This study is to evaluate the efficacy and safety of elacestrant, in participants with advanced estrogen receptor (ER)-positive uterine sarcomas. The name of the study drug involved in this research study is:

-Elacestrant (a type of selective estrogen receptor degrader)

This is a single-arm, open-label, phase 2 study evaluating the efficacy and safety of elacestrant in participants with advanced estrogen receptor (ER)-positive uterine sarcomas. Elacestrant is designed to block estrogen receptors, which may slow down or stop the growth of cancers that rely on estrogen to grow.

The U.S. Food and Drug Administration (FDA) has not approved elacestrant as a treatment for ER positive uterine sarcoma.

The research study procedures include screening for eligibility, in-clinic visits, blood tests, urine tests, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, or Positron Emission (PET) scans, and electrocardiograms (ECGs).

It is expected that about 30 people will take part in this research study. Stemline-Menarini is supporting this research study by providing the study drug.

Inclusion Criteria:

Participant must have histologically confirmed uterine sarcoma of one of the following subtypes: uterine leiomyosarcoma (uLMS), endometrial stromal sarcoma (ESS), uterine adenosarcoma, or uterine PEComa.

Tumor must have moderate to strong immunohistochemical expression in ≥75% of tumor cells of estrogen receptor (ER) as assessed by institutional pathology review.

Participants must have locally advanced or metastatic disease that is not amenable to surgery.

Participants must have measurable disease, 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) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.

Age ≥18 years at the time of consent

ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

Participants must have adequate organ and marrow function as defined below:

Hemoglobin ≥ 8.0 g/dL

absolute neutrophil count ≥1,000/mcL

platelets ≥100,000/mcL

total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

AST(SGOT)/ALT(SGPT) ≤3.0 × institutional ULN (unless liver metastases are present in which case it must be ≤ 5 × ULN)

glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2

Human immunodeficiency virus (HIV)-infected participants on effective non-CYP3A4 interacting (see Section 3.2.3) anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Participants with a history of hepatitis C virus (HCV) infection must 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.

Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

Participants must be disease-free of prior invasive malignancies for > 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. NOTE: If there is a history of prior malignancy, participants must not be receiving other specific treatment for that cancer.

Participants should have completed prior treatment for their cancer: chemotherapy or radiotherapy must have been completed for greater than 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.

Participants should have recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.

Participants must have a QTc interval length of below 450 msec. QTc will be calculated via the Fridericia's formula.

Participant must be willing to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Participant must be able to swallow and maintain pills.

Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) and/or family member available will also be eligible.

Women of childbearing age, women who are made postmenopausal through use of GNRH agonists must agree to use adequate contraception for the duration of protocol treatment and for at least 6 months after the last dose of elacestrant if the risk of conception exists.

Adequate contraception is defined as one highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner.

Highly Effective Non-Hormonal Contraception

Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly effective forms of contraception.

The following non-hormonal methods of contraception are acceptable:

• True abstinence when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and withdrawal are not acceptable methods of contraception].
• Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female participants, the vasectomized male partner should be the sole partner.

OR Effective Non-Hormonal Contraception

Alternatively, two of the following effective forms of contraception may be used instead:

Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS). Consideration should be given to the type of device being15used, as there is higher failure rates quoted for certain types, e.g., steel or copper wire.

• Condom with spermicidal foam/gel/film/cream/suppository.
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
• The use of barrier contraceptives should always be supplemented with the use of spermicide. Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective forms of contraception. Therefore, the use of additional spermicides does confer additional theoretical contraceptive protection. However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and should not be used alone.

It should be noted that two forms of effective contraception are required. A double barrier method is acceptable, which is defined as condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female participants who are:

• 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
• Documented Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation

Women must be postmenopausal, which is defined as any of the following:

• Age ≥ 60 years
• Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH, and estradiol in the postmenopausal range per local normal range
• Premenopausal women must be on GnRH agonist prior to study entry are eligible. Women in this group MUST remain on the GnRH agonist for the duration of protocol treatment.
• Status-post bilateral oophorectomy - After adequate healing post-surgery

Exclusion Criteria:

Participants who are receiving any other investigational agents.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to elacestrant.

Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk of

life- threatening complications in the short term.

Participants with uncontrolled intercurrent illness, including but not limited to active infection, uncontrolled diabetes, cardiac disease, hypertension or conditions that in the opinion of the investigator would compromise participant safety or study participation

Participants with psychiatric illness/social situations that would limit compliance with study requirements.

Treatment with strong CYP3A inducers/inhibitors within 2 weeks before first study treatment administration or five elimination half-lives, whichever is longest and cannot be replaced. See Appendix B for a list of medications that are CYP3A inducers/inhibitors.

Female participants who are pregnant or nursing.

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication

Contact the Beffer office for Dana -Farber Innovations(BODFI) at innovations@dfci.harvard.edu