Avelumab and M1774 in ARID1A-mutated Endometrial Cancer

NCT06518564 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 24-301
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

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)

Conditions

Endometrial Cancer; ARID1A Gene Mutation; Recurrent Endometrial Carcinoma

Keywords

Endometrial Cancer; ARID1A Mutated Recurrent Endometrial Cancer; Recurrent Endometrial Cancer

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival at 6 months (PFS6)

  PFS6 is the percent probability estimate at 6 months based on the Kaplan-Meier method. PFS is defined as the duration of time from study entry to documented disease progression (PD) or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.

  The observation period related to this endpoint is up to 6 months.

• Objective Response Rate (ORR)

  ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

  The observation period related to this endpoint is up to 2 years.

Secondary Outcomes (5)

• Median Progression Free Survival (PFS)

  The observation period related to this endpoint is up to 2 years.

• Median Overall Survival (OS)

  The observation period related to this endpoint is up to 5 years.

• Immune-Related Overall Response Rate(irORR)

  The observation period related to this endpoint is up to 2 years.

• Median Immune-related Progression-free Survival (irPFS)

  The observation period related to this endpoint is up to 2 years.

• Grade 3-5 Treatment-Related Toxicity Rate

  The observation period related to this endpoint is up to 2 years.

Study Arms (1)

Avelumab and M1774

EXPERIMENTAL

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 up to 3 years.

Drug: Avelumab; Drug: M1774

Interventions

Avelumab DRUG

Human IgG1 antibody, 20mL single-use vials, via intravenous (into the vein) infusion per protocol.

Also known as: MSB0010718C

Avelumab and M1774

M1774 DRUG

Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitor, 30 and 50 mg capsules, taken orally per protocol.

Also known as: MSC2584415A, Tuvusertib, VXc-400, VRT-1363004, 2-Amino-6-fluoro-pyrazolo[1,5-a] pyrimidine-3-carboxylic acid [5-fluoro-4-(3-methyl-3H-imidazol-4-yl)-pyridin-3-yl]-amide

Avelumab and M1774

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have endometrial cancer that is ARID1A-mutated \[loss of function (LOF) mutations\] determined by any CLIA-certified next-generation sequencing assay. ARID1A LOF mutation status must be confirmed by the principal investigator prior to participant enrollment.
• Participants must have measurable disease per RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions). Each lesion must be \>= 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or \>= 20 mm when measured by chest x-ray. Lymph nodes must be \> 15 mm in short axis when measured by CT or MRI.
• Prior Therapy: There is no upper limit of prior therapies, but patients must have had one prior chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy. Furthermore, patients who have only received chemotherapy with immunotherapy in the adjuvant setting will be eligible for the study.
• Prior hormonal therapy is allowed (no washout period is required after hormonal therapy).
• Participants must have received prior immunotherapy targeting the PD-1/PD-L1 pathway either in the adjuvant, first-line or recurrent setting. Up to 50% of participants (i.e. a maximum of 12 participants) who do not meet this requirement may enroll in the study.
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of the combination of avelumab and M1774 in participants \<18 years of age, children are excluded from this study.
• ECOG performance status 0, 1, or 2 (reference Appendix A for ECOG performance status criteria).
• Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue OR 15 unstained 5-micron slides from the original surgery or biopsy or from a biopsy of recurrent disease.
• Participants must meet the following organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,500/mcL
• Hemoglobin ≥ 9.0 g/dL (with no erythropoietin or red blood cell transfusion within the last 14 days)
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) in the case of documented Gilbert's syndrome, total bilirubin ≤3 x ULN is allowed
• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN in patients with documented hepatic involvement, AST/ALT ≤ 5 x ULN is allowed
• Creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault formula or institutional standard method OR

You may not qualify if:

• Participants who have had chemotherapy, immunotherapy, other investigational therapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. There is no required washout period for hormonal therapy.
• Participants whose adverse events due to prior anti-cancer therapy have not recovered to ≤ Grade 1, unless toxicity does not constitute a safety risk and/or is stable on supportive therapy in the opinion of the investigator (e.g., alopecia, sensory neuropathy ≤ Grade 2, etc.)
• Participants who are receiving any other investigational agents.
• Participants with clinically controlled brain metastases, which is defined as individuals with central nervous system metastases that have been treated for, are asymptomatic, and have discontinued corticosteroids for \> 14 days or are on a stable or decreasing steroid dose (for the treatment of brain metastases) may be enrolled. Participants with meningeal carcinomatosis are excluded.
• Known prior severe hypersensitivity to avelumab or M1774 or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (≥ Grade 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
• Active and/or uncontrolled infection. The following exceptions apply:
• Participants with HIV infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction
• Participants with evidence of chronic HBV infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have ALT, AST, and total bilirubin levels \< ULN, and provided there is no expected drug- drug interaction
• Participants with a history of HCV infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels \< ULN.
• Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day.
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
• History of prior organ transplantation including allogeneic stem-cell transplantation.

Sponsors & Collaborators

• Panagiotis Konstantinopoulos, MD, PhD: lead
• EMD Serono: collaborator
• The Applebaum Foundation: collaborator

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

avelumab

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Panagiotis Konstantinopoulos, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Panagiotis Konstantinopoulos, MD, PhD

CONTACT

617-632-5269; Panagiotis_Konstantinopoulos@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: July 18, 2024
• First Posted: July 24, 2024
• Study Start: November 14, 2024
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2029
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)