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 endometrioidendometrial carcinoma. Histologic documentation of the recurrence is suggested butnot required.

2. All patients must have 1 or more measurable target lesion at baseline by computedtomography (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 surgicalresection is not an option or likely to result in severe morbidity.

4. Prior treatment history:

5. Adjuvant setting - treatment with chemotherapy, hormonal therapy,checkpointinhibitors, and/or other therapy is permitted as long as theadjuvant therapyended ≥6 months from enrollment.

6. Recurrent/advanced/metastatic setting - treatment with 0-1 prior chemotherapyregimens is permitted (patients may be naïve to chemotherapy); chemotherapymust have been completed ≥3 months prior to enrollment. Patients are permittedto have received adjuvant chemotherapy and no more than 1 line of chemotherapyin the recurrent/advanced/metastatic setting.

7. Non-chemotherapy-based treatment (eg, checkpoint inhibitors, hormonal therapy,and/or small molecule agents) is permitted at any point as long as therapyended ≥4 weeks prior to enrollment.

8. Patients who have received prior therapy in the recurrent/advanced/metastaticsetting must have achieved a complete or partialresponse(investigator-assessed) to at least 1 therapy.

9. Age: 18 years or older.

10. Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0or 1.

11. Adequate liver function:

12. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert'ssyndrome, then ≤3 × ULN)

13. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to livermetastases)

14. Adequate renal function: creatinine clearance (CrCL) ≥30 mL/min based onCockcroft-Gault

15. Adequate hematologic parameters:

16. Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed)

17. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factorsupport allowed)

18. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)

19. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must beless than or equal to 350 mg/dL.

20. Minimum of 4 weeks since any major surgery, completion of radiation, or completionof prior systemic anticancer therapy, or at least 5 half-lives if the prior therapyis a single agent small-molecule therapeutic, and adequately recovered from theacute toxicities of any prior therapy, including neuropathy, to Grade ≤1.

21. Non-pregnant and non-breastfeeding female:

22. Females of childbearing potential must agree to use effective contraception orabstinence without interruption from 28 days prior to starting nab-Sirolimusthrough 3 months after the last dose of nab-Sirolimus and have a negative serumpregnancy test (beta human chorionic gonadotropin [β-hCG]) result at screeningand agree to ongoing pregnancy testing during the course of the study, andafter the end of study treatment. A second form of birth control is requiredeven if she has had a tubal ligation.

23. Sexual abstinence is considered a highly effective contraceptive method only ifdefined as refraining from heterosexual intercourse from 28 days prior tostarting study medication throughout 3 months after last dose of studymedication. The reliability of sexual abstinence should be evaluated inrelation to the duration of the study and the preferred and usual lifestyle ofthe patient.

24. The patient understands and signs the informed consent.

25. Willingness and ability to comply with scheduled visits, laboratory tests, and otherstudy procedures.

26. Patients with a known history of human immunodeficiency virus (HIV)infection areeligible if:

27. There has been no acquired immunodeficiency syndrome (AIDS)-definingopportunistic infection in 12 months prior to enrollment.

28. The patient has been receiving an antiretroviral therapy regimen for≥4 weeksand the HIV viral load is <400 copies/mL prior to enrollment.

29. Antiretroviral therapy regimen does not include strong cytochrome(CYP)3A4inhibitors 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 liquidnext generation sequencing [NGS]) unless the PRECISION 1 study (NCT05103358) hasbeen closed to enrollment.

3. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infectivetreatment, either ongoing or completed ≤7 days prior to enrollment.

4. Patients with primary refractory disease (ie, those who have never achieved acomplete or partial response to prior therapy) are not permitted on study.

5. Patients with the following are excluded:

6. Known or suspected brain metastases.

7. Severe heart disease defined as unstable angina pectoris, New York HeartAssociation (NYHA) Class III or IV congestive heart failure, myocardialinfarction ≤6 months prior to first study treatment, serious uncontrolledcardiac arrhythmia or any other clinically significant cardiac disease.

8. 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 onroom air (Note: spirometry and pulmonary function tests [PFTs] are not requiredto be performed unless clinically indicated).

9. Nonmalignant medical illnesses that are uncontrolled or whose control may bejeopardized by the treatment with the study therapy.

10. A history of malignancies other than the one under treatment unless the patientis disease-free for more than 5 years from completion of therapy administeredwith curative intent. Controlled non-melanoma skin cancers, carcinoma in situof the cervix, resected incidental prostate cancer, certain low gradehematologic malignancies (eg, chronic lymphocytic leukemia [CLL], follicularlymphoma, etc), or other adequately treated carcinoma in situ may be eligible,after discussion with the Medical Monitor.

11. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolicblood pressure ≥100 mmHg

12. Patients with history of interstitial lung disease and/or pneumonitis, orpulmonary hypertension.

13. Active hepatitis B and/or hepatitis C infection and detectable viral loaddespite antiviral therapy

14. Required use of concomitant medications with strong CYP3A4 interactions (inductionor inhibition) should be discontinued (strong inhibitors include ketoconazole,itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin; stronginducers include rifampin and rifabutin). These agents must be discontinued prior tofirst dose of nab-sirolimus.