Trial of Nab-Sirolimus in Combination With Letrozole in Patients With Advanced or Recurrent Endometrioid Endometrial Cancer

Inclusion Criteria: 1. Patients must have clinically confirmed advanced or recurrent endometrioid endometrial carcinoma. Histologic documentation of the recurrence is suggested but not required. 2. All patients must have 1 or more measurable target lesion at baseline by computed tomography (CT; or magnetic resonance imaging \[MRI\] if CT scans are contraindicated) as defined by RECIST version 1.1. 3. Patients must have EEC that is metastatic or locally advanced where surgical resection is not an option or likely to result in severe morbidity. 4. Prior treatment history: 1. Adjuvant setting - treatment with chemotherapy, hormonal therapy,checkpoint inhibitors, and/or other therapy is permitted as long as theadjuvant therapy ended ≥6 months from enrollment. 2. Recurrent/advanced/metastatic setting - treatment with 0-1 prior chemotherapy regimens is permitted (patients may be naïve to chemotherapy); chemotherapy must have been completed ≥3 months prior to enrollment. Patients are permitted to have received adjuvant chemotherapy and no more than 1 line of chemotherapy in the recurrent/advanced/metastatic setting. 3. Non-chemotherapy-based treatment (eg, checkpoint inhibitors, hormonal therapy, and/or small molecule agents) is permitted at any point as long as therapy ended ≥4 weeks prior to enrollment. 4. Patients who have received prior therapy in the recurrent/advanced/metastatic setting must have achieved a complete or partial response(investigator-assessed) to at least 1 therapy. 5. Age: 18 years or older. 6. Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Adequate liver function: 1. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert's syndrome, then ≤3 × ULN) 2. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to liver metastases) 8. Adequate renal function: creatinine clearance (CrCL) ≥30 mL/min based on Cockcroft-Gault 9. Adequate hematologic parameters: 1. Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed) 2. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factor support allowed) 3. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed) 10. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be less than or equal to 350 mg/dL. 11. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of prior systemic anticancer therapy, or at least 5 half-lives if the prior therapy is a single agent small-molecule therapeutic, and adequately recovered from the acute toxicities of any prior therapy, including neuropathy, to Grade ≤1. 12. Non-pregnant and non-breastfeeding female: 1. Females of childbearing potential must agree to use effective contraception or abstinence without interruption from 28 days prior to starting nab-Sirolimus through 3 months after the last dose of nab-Sirolimus and have a negative serum pregnancy test (beta human chorionic gonadotropin \[β-hCG\]) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. A second form of birth control is required even if she has had a tubal ligation. 2. Sexual abstinence is considered a highly effective contraceptive method only if defined as refraining from heterosexual intercourse from 28 days prior to starting study medication throughout 3 months after last dose of study medication. The reliability of sexual abstinence should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the patient. 13. The patient understands and signs the informed consent. 14. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures. 15. Patients with a known history of human immunodeficiency virus (HIV)infection are eligible if: 1. There has been no acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection in 12 months prior to enrollment. 2. The patient has been receiving an antiretroviral therapy regimen for≥4 weeks and the HIV viral load is \<400 copies/mL prior to enrollment. 3. Antiretroviral therapy regimen does not include strong cytochrome(CYP)3A4 inhibitors or inducers Exclusion Criteria: 1. Prior treatment with an mTOR inhibitor, including nab-sirolimus. 2. Patients with known inactivating TSC1 or TSC2 alterations (based on tissue or liquid next generation sequencing \[NGS\]) unless the PRECISION 1 study (NCT05103358) has been closed to enrollment. 3. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infective treatment, either ongoing or completed ≤7 days prior to enrollment. 4. Patients with primary refractory disease (ie, those who have never achieved a complete or partial response to prior therapy) are not permitted on study. 5. Patients with the following are excluded: 1. Known or suspected brain metastases. 2. Severe heart disease defined as unstable angina pectoris, New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease. 3. Severe lung disease defined as a diffusing capacity for carbon monoxide (DLCO) that is ≤50% of normal predicted value and/or an O2 saturation ≤88% at rest on room air (Note: spirometry and pulmonary function tests \[PFTs\] are not required to be performed unless clinically indicated). 4. Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. 5. A history of malignancies other than the one under treatment unless the patient is disease-free for more than 5 years from completion of therapy administered with curative intent. Controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, certain low grade hematologic malignancies (eg, chronic lymphocytic leukemia \[CLL\], follicular lymphoma, etc), or other adequately treated carcinoma in situ may be eligible, after discussion with the Medical Monitor. 6. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg 7. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 8. Active hepatitis B and/or hepatitis C infection and detectable viral load despite antiviral therapy 6. Required use of concomitant medications with strong CYP3A4 interactions (induction or inhibition) should be discontinued (strong inhibitors include ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin; strong inducers include rifampin and rifabutin). These agents must be discontinued prior to first dose of nab-sirolimus.