Immunotherapy + Chemotherapy for Bladder Cancer

(NILE Trial)

Not currently recruiting at 232 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether combining the immunotherapy drugs durvalumab and tremelimumab with standard chemotherapy improves treatment outcomes for people with advanced bladder cancer. Participants will receive either standard chemotherapy alone or with these immunotherapy drugs. The trial aims to determine if these combinations are more effective than chemotherapy alone. It targets individuals with bladder cancer that cannot be surgically removed and has not been treated with first-line chemotherapy. Eligible participants should have a specific type of bladder cancer and must not have previously received certain immune therapies. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

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.

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

Research has shown that durvalumab, when combined with standard chemotherapy, generally causes manageable side effects, allowing most people to tolerate them. In patients with bladder cancer, studies have shown promising results, with many responding well to the treatment.

Combining durvalumab with tremelimumab remains generally safe and tolerable. However, some patients have experienced immune-related side effects. For instance, a small number reported lung inflammation (pneumonitis), with some cases being serious.

Overall, both treatment combinations are considered well-tolerated, but awareness of possible side effects is important. Clinical trial participants will receive close monitoring to manage any adverse effects. ^{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 combine traditional chemotherapy with innovative immunotherapy approaches. Unlike standard chemotherapy regimens like cisplatin and gemcitabine, the investigational treatments include durvalumab and tremelimumab, which are designed to boost the body's immune response against cancer cells. Durvalumab is a checkpoint inhibitor that helps the immune system recognize and attack cancer, while tremelimumab is used to enhance this effect further. By combining these immunotherapy drugs with chemotherapy, there's potential not only to directly kill cancer cells but also to stimulate the immune system to keep fighting the cancer long-term. This dual approach could offer improved outcomes for patients, especially those who are ineligible for certain chemotherapies like cisplatin.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research has shown that durvalumab, one of the treatments in this trial, is effective in treating bladder cancer when combined with chemotherapy. In one study, patients with PD-L1-positive tumors responded well, indicating the treatment's potential success. In this trial, some participants will receive durvalumab with standard chemotherapy. Durvalumab alone has also shown results, with some patients seeing improvement in about six weeks. Another group in this trial will receive a combination of durvalumab and another immune therapy drug, tremelimumab, alongside chemotherapy. Early trials have shown promise for patients with more serious bladder cancer. This combination aims to enhance the immune system's ability to fight the cancer. Overall, evidence suggests these treatments could improve outcomes for bladder cancer patients. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02516241

NCT02516241 | Study of MEDI4736 (Durvalumab) With or ... This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6452813/

Durvalumab for the management of urothelial carcinoma Durvalumab is a safe and effective therapeutic option in UC and was granted FDA approval in May 2017 based on the results of the Phase I/II trial.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02812420

NCT02812420 | Durvalumab and Tremelimumab in ... This pilot phase I trial studies the side effects of durvalumab and tremelimumab in treating patients with muscle-invasive, high-risk urothelial cancer

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7897955/

A phase II trial of durvalumab and tremelimumab in ... This was a phase II open‐label study of durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for four cycles followed by durvalumab 1500 mg every 4 weeks.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.6_suppl.TPS504

A phase III, randomized, open-label, multicenter, global ... A phase 3 study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC) chemotherapy (CT) in patients (pts) with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6038862/

Safety and efficacy of durvalumab (MEDI4736) in various ... Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved ...

7. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions.

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02812420/

Clinical Trial: NCT02812420 To evaluate the safety and tolerability of durvalumab and tremelimumab in patients with muscle-invasive, high-risk bladder cancer who are ...