Triple Therapy for Bladder Cancer

(RESOLVE Trial)

Overseen By Susan Sharry

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Valproic acid, Immunosuppressants

Disqualifiers: Gilbert syndrome, Active malignancy, others

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

Compensation: Varies

Number of Visits: 24

Duration: Up to 24 cycles

9 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments to determine the best dose and understand the side effects for people with advanced urothelial cancer, a type of bladder cancer that cannot be surgically removed or has spread. The study combines durvalumab, an immunotherapy drug that helps the immune system fight cancer, with belinostat, a drug that may stop cancer cell growth, and tremelimumab, another immunotherapy drug. Patients with advanced bladder cancer who have tried other treatments without success or have declined standard treatments might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement for a washout period (time without taking certain medications) of at least 5 half-lives for prohibited medications before starting the trial treatment.

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

Research shows that the combination of durvalumab and belinostat has been tested for safety in people with advanced bladder cancer. Most people can manage the common side effects of durvalumab, which include fatigue, nausea, and reduced appetite. These side effects are usually mild to moderate.

Belinostat, still under study, works by blocking certain enzymes that help cancer cells grow. As this is an early-stage trial, the goal is to find safe doses and monitor side effects. Earlier studies suggest that participants have tolerated these treatments fairly well.

Since reactions vary, discussing any concerns with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple therapy for bladder cancer because it combines three powerful agents: belinostat, durvalumab, and tremelimumab, each offering unique benefits. Unlike standard treatments like chemotherapy, which target rapidly dividing cells, belinostat is a histone deacetylase inhibitor that can modify gene expression and potentially reverse cancer cell resistance. Durvalumab and tremelimumab are both immune checkpoint inhibitors, but they work at different points in the immune response, enhancing the body's ability to recognize and attack cancer cells more effectively. This combination has the potential to not only improve treatment response but also extend the duration of its effectiveness, offering new hope for patients with bladder cancer.

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

Research has shown that durvalumab yields promising results in treating bladder cancer. In earlier studies, patients who received durvalumab experienced longer periods without disease progression. Durvalumab enhances the immune system's ability to identify and destroy cancer cells. In this trial, participants will receive a combination of durvalumab and belinostat. Belinostat slows cancer cell growth by targeting specific proteins involved in cell growth and survival. Using durvalumab and belinostat together may enhance the body's ability to fight cancer, offering hope for improved outcomes in treating urothelial cancer. ^{1 2 3 5 6}

Who Is on the Research Team?

Sumati V Gupta

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Are You a Good Fit for This Trial?

Adults (18+) with advanced urothelial carcinoma that's spread or can't be surgically removed, who've tried at least one therapy or declined/aren't suitable for standard treatments. They must have ARID1A gene alterations, measurable disease, good organ function and blood counts, and a life expectancy of over 12 weeks. Women must not be pregnant and use effective contraception.

Inclusion Criteria

My cancer can be measured by scans.

I have recovered from previous treatment side effects, or they are minor and stable.

My kidneys are working well enough, with a creatinine clearance of at least 30 mL/min.

Exclusion Criteria

I have brain metastases or cranial epidural disease.

I have been treated with durvalumab and tremelimumab before.

I haven't had cancer treatment or experimental therapy in the last 14 days or within 5 half-lives of the drug.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab and tremelimumab initially, followed by belinostat starting from cycle 2. Treatment repeats every 21 days for 7 cycles, then durvalumab every 28 days for up to 24 cycles.

Up to 24 cycles

Visits every 21 days for 7 cycles, then every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Every 3 months for 1 year, then every 6 months for 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Belinostat
• Durvalumab
• Tremelimumab

Trial Overview The trial is testing the combination of two drugs: Belinostat (an HDAC inhibitor that may stop cancer cells from growing) and Durvalumab (a monoclonal antibody designed to help the immune system attack cancer). It aims to find the safest dose with acceptable side effects for patients with specific genetic changes in their tumors.

How Is the Trial Designed?

Group I: Treatment (durvalumab, belinostat) Experimental Treatment 2 Interventions

Phased Doublet Therapy Eligible patients enrolled will be administered durvalumab 1120 mg every 3 weeks C1 through C7 followed by durvalumab 1500 mg every four weeks C8 through C15 (T300+D). Belinostat administration will begin with Cycle 2 for 6 cycles. From cycle 8 on, durvalumab will be administered in 28-day cycles to complete up to a total of 15 cycles of treatment or until treatment discontinuation criteria is met. Belinostat will be administered at the assigned dose level on days one through five of every applicable cycle. Belinostat administration on five consecutive days is preferred. Administration within seven days of Day 1 is allowed as needed to accommodate holidays and infusion schedules. Durvalumab will be infused over 60 minutes (±10 minutes). For Cycles 2-7, belinostat will be infused over 30 minutes (-5 minutes/+15 minutes) and will be administered after durvalumab. Separate infusion bags and filters must be used for each infusion.

Belinostat is already approved in United States for the following indications:

Approved in United States as Beleodaq for:

• Peripheral T-cell lymphoma (PTCL)

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of nivolumab, an immune checkpoint inhibitor, with neoadjuvant chemotherapy (NAC) is being investigated in a Phase III trial (ENERGIZE) for its efficacy in treating muscle-invasive bladder cancer (MIBC) in cisplatin-eligible patients, potentially improving overall survival rates.

Linrodostat mesylate, an IDO1 inhibitor, shows promise when combined with nivolumab, as it has demonstrated safety and preliminary clinical activity in metastatic urothelial carcinoma, suggesting a synergistic effect that could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Sonpavde, G., Necchi, A., Gupta, S., et al.[2020]

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 1 study involving 8 patients with localized muscle invasive bladder cancer, the combination of atezolizumab, radiation therapy, and gemcitabine resulted in significant gastrointestinal toxicity, leading to dose adjustments and the study's termination.

Despite the serious side effects observed, no grade 4 or 5 adverse effects were reported, indicating that while the treatment combination is concerning in terms of safety, it did not lead to the most severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer. Marcq, G., Souhami, L., Cury, FL., 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 immune checkpoint inhibitors (ICI) and antibody-drug conjugates like enfortumab vedotin show promising safety and potential for achieving pathologic complete response (pCR) in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy, based on recent clinical trials.

Combining ICIs with radiation therapy appears to be safe and effective, highlighting the need for biomarkers to tailor treatment options and improve outcomes for individual patients with MIBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle invasive bladder cancer: where is the field headed? Ghatalia, P., Kaur, J., Sonpavde, G.[2023]

Citations

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Efficacy and Clinical Trial Data for IMFINZI® (durvalumab) Healthcare professionals can review efficacy data for IMFINZI and clinical trial results in FDA-approved indications.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05154994

Tremelimumab + Durvalumab(MEDI4736)+ Belinostat in ... This phase I trial studies the side effects and best dose of belinostat when given together with durvalumab in treating patients with urothelial cancer that ...

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IMFINZI® (durvalumab) regimen demonstrated statistically ... Patients lived significantly longer without high-risk disease recurrence or progression after one year of IMFINZI treatment plus Bacillus Calmette-Guérin (BCG) ...

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Safety and Efficacy of Durvalumab (MEDI4736), an ... - PubMed Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, ...

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FDA approves durvalumab for muscle invasive bladder ... The major efficacy outcome was event-free survival (EFS) by blinded independent central review. Overall survival (OS) was an additional efficacy ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5569690/

Safety and Efficacy of Durvalumab (MEDI4736), an Anti ... Durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.