Avelumab + M1774 for Endometrial Cancer

Recruiting at1 trial location

Overseen by Panagiotis Konstantinopoulos, MD, PhD

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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 cancer. The names of the study drugs involved in this study are: * Avelumab (a type of human IgG1 antibody) * M1774 (a type of ATR inhibitor)

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.

What data supports the effectiveness of the drug Avelumab + M1774 for endometrial cancer?

Research shows that similar drugs, like pembrolizumab combined with lenvatinib, have been effective in treating advanced endometrial cancer, improving outcomes compared to traditional chemotherapy. This suggests that combining immune-based treatments, like Avelumab, could also be beneficial for endometrial cancer. ^{1 2 3 4 5}

How is the drug Avelumab + M1774 unique for treating endometrial cancer?

Avelumab + M1774 is unique because it combines an immune checkpoint inhibitor (Avelumab) with a novel agent (M1774), potentially offering a new mechanism of action compared to existing treatments like pembrolizumab and lenvatinib, which are also used for advanced endometrial cancer. ^{1 3 4 5 6}

Research Team

Panagiotis Konstantinopoulos, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Avelumab (Monoclonal Antibodies)
• M1774 (Other)

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.

Participant Groups

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 Japan for the following indications:

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

Findings from Research

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]

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]

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]

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]

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 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]

References

1. United States 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. [2022]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab. [2023]

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

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. [2022]

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

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. [2023]

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

Pembrolizumab plus lenvatinib combination therapy for advanced endometrial carcinoma. [2023]