Chemotherapy for Bladder Cancer

(NAUTICAL Trial)

Recruiting at 1 trial location

Overseen By Emily Hickey

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University Health Network, Toronto

Must be taking: Cisplatin-based chemotherapy

Must not be taking: Investigational drugs

Disqualifiers: Metastatic disease, Solitary kidney, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

14 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether administering chemotherapy before surgery can improve outcomes for individuals with upper tract urothelial cancer (UTUC), a rare cancer in the kidney or ureter lining. The research compares this approach to the standard practice of administering chemotherapy after surgery. Two treatment plans are tested: one with chemotherapy before surgery and another with chemotherapy after. Suitable candidates for this trial are those newly diagnosed with UTUC, deemed eligible for surgery and cisplatin-based chemotherapy by their doctor. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use any other investigational drugs or have had systemic chemotherapy within 2 years of joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the chemotherapy drugs cisplatin and gemcitabine are generally well-tolerated for treating cancers such as bladder cancer. One study found that patients using these drugs experienced better safety and tolerability compared to other chemotherapy options, with fewer serious side effects while still achieving similar survival benefits.

For the combination of carboplatin and gemcitabine, studies have also shown a good safety record. Specifically, one study involving patients with various cancers found this combination effective and well-tolerated, meaning the drugs worked well for many patients without causing unexpected harmful effects.

Both drug combinations have approval for use in other types of cancer, indicating they have passed safety checks for those conditions. While these drugs are used differently in this trial, their established safety profiles make them promising options for individuals considering participation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for bladder cancer because they explore different chemotherapy combinations based on kidney function, which could personalize and optimize treatment plans. Unlike the standard approach, which typically involves a one-size-fits-all regimen, this trial tailors chemotherapy choices—using Gemcitabine with Cisplatin or Carboplatin—depending on the patient's kidney filtration rate. This personalized approach aims to maximize treatment efficacy while minimizing side effects, potentially offering better outcomes for patients with varying levels of kidney function.

What evidence suggests that this trial's treatments could be effective for upper tract urothelial cancer?

Research has shown that using chemotherapy drugs like gemcitabine and cisplatin before surgery can help treat cancers similar to upper tract urothelial cancer (UTUC). In studies with bladder cancer, this combination of treatments achieved a 41% success rate in shrinking tumors and significantly improved survival rates. Specifically, patients lived for an average of about 8.5 months with this treatment. In this trial, participants in the Neoadjuvant Chemotherapy Arm will receive gemcitabine and cisplatin before surgical intervention.

For those unable to use cisplatin, gemcitabine combined with carboplatin has also yielded good results. This combination achieved a 46.2% success rate in reducing tumor size, with patients living an average of 13.6 months. In the Adjuvant Chemotherapy Arm of this trial, patients with a GFR greater than or equal to 30 mL/min but less than 60 mL/min will receive gemcitabine and carboplatin after surgery. These findings suggest that these chemotherapy options could effectively manage UTUC by shrinking tumors and slowing disease progression. ^{2 4 6 7 8}

Who Is on the Research Team?

Girish Kulkarni, MD

Principal Investigator

University Health Network - Princess Margaret Hospital

Are You a Good Fit for This Trial?

Adults with newly diagnosed high-grade urothelial cancer of the kidney or ureter, visible on scans, who are fit for surgery and chemotherapy. They must have good organ function and an ECOG score of 0-1 (indicating they are fully active or restricted in physically strenuous activity but ambulatory). Pregnant or breastfeeding individuals, those with metastatic disease, other cancers within 2 years, serious infections, or conditions excluding cisplatin use cannot participate.

Inclusion Criteria

I am considered suitable for major kidney or ureter surgery by a cancer surgeon.

I will be evaluated for further chemotherapy after my kidney or ureter surgery.

My cancer is in the bladder or urinary tract and has not spread to distant organs.

Exclusion Criteria

I haven't had any cancer or chemotherapy, except for bladder cancer, in the last 2 years.

I have only one kidney.

My bladder cancer has not spread into the bladder muscles.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Participants receive Gemcitabine/Cisplatin or Gemcitabine/Carboplatin on a 3-week cycle for up to 4 cycles

12 weeks

Surgical Intervention

Participants undergo nephroureterectomy or ureterectomy following chemotherapy

1 week

Follow-up

Participants are monitored for disease-free survival and complete pathologic response

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Gemcitabine

Trial Overview The NAUTICAL trial is testing if giving chemotherapy before surgery can improve survival in patients with upper tract urothelial cancer. It's a first-of-its-kind study in Canada to see if this approach works like it does for similar bladder cancers. The drugs tested include Gemcitabine and Cisplatin (or Carboplatin for those not suitable for Cisplatin).

How Is the Trial Designed?

Group I: Neoadjuvant Chemotherapy Arm Experimental Treatment 2 Interventions

Gemcitabine/Cisplatin will be administered on a 3-week cycle for up to 4 cycles. This will be followed by surgical intervention (nephroureterectomy or ureterectomy).

Group II: Adjuvant Chemotherapy Arm (Standard of Care) Active Control 3 Interventions

Patients will undergo surgical intervention (nephroureterectomy or ureterectomy) followed by adjuvant chemotherapy. Patients with a GFR greater or equal to 60 mL/min will receive Gemcitabine/Cisplatin while those with a GFR greater or equal to 30 mL/min but less than 60 mL/min will receive Gemcitabine/Carboplatin. Gemcitabine/Cisplatin will be administered on a 3-week cycle for up to 4 cycles. Gemcitabine/Carboplatin will be administered on a 3-week cycle for up to 4 cycles.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Bladder Cancer Canada

Collaborator

Trials

3

Recruited

280+

Published Research Related to This Trial

In a multicenter study involving 48 patients with metastatic transitional cell carcinoma, Carboplatin, a less toxic analogue of Cisplatin, showed minimal activity with no complete remissions and only 3 partial responses.

The study indicates that Carboplatin may not be an effective treatment option for bladder cancer, especially since 30 of the patients had not previously undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of carboplatin in metastatic transitional cell carcinoma of the bladder (a report of the Medical Research Council Working Party on Urological Cancer, Subgroup in Advanced Bladder Cancer). [2013]

Carboplatin shows a moderate efficacy in treating advanced-stage urothelial tumors, achieving a 12.9% objective response rate when used alone, and significantly higher response rates (63% overall response) when combined with other drugs like methotrexate and vinblastine in polychemotherapy.

Unlike cisplatin, carboplatin has minimal renal toxicity and does not require hyperhydration, making it a safer alternative for patients, especially when dosages are adjusted based on kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Carboplatin and urothelial tumors: review of the literature]. Mottet Auselo, N., Bons-Rosset, F., Pellae-Cosset, B., et al.[2013]

In a study of 22 patients with muscle-invasive bladder cancer, neoadjuvant chemotherapy using gemcitabine plus cisplatin achieved downstaging rates of 50% to pT0 and 63.6% to <pT2, which is comparable to the rates achieved with methotrexate, vinblastine, doxorubicin, and cisplatin in a comparator group of 9 patients.

Gemcitabine plus cisplatin demonstrated a better safety profile, with significantly lower rates of non-hematologic toxicity compared to the traditional chemotherapy regimen, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer. Kaneko, G., Kikuchi, E., Matsumoto, K., et al.[2022]

Standard chemotherapy for transitional cell carcinoma of the bladder, known as MVAC (cisplatin, methotrexate, vinblastine, and doxorubicin), shows a high response rate but rarely leads to long-term survival, indicating a need for more effective and less toxic treatments.

Alternative agents like paclitaxel, gemcitabine, and gallium nitrate have demonstrated significant activity, either alone or in combination with cisplatin or carboplatin, achieving response rates of 40% to 70% in patients with advanced disease, although the best treatment regimen is still not established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current chemotherapy of locally advanced or metastatic bladder tumors]. Dourthe, LM., Ceccaldi, B., Fournier, R., et al.[2006]

The combination of gemcitabine and carboplatin shows a promising overall response rate of 60% in treating transitional cell carcinoma of the bladder, making it a potential alternative for patients who cannot tolerate cisplatin due to renal impairment or other comorbidities.

Given the high chemosensitivity of transitional cell carcinoma, this new treatment combination warrants further investigation in future phase III trials to confirm its efficacy and safety in a broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine/carboplatin in advanced urothelial cancer. Carles, J., Nogué, M.[2022]

The gemcitabine and cisplatin doublet regimen has shown a better efficacy-toxicity profile compared to the traditional MVAC chemotherapy for bladder cancer, making it a more suitable option for elderly patients with metastatic disease.

Ongoing phase II studies of triplet regimens combining gemcitabine, paclitaxel, and either cisplatin or carboplatin have demonstrated promising activity and improved median survival, particularly in patients with visceral disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of gemcitabine triplets in metastatic bladder cancer. de Wit, R., Bellmunt, J.[2022]

In a phase II study involving 27 patients with advanced transitional cell carcinoma, the sequential treatment of gemcitabine and carboplatin followed by paclitaxel resulted in an objective response rate of 40.7%, with one complete response and ten partial responses.

The treatment was generally safe, with hematologic toxicities being the most common, but the study concluded that while this sequential approach appears safer than triplet therapy, it did not significantly improve patient outcomes, indicating a need for further research with larger groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential therapy with gemcitabine and Carboplatin followed by Paclitaxel as first line treatment for advanced urothelial cancer. Kattan, JG., Boutros, CY., Farhat, FS., et al.[2021]

In a phase III trial with 405 patients, the gemcitabine/cisplatin (GC) regimen showed comparable effectiveness to the standard MVAC regimen for advanced bladder cancer, with similar response rates and overall survival.

The GC regimen demonstrated significantly better safety and tolerability, with much lower rates of severe side effects like mucositis and neutropenic fever, suggesting it should be preferred as the standard treatment for advanced bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in advanced bladder cancer. von der Maase, H.[2022]

Carboplatin, a new platinum salt, shows moderate efficacy in treating advanced-stage bladder cancer with objective response rates of 14% when used alone and 63% in combination therapies, while being significantly less toxic than traditional platinum-based chemotherapy.

Carboplatin has excellent tolerability, with minimal renal toxicity and manageable side effects, such as temporary thrombocytopenia, making it a safer alternative to cisplatin for patients with advanced urothelial tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and urothelial tumors. Mottet-Auselo, N., Bons-Rosset, F., Costa, P., et al.[2018]

In a study of 140 patients with non-metastatic muscle-invasive bladder cancer, both gemcitabine plus cisplatin (Gem/Cis) and gemcitabine plus carboplatin (Gem/Carbo) regimens showed similar rates of complete clinical response (cCR) before surgery, indicating that both treatments are effective in this context.

However, patients receiving Gem/Cis had significantly better overall survival (OS) compared to those on Gem/Carbo, with median OS of 41 months versus 26 months, suggesting that while both regimens are effective, Gem/Cis may offer a survival advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncological Outcomes of Neoadjuvant Gemcitabine plus Carboplatin versus Gemcitabine plus Cisplatin in Locally Advanced Bladder Cancer: A Retrospective Analysis. Mofid, B., Razzaghdoust, A., Ghajari, M., et al.[2022]

In a study of 44 patients with advanced urinary bladder cancer, 69.2% achieved a complete response to treatment combining cisplatin and full-dose radiotherapy, indicating significant efficacy of this approach.

The treatment was associated with notable gastrointestinal toxicity, including loss of appetite (64%), nausea/vomiting (48%), and diarrhea (18%), along with some cases of blood cell count reductions, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined cisplatin and radiation therapy for advanced bladder cancer. Matsushima, M., Tajima, M., Kase, T., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1906828/

A phase II trial of gemcitabine plus carboplatin in advanced ... This combination regimen demonstrated promising efficacy with a tumor response rate of 46.2%, a median PFS of 7.5 months and a median overall survival of 13.6 ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090429504005163

Gemcitabine and carboplatin combination as first-line ... The combination of gemcitabine and carboplatin has some activity as first-line treatment of advanced bladder carcinoma in the elderly and those unfit for ...

3. ar.iiarjournals.org ar.iiarjournals.org/content/anticanres/40/2/1141.full-text.pdf

The Efficacy of Second-line Chemotherapy for Advanced or ... In bladder cancer, anti-PD-L1 antibody has been shown to have a favorable outcome in patients with metastatic bladder cancer and in those who had rare serious.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11217220/

Successful pre-surgical treatment with carboplatin and ... After the patient received two courses of carboplatin and gemcitabine chemotherapy, the bladder tumor size had reduced by 60%. No nausea or ...

5. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/1471-2407-7-98

A phase II trial of gemcitabine plus carboplatin in advanced ... The results in 50 and 60 patients showed a 56% and 38% ORR with a median PFS/TTP of 11 and 7.6 months and a median OS of 11.3 and 16.3 months, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16342065/

The combination of gemcitabine and carboplatin as first- ... Conclusions: The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00179

The iNDUCT-GETUG V08 Trial | Journal of Clinical Oncology This study evaluated safety and efficacy of neoadjuvant chemotherapy (cisplatin or carboplatin + gemcitabine) in combination with durvalumab in these patients.

8. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.21604

The combination of gemcitabine and carboplatin as first‐line ... 18 We found an ORR of 36%, a median time to disease progression (TTP) of 4.8 months, and a median overall survival (OS) of 7.2 months. These ...