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

Trial Summary

What is the purpose of this trial?

Upper tract urothelial cancer (UTUC) is cancer in the lining of the kidney or ureter (the tube that drains the kidney). This type of cancer is rare and as a result, there are only a few studies that have looked at it. Standard of care for UTUC would be surgery followed by chemotherapy (adjuvant chemotherapy). However, we know from studies that have looked at cancer of the lining of the bladder, which is a similar cancer in many ways, that treating people with chemotherapy before surgery (neoadjuvant chemotherapy) can lead to longer survival compared to the standard of care. There are no studies to show this in UTUC. Neoadjuvant chemotherapy is thought to help improve survival by treating any cancer that may have spread from the original tumour but that is not visible yet on scans. This study would be the first clinical trial in Canada to evaluate the use of chemotherapy before surgery in this disease setting. Since UTUC is rare, the purpose of this study is to determine if it is possible to enrol enough patients to a trial looking at the use of chemotherapy before surgery.

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.

What data supports the effectiveness of the drug combination of gemcitabine and cisplatin for bladder cancer?

Research shows that the combination of gemcitabine and cisplatin is effective for treating advanced bladder cancer, with similar response rates and survival outcomes to the older MVAC regimen, but with fewer side effects. This makes it a preferred option for patients, especially those who are older or have other health issues. ^{1 2 3 4 5}

What safety data exists for chemotherapy drugs like Carboplatin and Cisplatin used in bladder cancer treatment?

Carboplatin and Cisplatin, used in bladder cancer treatment, have been studied for safety. Common side effects include gastrointestinal issues like nausea and vomiting, and blood-related issues like low white blood cell counts. These drugs are generally considered safe, but they can cause side effects, especially in patients with other health conditions. ^{2 3 6 7 8}

How does this chemotherapy drug for bladder cancer differ from other treatments?

This chemotherapy drug for bladder cancer is unique because it combines gemcitabine with platinum-based compounds like cisplatin or carboplatin, which have shown a better balance of effectiveness and lower toxicity compared to the traditional MVAC regimen. Additionally, carboplatin is less toxic to the kidneys than cisplatin, making it a safer option for patients with renal concerns. ^{1 2 9 10 11}

Research Team

Girish Kulkarni, MD

Principal Investigator

University Health Network - Princess Margaret Hospital

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Overview of gemcitabine triplets in metastatic bladder cancer. [2022]

2. Australia pubmed.ncbi.nlm.nih.gov

Sequential therapy with gemcitabine and Carboplatin followed by Paclitaxel as first line treatment for advanced urothelial cancer. [2021]

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

Gemcitabine/carboplatin in advanced urothelial cancer. [2022]

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

Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer. [2022]

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

Gemcitabine in advanced bladder cancer. [2022]

6. England 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]

7. Iran pubmed.ncbi.nlm.nih.gov

Oncological Outcomes of Neoadjuvant Gemcitabine plus Carboplatin versus Gemcitabine plus Cisplatin in Locally Advanced Bladder Cancer: A Retrospective Analysis. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Combined cisplatin and radiation therapy for advanced bladder cancer. [2018]

9. France pubmed.ncbi.nlm.nih.gov

[Current chemotherapy of locally advanced or metastatic bladder tumors]. [2006]

10. France pubmed.ncbi.nlm.nih.gov

[Carboplatin and urothelial tumors: review of the literature]. [2013]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Carboplatin and urothelial tumors. [2018]