Durvalumab + Monalizumab for Bladder Cancer

(ENHANCE Trial)

Recruiting at 1 trial location

Overseen By Rebecca Mottier

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: John Sfakianos

Must not be taking: Immunosuppressants, PD-1/PD-L1 blockers

Disqualifiers: Metastatic disease, Autoimmune disorders, 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: 13

Duration: 12 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two immunotherapy drugs, durvalumab and monalizumab, to evaluate their effectiveness against certain types of bladder cancer. It targets non-muscle-invasive bladder cancer that has not responded well to a common treatment called BCG. Participants will receive both drugs through an IV every four weeks for up to a year. Individuals with persistent high-risk bladder cancer after BCG therapy might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you cannot be on certain immunosuppressive therapies or have had prior PD-1/PD-L1 treatments. It's best to discuss your current medications with the study team to ensure they don't conflict with the trial requirements.

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

Research has shown that durvalumab is generally safe for people with advanced bladder cancer. The FDA has already approved it for treating certain types of bladder cancer, indicating it is usually well-tolerated. One study found that most patients managed the treatment well, although some experienced side effects like tiredness and nausea.

Monalizumab remains under study, and early research suggests it might be safe when used with durvalumab. This trial is in its early stages and focuses on assessing the safety of using both drugs together. So far, combining these treatments hasn't revealed any major safety issues. However, monitoring for any side effects during the trial remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Durvalumab and Monalizumab for bladder cancer because they offer a fresh approach compared to traditional treatments like chemotherapy or surgery. Most standard treatments focus on directly attacking cancer cells, but these drugs target the immune system. Durvalumab is a checkpoint inhibitor that unleashes the immune system to attack cancer cells by blocking the PD-L1 protein. Monalizumab, on the other hand, is an innovative NK cell checkpoint inhibitor that enhances the activity of natural killer cells, another vital player in the immune response. This dual approach not only aims to effectively target cancer cells but also hopes to reduce side effects commonly associated with more aggressive treatments.

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

Research shows that durvalumab holds promise for treating advanced bladder cancer. It blocks a protein that typically helps cancer evade the immune system, enabling the body to combat the cancer more effectively. Studies have found durvalumab to be safe and effective for patients with urothelial carcinoma, a type of bladder cancer, leading to its FDA approval. In this trial, participants in both Cohort A and Cohort B will receive a combination of durvalumab and monalizumab. Researchers believe monalizumab enhances the immune response further when combined with durvalumab. Early studies suggest this combination could benefit bladder cancer patients, especially those unresponsive to other treatments. ^{1 2 3 5 6}

Who Is on the Research Team?

John Sfakianos, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

Adults over 18 with non-muscle-invasive bladder cancer who've had BCG treatment but still have disease signs. They must be able to follow the study plan and give consent. Those with mixed cancer types are eligible, but not those with purely variant histology.

Inclusion Criteria

I have CIS with or without high-grade bladder cancer.

I am willing and able to follow the study's requirements and provide consent.

My lung cancer is a mix of adenocarcinoma and squamous cell, not just one type.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 13 cycles of monthly combination of monalizumab and durvalumab administered intravenously every 28 days

12 months

13 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Monalizumab

Trial Overview The trial is testing a combination of two drugs, Monalizumab and Durvalumab, given monthly through IV for up to 13 cycles in patients with specific types of bladder cancer that haven't responded well to BCG therapy.

How Is the Trial Designed?

Group I: Cohort B: Durvalumab and Monalizumab for high grade papillary urothelial cancer without CIS Experimental Treatment 2 Interventions

Durvalumab 1500mg IV and monalizumab 1500mg IV will be administered to all patients once every 4 weeks. A cycle is equal to 4 weeks. This will continue until disease progression, unacceptable toxicity, or for a maximum of 1 year.

Group II: Cohort A: Durvalumab and Monalizumab for CIS +/- high grade papillary urothelial cancer Experimental Treatment 2 Interventions

Durvalumab 1500mg IV and monalizumab 1500mg IV will be administered to all patients once every 4 weeks. A cycle is equal to 4 weeks. This will continue until disease progression, unacceptable toxicity, or for a maximum of 1 year.

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?

John Sfakianos

Lead Sponsor

Trials

1

Recruited

60+

Bladder Cancer Advocacy Network

Collaborator

Trials

2

Recruited

190+

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

Icahn School of Medicine at Mount Sinai

Collaborator

Trials

933

Recruited

579,000+

Bladder Cancer Advocacy Network

Collaborator

Trials

4

Recruited

430+

Published Research Related to This Trial

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 II study involving 61 patients with muscle-invasive urothelial carcinoma, the addition of neoadjuvant durvalumab to standard chemotherapy resulted in a high event-free survival (EFS) rate of 76% at 2 years, indicating promising efficacy in this treatment approach.

The study also reported an overall survival (OS) rate of 85% at 2 years, although 42% of patients experienced grade 3 or 4 treatment-related adverse events during the neoadjuvant phase, highlighting the need to balance efficacy with safety in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. Cathomas, R., Rothschild, SI., Hayoz, S., et al.[2023]

Atezolizumab, an anti-PD-L1 therapy, showed significant efficacy in treating metastatic urothelial carcinoma (mUC) patients who had progressed after platinum-based chemotherapy, with objective response rates and overall survival benefits observed across all treatment lines in a study of 315 patients.

The treatment was found to be safe and well-tolerated, with no significant differences in efficacy or adverse effects based on the number of prior therapies, indicating its potential as a viable option for patients regardless of their treatment history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens. Perez-Gracia, JL., Loriot, Y., Rosenberg, JE., et al.[2022]

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]

In a phase II study involving 17 patients with BCG-unresponsive carcinoma in situ of the bladder, durvalumab showed a low complete response rate of only 12% at 6 months, indicating minimal efficacy for this condition.

The treatment was associated with some immune-related adverse events in 41% of patients, and a potential mechanism for resistance was identified through elevated complement activation genes post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Li, R., Sexton, WJ., Dhillon, J., 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]

The combination of durvalumab and cabozantinib was found to be safe in a phase 2 study with 16 patients, showing no severe treatment-related adverse events in the first two cycles, although common mild side effects included fatigue and diarrhea.

Preliminary results indicated that 37.5% of patients experienced objective responses, including two complete responses, suggesting that this combination therapy may be effective for patients with advanced metastatic urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial. Marandino, L., Raggi, D., Calareso, G., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06503614

Study Details | NCT06503614 | A Trial of Durvalumab ... This is a phase 2 open-label two cohort study of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed CIS NMIBC.

2. 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.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.778

Feasibility and safety results from RAD-IO A multi-stage trial of durvalumab (Medi4736) with chemoradiotherapy with 5-fluorouracil and mitomycin C in patients with muscle-invasive bladder cancer.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6452813/

Durvalumab for the management of urothelial carcinoma Durvalumab is a safe and effective therapeutic option in UC and was granted FDA approval in May 2017 based on the results of the Phase I/II trial.

5. imfinzihcp.com imfinzihcp.com/bladder-cancer/muscle-invasive/efficacy.html

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

6. researchgate.net researchgate.net/publication/303832509_Safety_and_Efficacy_of_Durvalumab_MEDI4736_an_Anti-Programmed_Cell_Death_Ligand-1_Immune_Checkpoint_Inhibitor_in_Patients_With_Advanced_Urothelial_Bladder_Cancer

(PDF) Safety and Efficacy of Durvalumab (MEDI4736), an ... Purpose: To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), ...