Elacestrant With Everolimus for the Treatment of Recurrent Advanced or Metastatic ER-Positive Endometrial Cancer

Inclusion Criteria: * Must be ≥ 18 years of age * Ability to understand and the willingness to sign a written informed consent document. Patient must sign the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Participants must have histologically confirmed advanced (International Federation of Gynecology and Obstetrics \[FIGO\] stage III or IV), persistent, or recurrent endometrial cancer (histologic documentation of recurrence not required) that has * Patient's archival endometrial cancer tumor specimen has positive hormone receptor expression defined as "positive" or ≥ 1% by immunohistochemistry (IHC) performed at any Clinical Laboratory Improvement Act (CLIA)-certified laboratory * Can be any histologic subtype including endometrioid, mixed, serous, clear cell, carcinosarcoma * Prior treatment with at least one line of platinum-based chemotherapy is required (can be in the adjuvant setting): * Patients with mismatch repair deficiency (dMMR) tumors must have received at least one prior line of immunotherapy. An exception may be made for patients with documented contraindications to immunotherapy, including but not limited to severe autoimmune conditions, solid organ transplantation, or lack of access to immunotherapy. * Prior exposure to to progestins, aromatase inhibitors, tamoxifen, selective estrogen receptor down regulator (SERD) is allowed if the last dose was ≥ 4 weeks before enrollment Availability of adequate archival tumor tissue (from initial biopsy, surgical specimen, or repeat biopsy) is preferred but not required for study entry. When available, archival tissue should consist of either one unstained slide cut at 4-5 µm or one formalin-fixed paraffin-embedded (FFPE) tissue block with one corresponding H\&E slide, submitted per the Lab Manual. If archival tissue is not available, the participant may still be enrolled with Principal Investigator approval prior to study entry * No prior history of other malignancies within past 2 years (besides endometrial cancer as per Inclusion #4). Individuals with the following cancers are eligible if diagnosed and treated within the past 2 years: ductal carcinoma in situ of the breast, cervical cancer in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin, early stage breast cancer or cervical cancer, early stage renal cell carcinoma or any other likely curatively treated early stage malignancy. No concurrent malignancy or other serious medical condition as deemed by the investigator * Patients who received chemotherapy or hormonal therapy must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] grade ≤ 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy prior to enrollment. A washout period of at least 21 days is required between last chemotherapy dose and enrollment (provided the patient did not receive radiotherapy) * Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and cycle 1 day 1. Radiation therapy that is given for palliative purposes, e.g. for pain control or prevention of a tumor associated complication is allowed during the study, with the exclusion of thoracic radiation. However, study medication should be held during the duration of the radiation therapy and the radiated tumor lesion cannot be used for assessment of treatment response. Radiation therapy should not be administered before the first response assessment * Able to take study medication by mouth * Pre- and postmenopausal women are eligible. Premenopausal women of childbearing potential must have a negative serum pregnancy test at time of screening. Woman of childbearing potential (WOCBP) is defined as follows: * Any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a bilateral oophorectomy) OR * Any female who is not postmenopausal defined as: * Age ≥ 60 years; OR * Age \< 60 with intact uterus AND amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; OR * Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential * Women of child-bearing potential must use highly effective methods of contraception throughout the study and for 120 days after study drug discontinuation. Highly effective contraception methods include: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Use of non-hormonal methods of contraception or placement of an nonhormonal intrauterine device (IUD) or intrauterine system (IUS) * Absolute neutrophil count ≥ 1.5 × 10\^9/L (at screening) * Platelets ≥ 100 × 10\^9/L (at screening) * Hemoglobin ≥ 8.0 g/dL (at screening) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 x institutional upper limit of normal (ULN) (at screening) * Total serum bilirubin \< 1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN (at screening) * Patients with type 2 diabetes are eligible if on stable therapy and hemoglobin A1c ≤ 8% * Patients fasting triglycerides must be ≤ 300 mg/dL * No evidence of clinically significant, active interstitial lung disease or pneumonitis on history or baseline imaging. Patients with pneumonitis related to radiation or prior therapies may be eligible at investigator discretion discretion if recovered at the time of study initiation * Patient can safely discontinue strong and moderate CYP3A4 inhibitors or inducers (e.g., certain azole antifungals, rifampin, some anticonvulsants) at least 14 days or 5 half lives whichever is shorter prior to first dose of study drug, or switch to acceptable alternatives Exclusion Criteria: * Patients who have previously received everolimus or any another mTOR (mammilian target of rapamycin) inhibitor (eg. sirolimus, temsirolimus) for the treatment of endometrial cancer and are no longer receiving therapy with washout * Participants who are receiving any other anti-cancer approved or investigational agents within \< 21 days or 4 weeks if fulvestrant prior to cycle 1 day 1. Participation in other observational studies is permitted * Symptomatic brain metastases or carcinomatous meningitis. Patients with treated brain metastases may be eligible if they are asymptomatic and neurologically stable, and demonstrate radiographic stability at screening, confirmed at least 28 days following completion of definitive treatment (e.g., surgery and/or radiation therapy) * History of other malignancies within past 2 years, except ductal carcinoma in situ of the breast, cervical cancer in situ, melanoma in situ, basal cell or squamous cell carcinoma of the skin or early stage cancers deemed curable by investigator. No concurrent malignancy or other serious medical condition as deemed by the investigator * Herbal preparations/medications are prohibited throughout the study. These herbal medications include, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, black cohosh, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to first dose of study drug * Patients receiving chronic treatment with systemic steroids (\> 10mg prednisone equivalent) or another immunosuppressive agent * Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance \< 30ml/min), symptomatic angina pectoris, cardiac arrhythmia, a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea) are ineligible * Patient with active systemic bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]) * Screening for HIV and hepatitis is not required for enrollment * The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest * Any of the following within 6 months prior to trial registration: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism * History of hypersensitivity or intolerance to elacestrant, everolimus, other rapamycin analogs (eg. temsirolimus, sirolimus) or any of the components in either medication * Pregnant women are excluded from this study because embryo-fetal toxicity is a potential side effect of elacestrant and everolimus. For this reason, women of child-bearing potential (WOCBP) must agree to use highly effective contraception prior to study entry, for the duration of treatment, and for at least 120 days after the completion of treatment. Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy * Women of child-bearing potential, who will not use a highly effective method of contraception * Women who are lactating * Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the patient's safety, inhibit protocol participation, or interfere with interpretation of trial results, and in the judgment of the investigator would make the patient inappropriate for entry into this trial * Patients must be able to follow concomitant medication restrictions: * Strong CYP3A4 inhibitor drugs, food and herbal products, including but not limited to: ceritinib, clarithromycin, cobicistat, danoprevir, dasabuvir, elvitegravir, idelalisib, itraconazole, ketoconazole, lopinavir, nefadozone, nelfinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telithromycin, tipranavir, troleandomycin, voriconazole * Moderate CYP3A4 inhibitor drugs, food and herbal products, including but not limited to: amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, darunavir, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, faldaprevir, fluconazole, fluvoxamine, fosamprenavir, imatinib, isavuconazole, letermovir, netupitant, nilotinib, octreotide, tofisopam, verapamil * Strong CYP3A4 inducer drugs, food and herbal products, including but not limited to: carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifampin, rifabutin * Moderate CYP3A4 inducer drugs, food and herbal products, including but not limited to: bosentan, dabrafenib, efavirenz, etravirine, lesinurad, lopinavir, metamizole, modafinil, nafcillin, thioridazine, tipranavir/ritonavir, telotristat ethyl * Herbal preparations, including, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, DHEA, yohimbe, saw palmetto, and ginseng * Grapefruit, grapefruit juice, and grapefruit-containing beverages and other foods known to inhibit CYP3A4 and P-gp activity * Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, bacillus Calmette-Guérin (BCG), yellow fever, varicella and TY21a (Typhoid Vaccine Live Oral Ty21a) typhoid vaccines * Patients with rare hereditary disorders of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption are excluded, as everolimus contains lactose * Patients who require use of systemic corticosteroids is prohibited with the following exceptions: * Participants on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis. * Low dose systemic corticosteroids are needed to manage certain conditions (e.g., rheumatoid arthritis) if the dose is not expected to lead to moderate or strong CYP3A4 induction. * Single doses, topical applications (including mouthwashes), inhaled sprays, eye drops, and local injections are allowed. * Systemic short-term steroids are also allowed for treatment of adverse events (AEs)