Inclusion Criteria:
* 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.
* 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
* Creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault formula or institutional standard method OR
* Glomerular filtration rate (GFR) ≥ 60 mL/min by measured 24-hour urine collection
* The effects of avelumab and M1774 on the developing human fetus are unknown. For this reason and because these agents are known to be teratogenic, women of child-bearing potential must have a negative serum pregnancy test at screening. Women of child- bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 30 days after last avelumab treatment administration and at least 6 months after last M1774 treatment administration. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
--Women of child-bearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation or salpingectomy, bilateral oophorectomy, or total hysterectomy) or post-menopausal (defined as ≥ 12 months with no menses without an alternative medical cause)
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
* 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.
* Current or prior use of immunosuppressive medication within 7 days prior to enrollment with the following exceptions to this exclusion criterion:
* 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.
* Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4 weeks prior to enrollment, or history of inflammatory bowel disease.
* Participants with psychiatric conditions (including active or recent \[within the past year\] suicidal ideation of behavior)/social situations that, in the judgment of the investigator, would make the participant inappropriate for study entry.
* Participants with uncontrolled or poorly controlled arterial hypertension, symptomatic congestive heart failure (≥ New York Heart Association Classification Class III), uncontrolled cardiac arrhythmia, unstable angina pectoris, myocardial infarction or a coronary revascularization procedure, cerebral vascular incident, transient ischemic attack, or any other significant vascular disease within 180 days of study intervention start.
* Known alcohol or drug abuse.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years or if they are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
* All other severe acute or chronic medical conditions (for example, immune colitis, inflammatory bowel disease, uncontrolled asthma, immune pneumonitis, or pulmonary fibrosis) or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration in the opinion of the investigator and would make the participant inappropriate for entry into the study.
* Vaccination within 4 weeks of treatment initiation and while on trial is prohibited except for administration of inactivated vaccines.
* Patients may not use natural herbal products or other "folk remedies" while participating in this study. Herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.
* Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or CYP1A2 enzymes, proton pump inhibitors, or other prohibited concomitant medications within 7 days prior to treatment initiation are ineligible. Examples are provided in Appendix B. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
* Pregnant women are excluded from this study because avelumab and M1774 are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated with either agent. Women should not breastfeed during the study and for at least 1 month after last treatment administration.
* Calculated QTc average (using the Fridericia correction calculation) of \> 470 msec that does not resolve with correction of electrolyte abnormalities.
Active drug
