of the urinary bladder and/or in patients ineligible for surgery: a phase I trial. [2023]

6. Australia pubmed.ncbi.nlm.nih.gov

Gemcitabine and paclitaxel chemotherapy as a second-line treatment for advanced or metastatic urothelial carcinoma. [2022]

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

Intravesically instilled gemcitabine-induced lung injury in a patient with invasive urothelial carcinoma: A case report. [2020]

8. Japan pubmed.ncbi.nlm.nih.gov

Third-line gemcitabine monotherapy for platinum-resistant advanced urothelial cancer. [2022]

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

Systemic absorption and pharmacokinetics of single-dose intravesical gemcitabine after transurethral resection of the bladder in non-muscle-invasive bladder cancer. [2022]