Durvalumab +/- Tremelimumab for Bladder Cancer

Recruiting at 188 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Brain metastases, Active infection, 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: 11

Duration: Up to 2 years

1126 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use immunosuppressive medications within 14 days before starting the trial. Some exceptions include certain steroids and premedications for allergies.

What data supports the effectiveness of the drug Durvalumab +/- Tremelimumab for Bladder Cancer?

Research shows that combining durvalumab and tremelimumab, which are drugs that help the immune system fight cancer, can improve outcomes for patients with advanced bladder cancer. In one study, this combination led to a complete response in 37.5% of patients who were not eligible for standard chemotherapy, suggesting it could be a promising option for those with limited treatment choices. ^{1 2 3 4 5}

Is the combination of Durvalumab and Tremelimumab safe for treating bladder cancer?

The combination of Durvalumab and Tremelimumab has been studied for safety in various cancers, including bladder cancer. In one study, 21% of patients experienced serious immune-related side effects like liver inflammation and colon inflammation. Another analysis showed that serious side effects occurred in about 32.6% of patients receiving the combination, compared to 23.8% with Durvalumab alone, with common issues being reduced appetite and diarrhea. ^{2 3 4 5 6}

What makes the drug combination of Durvalumab and Tremelimumab unique for bladder cancer treatment?

This drug combination is unique because it uses two immune checkpoint inhibitors, Durvalumab (a PD-L1 inhibitor) and Tremelimumab (a CTLA-4 inhibitor), to enhance the body's immune response against cancer cells, offering a novel approach compared to traditional chemotherapy for patients with advanced bladder cancer. ^{1 2 3 4 7}

What is the purpose of this trial?

A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer

Eligibility Criteria

This trial is for adults with Stage IV bladder cancer who haven't had first-line chemotherapy. They must know their tumor PD-L1 status and can be eligible or ineligible for cisplatin-based chemo due to certain health conditions. People with prior immune therapy, autoimmune/inflammatory disorders, brain metastases not stable off steroids, active infections like TB/HIV, recent live vaccines, or current immunosuppressants (with some exceptions) cannot join.

Inclusion Criteria

My tumor's PD-L1 status has been confirmed by a lab test.

I have Stage IV bladder cancer that hasn't been treated with first-line chemotherapy.

I am either eligible or not for cisplatin chemotherapy based on specific health conditions.

Exclusion Criteria

I have previously received immunotherapy or vaccines for cancer, but not within the last 28 days.

My brain or spinal cord cancer is stable, and I haven't taken steroids for over 2 weeks.

I do not have active infections like TB, hepatitis B, C, or HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MEDI4736 (Durvalumab) monotherapy, MEDI4736 (Durvalumab) in combination with Tremelimumab, or standard of care chemotherapy until disease progression or unacceptable toxicity

Up to 2 years

Every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

At follow-up Month 3

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Gemcitabine
• MEDI4736 (Durvalumab)
• Tremelimumab

Trial Overview The study tests Durvalumab alone or combined with Tremelimumab against standard chemo drugs (Gemcitabine with Cisplatin or Carboplatin). It's a Phase III trial where patients are randomly assigned to one of these treatments to compare effectiveness as a first-line treatment in advanced bladder cancer.

Participant Groups

Group I: Monotherapy Experimental Treatment 1 Intervention

MEDI4736 (Durvalumab)

Group II: Combination Therapy Experimental Treatment 2 Interventions

MEDI4736 (Durvalumab) + Tremelimumab

Group III: Standard of Care Active Control 3 Interventions

Standard of Care Chemotherapy Treatment

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

In a phase I trial involving Japanese patients with advanced cancer, tremelimumab was found to be safe and well-tolerated, with no dose-limiting toxicities observed in the initial dosing phase, although 75% of patients reported treatment-related adverse events.

When combined with durvalumab, tremelimumab showed a manageable safety profile, with only two instances of serious adverse events (Grade 4 myasthenia gravis and hyperglycemia), indicating that the combination therapy can be administered with careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. Fujiwara, Y., Takahashi, Y., Okada, M., et al.[2022]

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]

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]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

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. 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]

2. England pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. [2022]

3. 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]

4. 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]

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

[Immunotherapy for Bladder Cancer]. [2019]

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

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

7. 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]