Immunotherapy + Chemotherapy for Bladder Cancer

(NILE Trial)

Recruiting at 181 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants

Disqualifiers: CNS metastases, Carcinomatous meningitis, 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

Compensation: Varies

Number of Visits: 6

Duration: 18 weeks

1246 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of combining durvalumab ± tremelimumab with standard of care (SoC) chemotherapy (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) followed by durvalumab monotherapy versus SoC alone as first-line chemotherapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you should not have severe conditions requiring immunosuppressive medication, and you should not have untreated CNS metastases or carcinomatous meningitis.

What data supports the effectiveness of the drug combination of immunotherapy and chemotherapy for bladder cancer?

Research shows that combining immunotherapy drugs like durvalumab and tremelimumab with chemotherapy can be effective for bladder cancer, especially for patients who cannot use cisplatin. Studies have shown promising results, such as a 37.5% complete response rate in patients with high-risk bladder cancer, suggesting this combination could be a beneficial treatment option. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy safe for bladder cancer treatment?

The combination of immunotherapy drugs like durvalumab and tremelimumab with chemotherapy has been studied for bladder cancer, showing an acceptable safety profile. Some patients experienced severe side effects, such as immune-related issues like hepatitis and colitis, but these were not common. Overall, these treatments are generally well-tolerated, though more research is needed to fully understand their safety. ^{4 5 6 7 8}

What makes the Immunotherapy + Chemotherapy treatment for bladder cancer unique?

This treatment combines immunotherapy drugs (durvalumab and tremelimumab) with chemotherapy agents (carboplatin, cisplatin, and gemcitabine) to target bladder cancer, especially for patients who cannot use standard cisplatin-based treatments. The combination of immune checkpoint inhibitors (which help the immune system attack cancer cells) with chemotherapy is novel and shows promise in improving outcomes for high-risk patients. ^{4 5 7 9 10}

Eligibility Criteria

This trial is for adults with advanced urothelial cancer that can't be surgically removed. They should not have had first-line chemotherapy but may have had other treatments if their disease worsened after a year. Participants need to be relatively healthy, able to perform daily activities with ease or some limitation, and women must not be pregnant.

Inclusion Criteria

I have not received first-line chemotherapy.

I am fully active or restricted in physically strenuous activity but can do light work.

I have at least one cancer lesion that has not been treated with radiation.

Exclusion Criteria

I am not on strong medication to suppress my immune system.

I may undergo or am considering major surgery as part of my treatment plan.

I have been treated with immune therapy before, but not Bacillus Calmette-Guerin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard of care chemotherapy every 3 weeks for 6 cycles, with or without durvalumab and tremelimumab

18 weeks

6 visits (in-person)

Durvalumab Monotherapy

Participants receive durvalumab monotherapy every 4 weeks following initial treatment

Duration not specified

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Durvalumab
• Gemcitabine
• Tremelimumab

Trial Overview The study tests the effectiveness of Durvalumab alone or combined with Tremelimumab alongside standard chemotherapy (Cisplatin + Gemcitabine or Carboplatin + Gemcitabine) versus just the chemotherapy. It's randomized and open-label, meaning patients are assigned treatment by chance and everyone knows which treatment they're getting.

Participant Groups

Group I: Durvalumab in Combination with Tremelimumab+SoC Chemotherapy Experimental Treatment 4 Interventions

Durvalumab and Tremelimumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks Tremelimumab will be provided for 4 cycles. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine

Group II: Durvalumab in Combination with SoC Chemotherapy Experimental Treatment 3 Interventions

Durvalumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine

Group III: SoC Chemotherapy Active Control 2 Interventions

Patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

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]

Urothelial carcinoma, the most common urological cancer, is primarily treated with Bacillus Calmette-Guerin (BCG) immunotherapy for superficial cases and cisplatin-based chemotherapy for metastatic disease, with vinflunine as the standard second-line option in Europe.

Novel PD-1/PD-L1 inhibitors like atezolizumab, nivolumab, and pembrolizumab have shown promise in treating bladder cancer, particularly for patients who cannot tolerate cisplatin, and are generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. Büchler, T.[2019]

Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) like anti-PD-(L)1 and anti-CTLA-4 antibodies shows promising efficacy in localized muscle-invasive bladder cancer, with pathological complete response rates between 31% and 46%.

The safety profile of these treatments is generally acceptable, with severe adverse events reported in 6% to 41% of patients, indicating that while there are risks, the potential benefits warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. Peyrottes, A., Ouzaid, I., Califano, G., et al.[2021]

In a phase 3 trial involving 1032 patients with metastatic urothelial carcinoma, durvalumab alone showed a median overall survival of 14.4 months in patients with high PD-L1 expression, compared to 12.1 months with standard chemotherapy, although this difference was not statistically significant.

The combination of durvalumab and tremelimumab resulted in a median overall survival of 15.1 months in the overall patient population, compared to 12.1 months for chemotherapy, but again, this did not meet the primary endpoint for significance, highlighting the need for further research into which patients may benefit from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Powles, T., van der Heijden, MS., Castellano, D., et al.[2021]

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 the CASPIAN study involving 805 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of durvalumab and platinum-etoposide significantly improved overall survival compared to platinum-etoposide alone, with a median survival of 12.9 months versus 10.5 months.

However, adding tremelimumab to durvalumab and platinum-etoposide did not provide a significant survival benefit, indicating that durvalumab plus platinum-etoposide should be considered the new standard of care for first-line treatment of ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Goldman, JW., Dvorkin, M., Chen, Y., et al.[2021]

References

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

Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have? [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Perioperative Immunotherapy in Muscle-Invasive Bladder Cancer. [2023]

4. Czech Republic pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. [2019]

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

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. [2021]

8. Australia pubmed.ncbi.nlm.nih.gov

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

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

Efficacy and Tolerability of Tremelimumab in Locally Advanced or Metastatic Urothelial Carcinoma Patients Who Have Failed First-Line Platinum-Based Chemotherapy. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. [2021]