Imlunestrant/Abemaciclib/Selinexor in Ovarian and Endometrial

• For Cohort 1A: Participants must have histologically confirmed diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum that is recurrent or metastatic and/or resistant to standard therapies; original diagnosis of de novo low-grade serous carcinoma or original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma are allowed. Participants whose tumors contain both low-grade serous carcinoma and high-grade serous carcinoma are not eligible.
• For Cohort 1B: Participants must have cytologically or histologically confirmed endometrial cancer that is recurrent or metastatic and/or resistant to standard therapies. Participants must have histologically confirmed either i) endometrioid endometrial cancer or ii) endometrial carcinosarcoma with endometrioid epithelial component.
• For both cohorts, tumor must be TP53 wild-type as determined by immunohistochemistry (IHC) or via CLIA-certified targeted NGS.
• 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 11 (Measurement of Effect) for the evaluation of measurable disease.
• For Cohort 1A: After the safety lead-in, participants must have biopsiable disease in a lesion that is not being utilized as the target lesion for RECIST assessment and willing to undergo two on-treatment biopsies.

(NOTE: If a patient is included in the safety lead-in, the presence of biopsiable disease and willingness to undergo serial on-treatment biopsies is not required. After the safety lead-in, this requirement will remain for 14 participants, after which the biopsy requirement will no longer be mandatory for enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix A)
• Age ≥ 18 years
• Participants must have normal organ and bone marrow function within 14 days before starting protocol therapy as defined below:

Hematologic

ANC ≥1.5 × 10\^9/L

Platelets ≥100 × 10\^9/L Patients must have at least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment.

Hemoglobin

≥9 g/dL Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.

Hepatic

Total bilirubin ≤1.5 × ULN Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.

ALT and AST ≤3 × ULN or ≤5 × ULN if liver metastases

Creatinine

≤ 1.5 × institutional ULN, OR ≥ 60 mL/min/1.73 m2 per the CKD-EPI formula for participants with creatinine levels above 1.5 x institutional ULN.

The CKD-EPI formula is calculated as:

GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 ×

Creatinine clearance 0.993Age × 1.018 [if female] × 1.159 [if black]

where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /κ or 1, and max indicates the maximum of Scr /κ or 1. Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal.

• Ability to understand and the willingness to sign a written informed consent document.
• Ability to swallow and retain oral medications.
• Participants can have received an unlimited number of prior therapies.
• Participants must have previously received hormonal therapy of any type, including, but not limited to, aromatase inhibitors, tamoxifen or other selective estrogen receptor modulators, progestin analogues, selective estrogen receptor degraders (such as fulvestrant or elacestrant), agents targeting the GnRH-LH-FSH pathway (such as leuprolide acetate or goserelin acetate). Prior imlunestrant is allowed.
• Participants must be willing to release archival tissue if available. Please see section 9.1 and the laboratory manual for tissue requirements.
• The effects of the study agents on the developing human fetus are unknown. Female patients of childbearing potential must have a negative serum pregnancy test at screening. Furthermore, 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 treatment, and for 90 days following the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
• Female participants must agree not to donate egg during the study treatment period and for 90 days following last dose of study treatment.
• HIV-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. However, participants who are on antiretroviral therapy that includes strong inhibitors or inducers of CYP3A4 are not eligible, given the potential for interaction with abemaciclib.
• Participants with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression. Participants with new or progressive brain metastases (active brain metastases) are eligible only if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first two cycles of therapy. Participants with known leptomeningeal disease are not eligible.
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Exclusion Criteria:

• Participants who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of protocol therapy. Participants who have had hormonal therapy within 2 weeks of the first dose of protocol therapy. Participants who have received experimental treatment within the last 28 days or 5 half-lives, whichever is shorter, prior to initiation of study therapy
• Patients who had wide-field radiotherapy ≤4 weeks (defined as involving ≥25% of the bone marrow), or limited field radiation for palliation ≤1 week prior to initiation of study therapy.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy administration (e.g., have residual toxicities > Grade 1) with the exception of alopecia. Patients with stable Grade 2 neuropathy that does not affect ability to perform ADLs or who have clinically recovered from prior adverse events but remain on appropriate medical management (e.g. therapeutic anticoagulation for thromboembolic events; antihypertensives for hypertension) may also be considered eligible for the study after discussion with the sponsor-investigator). Patients with residual Grade 2 anemia who meet the marrow function criteria as defined in 3.1.8 will also be considered eligible. Participants with prior Grade 2 endocrine toxicities (hypothyroidism, adrenal insufficiency, etc) from checkpoint inhibitor therapy that are well managed with hormone supplementation are allowed.
• Participants who are receiving any other investigational agents for this condition.
• Participants may not have had prior receipt of abemaciclib or any CDK4/6 inhibitor.
• Participants may not have had prior receipt of selinexor or any XPO1 inhibitor.
• Participants with an inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by NCCN Clinical Practice Guidelines in Oncology (NCCN CPGO) for antiemesis and anorexia/cachexia.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to imlunestrant, abemaciclib and selinexor.
• Participants 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 is not required for enrollment.
• Participants who at the time of study enrollment are known to require concomitant therapy with strong CYP3A4 inducers, or strong inhibitors of CYP3A4. Due to potential drug interactions, concomitant use of these medications is not permitted for the duration of treatment on trial. Participants are eligible for study entry if an appropriate substitution is made prior to the first dose of study medication.
• Pregnant women are excluded from this study because of the apoptotic and cytostatic effects of imlunestrant, abemaciclib and selinexor 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 the study drugs, breastfeeding should be discontinued if the mother is treated with the study drugs.
• Any gastrointestinal dysfunctions that could interfere with the absorption of study drugs (e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea).
• Major injuries or surgery within 28 days prior to starting study treatment and/or planned major surgery during the on-treatment study period.
• Hospitalization for any reason within 14 days of starting study treatment.
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease/pneumonitis, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance \<30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, cannabis, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, and ginseng). Participants should stop herbal medications at least 7 days prior to starting study treatment.
• Participants with personal history of any of the following conditions, in the judgment of the investigator: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.