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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests treatments for bladder cancer that cannot be surgically removed or has metastasized. It evaluates the effectiveness of radiation therapy combined with the drugs durvalumab and tremelimumab, antibodies that may inhibit cancer cell growth. The trial includes two groups: one receives radiation therapy with durvalumab, while the other also receives tremelimumab. It seeks participants with bladder cancer who are either ineligible for surgery or whose cancer has spread, and who have refused or are ineligible for certain chemotherapy treatments due to health reasons. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that durvalumab, when combined with radiation therapy, generally has manageable side effects. In studies with bladder cancer patients, some side effects appeared but were not overwhelming. Serious side effects occurred in about 8% of patients, including some rare but severe events.

The safety information for the combination of durvalumab and tremelimumab with radiation therapy is less clear. However, tremelimumab has been used safely with durvalumab in other cancers, such as liver and lung cancer. These treatments help the immune system fight cancer, which can sometimes lead to immune-related side effects.

Since the trial is in phase 2, the treatment has passed initial safety tests but is still under study for effectiveness and more detailed safety information. Participants in the trial will be closely monitored for any side effects, and doctors will take steps to manage them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for bladder cancer typically involve surgery, chemotherapy, or immunotherapy with agents like pembrolizumab. However, researchers are excited about the potential of combining radiation therapy with durvalumab and tremelimumab. Unlike standard treatments, durvalumab and tremelimumab are immune checkpoint inhibitors that enhance the body's immune response against cancer cells. The addition of external beam radiation therapy (EBRT) may boost the overall effectiveness by further damaging cancer cells and making them more susceptible to immune attack. This combination could offer a more powerful option for patients, potentially improving outcomes by harnessing the body's own defenses.

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

This trial will compare two treatment regimens for bladder cancer. In Regimen A, participants receive durvalumab combined with radiation therapy. Studies have shown that durvalumab, when paired with radiation therapy, benefits patients with bladder cancer by helping some high-risk patients live longer without disease progression.

In Regimen B, participants receive a combination of durvalumab, tremelimumab, and radiation therapy. Research suggests that this combination is safe and highly effective, potentially preserving the bladder in some patients with muscle-invasive bladder cancer. Overall, these treatments have shown promise in improving outcomes for people with advanced bladder cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Albert Chang, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03702179

Study Details | NCT03702179 | Durvalumab Plus ... This study has been design to determine the efficacy of durvalumab plus tremelimumab with concurrent radiotherapy in terms of pathological response rate in ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39957401/

A Phase II Spanish Oncology GenitoUrinary Group Trial This multimodal approach including durvalumab plus tremelimumab with concurrent radiotherapy is feasible and safe, showing high efficacy in terms of response.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02537418

Study Details | NCT02537418 | Durvalumab With or ... The purpose of this study is to find the highest dose of durvalumab or of durvalumab with tremelimumab that can be tolerated without causing very severe ...

4. aacr.org aacr.org/about-the-aacr/newsroom/news-releases/radiation-plus-combination-immunotherapy-may-help-preserve-bladder-in-some-patients-with-muscle-invasive-bladder-cancer/

Radiation Plus Combination Immunotherapy May Help ... Radiation plus immunotherapy may help some patients with invasive bladder cancer keep their bladders, according to a study published in ...

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK616624

Durvalumab (Imfinzi) and Tremelimumab (Imjudo) - NCBI - NIH Durvalumab and tremelimumab, in combination with platinum-based chemotherapy, have been approved by Health Canada for the first-line treatment of patients with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03601455

Study Details | NCT03601455 | Radiation Therapy and ... It is not yet known whether giving radiation therapy and durvalumab with or without tremelimumab will work better in treating participants with bladder cancer.

7. imfinzihcp.com imfinzihcp.com/imjudo.html

How IMJUDO® (tremelimumab-actl) works with IMFINZI® ... IMJUDO is approved in combination with IMFINZI in patients with uHCC and in combination with IMFINZI and platinum-based chemotherapy in patients with mNSCLC.

8. bcan.org bcan.org/clinicaltrials/study-of-medi4736-durvalumab-with-or-without-tremelimumab-versus-standard-of-care-chemotherapy-in-urothelial-cancer/

Study of MEDI4736 (Durvalumab) With or Without ... This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and ...