Avelumab + M1774 for Endometrial Cancer

Recruiting at 1 trial location

Overseen By Panagiotis Konstantinopoulos, MD, PhD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Panagiotis Konstantinopoulos, MD, PhD

Must be taking: Immunotherapy

Must not be taking: Immunosuppressants, Herbal products

Disqualifiers: Uncontrolled infection, Brain metastases, 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: 31

Duration: up to 2 years

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, avelumab and M1774, to evaluate their effectiveness and safety for people with endometrial cancer. Avelumab is an antibody that aids the immune system in fighting cancer, while M1774 (also known as Tuvusertib) blocks certain cancer cell processes. This trial may suit those with endometrial cancer who have a specific genetic mutation called ARID1A and have already tried other treatments. Participants will undergo regular scans and follow-up visits to monitor the treatment's effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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, but you cannot take certain herbal products or medications that strongly affect specific liver enzymes. It's best to discuss your current medications with the trial team to ensure there are no interactions.

Is there any evidence suggesting that the combination of avelumab and M1774 is likely to be safe for humans?

Research shows that the combination of avelumab and M1774 has been studied to assess its safety and tolerability. Avelumab is a medicine that helps the immune system identify and fight cancer cells, while M1774 targets specific proteins in cancer cells to inhibit their growth.

Studies have found that avelumab, whether used alone or with other drugs, is generally well-tolerated. Common side effects include fatigue, nausea, and injection site reactions, but these are usually manageable.

Earlier research on M1774 has also focused on its safety. Reports suggest that side effects for M1774 can include tiredness and stomach issues like nausea, but these are typically mild to moderate.

The combination of avelumab and M1774 has been studied, and initial findings suggest that it is safe enough for further research, leading to its testing in this trial. However, like any treatment, there is a risk of side effects, and researchers are closely monitoring participants to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avelumab combined with M1774 for endometrial cancer because it offers a unique approach compared to current treatments like surgery, radiation, and chemotherapy. Avelumab is an immunotherapy that helps the immune system recognize and attack cancer cells, a method distinct from traditional treatments. M1774 is a novel agent with a new mechanism that may enhance the effectiveness of Avelumab. Together, these treatments could provide a synergistic effect, potentially leading to better outcomes for patients.

What evidence suggests that the combination of avelumab and M1774 could be an effective treatment for endometrial cancer?

In this trial, participants will receive a combination of avelumab and M1774 to treat endometrial cancer. Research has shown that avelumab, which helps the immune system find and attack cancer cells, combined with M1774, a drug that prevents cancer cells from repairing themselves, may be effective. Early results suggest this combination might be particularly effective for cancers with specific mutations, such as ARID1A. Although more studies are necessary, this approach relies on a solid understanding of how these drugs work against cancer cells. ^{1 3 5 6 7}

Who Is on the Research Team?

Panagiotis Konstantinopoulos, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with endometrial cancer that has returned and have a specific genetic change called an ARID1A mutation. Details on who can join or reasons why someone might not be able to participate are not provided.

Inclusion Criteria

I can provide a tissue sample from my cancer surgery or biopsy.

My organ and bone marrow functions meet the required levels.

My endometrial cancer has a specific genetic change known as ARID1A mutation.

Exclusion Criteria

My side effects from previous cancer treatments have not fully improved.

I have not had chemotherapy or radiotherapy recently.

I have specific health conditions or lab test results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avelumab and M1774 with a dose de-escalation plan for M1774 in a 42-day cycle

up to 2 years

Days 1, 15, 29 of 42-day Cycle for Avelumab; Days 1-14 and 22-35 for M1774

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

30-day post-treatment, 90-day post-treatment, and every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• M1774

Trial Overview The study is testing the effectiveness and safety of combining two drugs, Avelumab (an antibody) and M1774 (an ATR inhibitor), in treating endometrial cancer with ARID1A mutations.

How Is the Trial Designed?

Group I: Avelumab and M1774 Experimental Treatment 2 Interventions

25 participants will be enrolled and complete study procedures. The first 6 participants enrolled will take part in a lead-in phase with a dose de-escalation plan for M1744, starting at Dose Level 0 and decreasing to Dose Level -1 and then -2 if applicable per the protocol depending on the occurrence of dose-limiting toxicities. Participants will complete: * Baseline visit with assessments and CT or MRI scan. * CT or MRI scans every 12 weeks * Cycle 1 through End of Treatment: * Days 1 - 14 and 22 - 35 of 42-day Cycle: Predetermined dose of M1774 1x daily. * Days 1, 15, 29 of 42-day Cycle: Predetermined dose of Avelumab 1x daily. * End of Treatment visit with with CT or MRI scan * 30 day post-treatment follow up visit * 90 day post-treatment follow up * Long term follow up every 6 months for 3 years.

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Panagiotis Konstantinopoulos, MD, PhD

Lead Sponsor

Trials

1

Recruited

30+

The Applebaum Foundation

Collaborator

Trials

2

Recruited

330+

EMD Serono

Industry Sponsor

Trials

147

Recruited

27,800+

Dr. Shepard

EMD Serono

Chief Medical Officer since 2021

MD from University of Cincinnati Medical School, Fellowships in Hematology and Oncology at University of Chicago Hospitals and Clinics

Miguel Fernández Alcalde

EMD Serono

Chief Executive Officer

Bachelor's Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master's Degree in Management from IESE Business School

Published Research Related to This Trial

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

In a study of 48 patients with recurrent endometrial cancer treated with pembrolizumab and lenvatinib, the best objective response rate was 23.8%, indicating a lower effectiveness compared to clinical trial results.

The treatment was associated with notable side effects, with 56.2% of patients requiring a dose reduction of lenvatinib and 16.7% discontinuing treatment due to adverse events, highlighting the importance of monitoring for safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. Kim, J., Noh, JJ., Lee, TK., et al.[2022]

The combination of pembrolizumab and lenvatinib has shown improved overall response rates (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced and recurrent endometrial cancer, particularly those who are microsatellite stable (MSS) or mismatch repair proficient (pMMR) after failing platinum-based chemotherapy.

This treatment regimen is considered safe and effective, but clinicians must monitor patients for potential toxicities and be prepared to adjust dosages as necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib combination therapy for advanced endometrial carcinoma. Walker, CA., Spirtos, AN., Miller, DS.[2023]

In a study of 44 women with advanced or recurrent MMRd/MSI-H endometrial adenocarcinomas treated with pembrolizumab, obesity (BMI≥30) was linked to a higher disease control rate (85.2%) compared to those with a BMI<30 (59.8%).

Patients with obesity also experienced significantly longer progression-free survival (PFS) while overall survival (OS) rates remained similar regardless of BMI, suggesting that body weight may influence treatment outcomes with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. Bernard, L., How, JA., Patel, S., et al.[2023]

The combination of lenvatinib and pembrolizumab significantly improved treatment outcomes for patients with advanced endometrial cancer compared to chemotherapy, regardless of tumor characteristics, based on data from Study-309/KEYNOTE-775.

Common adverse reactions included hypothyroidism, hypertension, and fatigue, with effective management strategies involving patient education, monitoring, and appropriate dose adjustments to minimize treatment interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab. Colombo, N., Lorusso, D., Monk, BJ., et al.[2023]

A patient with stage IV endometrial cancer, who was MMR-proficient and PD-L1-negative, showed a strong and lasting response to a combination of PD-1 and CTLA-4 inhibitors, nivolumab and ipilimumab, for over 12 months.

This case suggests that there may be an endometrial cancer subtype that responds to immune checkpoint inhibitors through mechanisms not solely related to MMR deficiency or PD-L1 positivity, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep and Durable Response With Combination CTLA-4 and PD-1 Blockade in Mismatch Repair (MMR)-proficient Endometrial Cancer. Oh, MS., Chae, YK.[2021]

Citations

1. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/518655

Avelumab and M1774 in ARID1A-mutated Endometrial Cancer The purpose of this research study is to see if the combination of study drugs avelumab and M1774 is effective and safe for participants ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05396833

NCT05396833 | Study of Tuvusertib (M1774) in ... This is an open-label, multicenter, clinical study conducted in multiple parts to establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-09545

Avelumab with M1774 for the Treatment of Patients ... This phase II trial tests how well avelumab in combination with M1774 work together for treating patients with ARID1A-mutated endometrial cancer.

4. sciencedirect.com sciencedirect.com/science/article/pii/S030573722400118X

Locally advanced and metastatic endometrial cancer This review provides a comprehensive overview of historical, current, and promising therapies in advanced and metastatic endometrial cancer.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11640124/

Advances in Immunotherapy for Endometrial Cancer In NCT06518564, researchers are testing the safety and efficacy of Avelumab in combination with M1774, a type of ATR inhibitor for ARID1A-deficient EC.

6. dana-farber.org dana-farber.org/clinical-trials/24-301

A Phase 2 Study of Avelumab in Combination with ATR ... The purpose of this research study is to see if the combination of study drugs avelumab and M1774 is effective and safe for participants with endometrial ...

7. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2022-0248.html?PageSpeed=noscript

An Open-label, Multicenter Phase Ib Study of the Safety, ... This is an open-label, multicenter, clinical study conducted in multiple parts to establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic ...