Durvalumab + Monalizumab for Bladder Cancer

(ENHANCE Trial)

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

Trial Summary

What is the purpose of this trial?

This is a phase 2 open-label two cohort study of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed CIS NMIBC. Arm A will enroll 43 participants who have cancer in situ (CIS) with or without high grade papillary urothelial cancer. Arm B will enroll 17 participants who do not have cancer in situ (CIS) but do have high grade papillary urothelial cancer. Eligible patients will be enrolled to receive up to 13 cycles of monthly combination of monalizumab and durvalumab. Both monalizumab and durvalumab will be administered intravenously (IV) every 28 days.

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.

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

Durvalumab has shown promising results in treating bladder cancer, particularly in patients who have not responded well to previous chemotherapy. It has been approved for use in advanced bladder cancer and has demonstrated meaningful clinical activity in improving patient outcomes. ^{1 2 3 4 5}

Is the combination of Durvalumab and Monalizumab safe for humans?

Durvalumab has been tested in various trials for bladder cancer and other conditions, showing an acceptable safety profile with severe treatment-related side effects occurring in 6% to 41% of patients. More research is needed to fully understand the safety of combining it with Monalizumab. ^{1 2 4 5 6}

How is the drug combination of Durvalumab and Monalizumab unique for treating bladder cancer?

The combination of Durvalumab and Monalizumab is unique because it involves two immune checkpoint inhibitors that work together to enhance the body's immune response against bladder cancer cells. Durvalumab blocks a protein that helps cancer cells evade the immune system, while Monalizumab targets another pathway to further boost immune activity, offering a novel approach compared to traditional chemotherapy. ^{1 2 4 5 7}

Research Team

John Sfakianos, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

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

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

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

I am fully active or have some restrictions but can still carry out light work.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. [2021]

2. 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]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens. [2022]

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

Durvalumab: First Global Approval. [2022]

5. United States 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. [2023]

6. United States 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. [2021]

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

A Phase II Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. [2023]