Durvalumab + Tremelimumab for Bladder Cancer

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: Autoimmune disease, HIV/AIDS, Hepatitis B/C, others

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

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

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the side effects of two immunotherapy drugs, durvalumab and tremelimumab, for treating bladder cancer that cannot be addressed with standard chemotherapy before surgery. These monoclonal antibodies may help the immune system stop cancer cells from growing and spreading. Individuals with muscle-invasive, high-risk bladder cancer who cannot undergo cisplatin-based treatment might be suitable candidates. This includes those whose tumors could not be fully removed and have high-risk features like micropapillary or plasmacytoid characteristics. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a chance to be among the first to receive these potentially groundbreaking therapies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Non-cancer-related medications like insulin for diabetes are allowed.

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

Research shows that people usually tolerate the combination of durvalumab and tremelimumab well. Studies have found this combination to be generally safe. Most side effects are mild to moderate, including fatigue, nausea, or skin reactions. Although less common, more serious side effects can occur. These treatments remain under study, so more information will emerge as research progresses. Overall, current evidence suggests that people can manage these treatments without major issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for bladder cancer, which typically involves chemotherapy and surgery, durvalumab and tremelimumab offer a novel approach by harnessing the power of the immune system. These treatments are immune checkpoint inhibitors that work by blocking proteins that prevent the immune system from attacking cancer cells, thereby allowing the body to better fight the cancer. Researchers are excited about these treatments because they target the disease differently, potentially offering more effective and longer-lasting results with fewer side effects compared to traditional chemotherapy.

What evidence suggests that durvalumab and tremelimumab might be effective for bladder cancer?

In this trial, participants will receive a combination of durvalumab and tremelimumab. Studies have shown that this combination can help the immune system fight cancer. It has sometimes slowed cancer growth and even shrunk tumors, particularly in patients with solid tumors. Research indicates that durvalumab alone can elicit a response in patients with bladder cancer in about 6.3 weeks. Tremelimumab provides additional immune support, potentially improving the chances of a positive response. Although risks exist, such as immune-related side effects, the potential for these treatments to help the body target cancer cells makes them promising options. ^{1 2 3 6 7}

Who Is on the Research Team?

Jianjun Gao

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with muscle-invasive, high-risk urothelial cancer who can't have cisplatin-based therapy. They need proof of cancer from a specific bladder tissue resection, good organ and marrow function, no prior immunotherapy, an ECOG status of 0-1, and must agree to use effective contraception if applicable. Exclusions include HIV/AIDS, recent vaccines or surgeries, pregnancy, uncontrolled illnesses, allergies to study drugs, other ongoing cancer treatments or trials (with exceptions), certain autoimmune diseases or conditions.

Inclusion Criteria

I use effective birth control because I can still have children.

I am a man who can father children and will use effective birth control.

I have a mild or well-controlled autoimmune condition.

Exclusion Criteria

I am not currently on any cancer treatments like chemotherapy or immunotherapy.

I haven't had major surgery in the last 28 days or am still recovering from one.

You have received any experimental cancer treatment within the 28 days before starting durvalumab and tremelimumab.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive tremelimumab and durvalumab intravenously on day 1 of weeks 1 and 4

4 weeks

2 visits (in-person)

Surgery

Patients undergo cystectomy with pelvic lymph node dissection surgery 4-6 weeks after the last infusion

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

1 visit at 90 days, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Therapeutic Conventional Surgery
• Tremelimumab

Trial Overview The trial tests durvalumab and tremelimumab's safety in treating urothelial cancers that are ineligible for cisplatin before surgery. These monoclonal antibodies may boost the immune system to stop tumor growth and spread. It's a phase I pilot study focusing on side effects as well as potential efficacy.

How Is the Trial Designed?

Group I: Treatment (tremelimumab, durvalumab) Experimental Treatment 3 Interventions

Patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1 of weeks 1 and 4. Beginning 4-6 weeks after the last infusion, patients undergo cystectomy with pelvic lymph node dissection surgery.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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 MYSTIC study involving 488 treatment-naïve patients with metastatic non-small-cell lung cancer, durvalumab alone or in combination with tremelimumab showed significant improvements in patient-reported outcomes (PROs) compared to chemotherapy, particularly in reducing fatigue and appetite loss.

Patients receiving durvalumab-containing treatments experienced a longer time to deterioration in quality of life and physical functioning, indicating that these treatments may help maintain better overall well-being without negatively impacting quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Garon, EB., Cho, BC., Reinmuth, N., 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]

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 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]

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/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 ...

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/PMC6452813/

Durvalumab for the management of urothelial carcinoma The median time to response was 6.3 weeks (95% CI, 5.6–12.1 weeks) in the 13 responding patients, and median duration of response has not been reached (range, ...

5. imfinzihcp.com imfinzihcp.com/hcc/unresectable/efficacy.html

Efficacy 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.

6. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D419BC00001/

Study of MEDI4736 (Durvalumab) with or without ... Study of MEDI4736 (Durvalumab) with or without Tremelimumab versus Standard of Care Chemotherapy in Urothelial Cancer ... data of durvalumab or tremelimumab ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2022/761289Orig1s000MultidisciplineR.pdf

761289Orig1s000 - accessdata.fda.gov The data supporting FDA's assessment of the safety of tremelimumab in combination with durvalumab is based primarily on the HIMALAYA trial, a global ...