Radiation Therapy + Durvalumab ± Tremelimumab for Bladder Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Immunosuppressants

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 13 months

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects and how well radiation therapy and durvalumab with or without tremelimumab work in treating participants with bladder cancer that cannot be removed by surgery, has spread to nearby tissue or lymph nodes, or that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and durvalumab with or without tremelimumab will work better in treating participants with bladder cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take any other systemic chemotherapy, biologic, or hormonal therapy for cancer treatment while participating in the trial. If you have been on prior systemic therapies, a washout period (time without taking certain medications) of at least 45 days is required.

What data supports the effectiveness of the drug Durvalumab in combination with Tremelimumab for treating bladder cancer?

Durvalumab has been approved for treating advanced bladder cancer after chemotherapy, and studies show that combining it with Tremelimumab can enhance immune responses against cancer. Additionally, in lung cancer, this combination has improved survival rates, suggesting potential benefits for bladder cancer as well. ^{1 2 3 4 5}

Is the combination of Durvalumab and Tremelimumab safe for humans?

The combination of Durvalumab and Tremelimumab has been studied in various cancers and generally shows a tolerable safety profile, though it can lead to significant side effects. In one study, 63.6% of patients experienced severe side effects, such as neutropenia (low white blood cell count), and some experienced serious adverse events, but these were mostly related to chemotherapy rather than the combination itself. ^{1 3 6 7 8}

What makes the treatment of Radiation Therapy + Durvalumab ± Tremelimumab for bladder cancer unique?

This treatment is unique because it combines radiation therapy with durvalumab, an immune-boosting drug that blocks a protein (PD-L1) to help the body's immune system attack cancer cells, and tremelimumab, which targets another protein (CTLA-4) to further enhance the immune response. This combination aims to improve outcomes for bladder cancer patients who have limited treatment options, especially those who cannot undergo standard chemotherapy. ^{1 2 5 9 10}

Research Team

Albert Chang, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with bladder cancer that can't be surgically removed, has spread locally or to other body parts. They should have a life expectancy of at least 12 weeks and cannot take cisplatin-based chemotherapy. Participants must not have had certain treatments before, like immunosuppressants or abdominal radiation, and women must not be pregnant.

Inclusion Criteria

Your bilirubin levels in the blood should not be higher than 1.5 times the normal limit, unless you have a specific condition called Gilbert's syndrome, in which case you can still participate after talking to your doctor.

My liver function tests are within the required range.

Your platelet count is at least 100,000 per cubic millimeter.

Exclusion Criteria

I have a history of autoimmune disease.

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

I do not have any serious ongoing illnesses that my doctor is not able to control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab with or without tremelimumab and undergo radiation therapy. Durvalumab is administered every 28 days for up to 13 courses, and radiation therapy is given for 5 fractions starting on day 8 of course 1.

Up to 13 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 8 weeks, then every 12 and 16 weeks.

Up to 3 years

Treatment Details

Interventions

• Durvalumab
• External Beam Radiation Therapy
• Tremelimumab

Trial Overview The study tests the effectiveness of radiation therapy combined with durvalumab (a monoclonal antibody) alone or alongside tremelimumab in treating advanced bladder cancer. The goal is to see if adding tremelimumab improves outcomes compared to just durvalumab and radiation.

Participant Groups

Group I: Regimen B (radiation therapy, durvalumab, tremelimumab) Experimental Treatment 3 Interventions

Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1.

Group II: Regimen A (radiation therapy and durvalumab) Experimental Treatment 2 Interventions

Participants receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo EBRT for 5 fractions beginning on day 8 of course 1.

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

AstraZeneca

Industry 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

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

The combination of durvalumab and tremelimumab was studied in 19 articles involving 2052 patients with solid tumors, showing some benefits over traditional chemotherapy in certain tumor types.

However, this combination did not consistently outperform durvalumab alone, indicating that while it may have potential, further research with larger and better-designed studies is needed to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Arru, C., De Miglio, MR., Cossu, A., et al.[2023]

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 phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

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

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. [2023]

3. 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]

4. Ireland pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). [2023]

5. England pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. [2022]

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

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

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

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

9. 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]

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

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023. [2023]