Romidepsin + Durvalumab for Bladder Cancer

Overseen By Sricharan Pusala

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Immune checkpoint inhibitors, CYP3A modulators

Disqualifiers: Autoimmune disease, Cardiac diseases, others

Stay on Your Current Meds You can continue your current medications while participating

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: Unknown

Duration: 8 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, we aim to evaluate the safety and efficacy of neoadjuvant combination using intravesical romidepsin and durvalumab in cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC).

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

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking medications that are strong inhibitors or inducers of CYP3A, or if you are on concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.

What data supports the effectiveness of the drug Durvalumab for bladder cancer?

Durvalumab has shown meaningful clinical activity in patients with metastatic urothelial carcinoma, a type of bladder cancer, as seen in Study 1108. Additionally, it has been effective in improving overall survival in patients with advanced lung cancer, suggesting its potential benefit in other cancers as well. ^{1 2 3 4 5}

Is the combination of Romidepsin and Durvalumab safe for humans?

Durvalumab has been studied for safety in various cancers, including bladder cancer. It has shown some adverse effects like reduced appetite and diarrhea, especially when combined with other drugs. However, specific safety data for the combination of Romidepsin and Durvalumab is not provided in the available research. ^{1 3 6 7 8}

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

The combination of Romidepsin and Durvalumab is unique because it combines a histone deacetylase inhibitor (Romidepsin) with an immune checkpoint inhibitor (Durvalumab), potentially enhancing the immune system's ability to fight bladder cancer by targeting different mechanisms. This approach is novel compared to standard treatments that typically focus on chemotherapy or single-agent immunotherapy. ^{1 2 9 10 11}

Research Team

Jingsong Zhang, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for patients with muscle invasive bladder cancer who cannot receive cisplatin. Participants should not have had prior treatments for their condition and must be fit enough to undergo the procedures involved in the study.

Inclusion Criteria

Willing to provide tumor tissue, blood, and urine samples for research.

Participants must have adequate organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1500/mcL; Platelet count ≥100,000/mcL; Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN); total bilirubin must be < 3 x ULN for patients with Gilberts syndrome; AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal; Measured creatinine CL >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.

Patient must have a life expectancy of at least 12 weeks.

Exclusion Criteria

Patients unwilling or unable to comply with the protocol.

Patients who have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion.

Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravesical romidepsin and durvalumab. Romidepsin is administered at varying dose levels on C1D1, and durvalumab is given at a fixed dose every 4 weeks on C1D1 and C2D1.

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of pathologic response and relapse-free survival.

Up to 1 year

Treatment Details

Interventions

• Durvalumab
• Romidepsin

Trial Overview The study tests a combination of two drugs, romidepsin (administered directly into the bladder) and durvalumab (given intravenously), to see if they are safe and effective when given before surgery to remove bladder tumors.

Participant Groups

Group I: Dose Level 3 Experimental Treatment 2 Interventions

Romidepsin Level 3: 2.0 ng/m on C1D1. Durvalumab: The recommended fixed dose of durvalumab is 1500 mg every 4 weeks and will be given on C1D1 and C2D1.

Group II: Dose Level 2 Experimental Treatment 2 Interventions

Romidepsin Level 2: 0.4 ng/ml on C1D1. Durvalumab: The recommended fixed dose of durvalumab is 1500 mg every 4 weeks and will be given on C1D1 and C2D1.

Group III: Dose Level 1 Experimental Treatment 2 Interventions

Romidepsin Level 1: 0.2 ng/ml on C1D1. Durvalumab: The recommended fixed dose of durvalumab is 1500 mg every 4 weeks and will be given on C1D1 and C2D1.

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

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

In a study of patients with metastatic urothelial carcinoma, treatment with durvalumab led to significant improvements in health-related quality of life (HRQOL) and disease-related symptoms, as measured by the FACT-Bl and EORTC QLQ-C30 questionnaires.

The improvements in patient-reported outcomes were correlated with better tumor shrinkage and reductions in inflammatory biomarkers, suggesting that durvalumab not only helps manage cancer symptoms but may also positively influence systemic inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose-escalation study 1108. O'Donnell, PH., Arkenau, HT., Sridhar, SS., et al.[2021]

Durvalumab, a monoclonal antibody targeting PD-L1, showed a manageable safety profile in patients with advanced urothelial bladder cancer, with common side effects including fatigue and diarrhea, but no severe (grade 4 or 5) adverse events reported.

The treatment demonstrated a 31% overall response rate, with a significantly higher response of 46.4% in patients with PD-L1-positive tumors, indicating that PD-L1 expression may play a crucial role in the efficacy of durvalumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. Massard, C., Gordon, MS., Sharma, S., et al.[2022]

The SUBDUE-1 trial is a phase I study evaluating the safety and immunological efficacy of sub-urothelial injections of durvalumab in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer, involving three dose levels (25, 75, 150 mg) to determine the optimal dose for future trials.

If successful, this local administration method may reduce tumor recurrence and progression while minimizing immunological side effects and costs compared to traditional systemic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (SUBDUE-1, SUB-urothelial DUrvalumab injection-1 study): clinical trial protocol. Moe, A., Liow, E., Redfern, A., et al.[2021]

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]

Thirteen clinical trials are currently investigating the use of immune checkpoint inhibitors as a treatment for high-risk non-muscle-invasive bladder cancer, particularly in patients who have not responded to Bacillus Calmette-Guérin (BCG) therapy.

Preliminary results from trials like SWOG S1605 and Keynote-057 indicate that checkpoint inhibitors, such as Pembrolizumab, show promising antitumor activity and are generally well-tolerated, suggesting they could be a viable alternative for patients with BCG-unresponsive bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoints inhibitors in the management of high-risk non-muscle-invasive bladder cancer. A scoping review. García-Perdomo, HA., Sánchez, AL., Spiess, PE.[2022]

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

Patient-reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose-escalation study 1108. [2021]

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

An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. [2022]

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

Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. [2022]

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

Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced, Unresectable KRAS-mutated Non-Small Cell Lung Cancer. [2023]

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

Five years after PACIFIC: update on multimodal treatment efficacy based on real-world reports. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (SUBDUE-1, SUB-urothelial DUrvalumab injection-1 study): clinical trial protocol. [2021]

7. 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]

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

Immune checkpoints inhibitors in the management of high-risk non-muscle-invasive bladder cancer. A scoping review. [2022]

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

Durvalumab: First Global Approval. [2022]

10. 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]

11. 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]