Study of Narazaciclib (ON 123300) Plus Letrozole in Endometrial Cancer and Other Gynecologic Malignancies

Inclusion Criteria

• •1. Must be 18 years of age, or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing informed consent form (ICF).
• •2. Phase 1 (Dose escalation cohorts): Have confirmed endometrial or other gynecologic malignancy that is amenable for treatment with hormonal therapy and do not have other standard treatment options. (Patients with endometrioid and other types of uterine cancer as well as ovarian cancers may be enrolled at the Investigator's discretion if hormonal based therapy is considered an appropriate option for the patient).
• •OR Phase 2a (Dose expansion cohort): Have confirmed low-grade (Federation of Gynaecology and Obstetrics \[FIGO\] Grade 1 or 2) endometrioid endometrial cancer (LGEEC). Mixed tumor histology is allowed if the non-endometrioid component is \<5%.
• •3. Recurrent metastatic disease or advanced (Stage IV) disease.
• •4. Phase 1 (Dose escalation cohorts): Patients may be enrolled regardless of prior checkpoint inhibitor therapy, at the Investigator's discretion.
• •OR Phase 2a (Dose expansion cohort): Have received prior checkpoint inhibitor therapy (single agent or in combination with another anti-cancer therapy) if available for this indication and NOT contraindicated.
• •5. Phase 1 (Dose escalation cohorts): Patients may be enrolled who have not received prior therapy for recurrent/metastatic disease, or have received any number of prior lines of therapy for recurrent/metastatic disease, at the Investigator's discretion.
• •OR Phase 2a (Dose expansion cohort): Have received 1 or 2 prior lines of systemic therapy for metastatic disease. Patient has NOT received more than 2 prior lines of systemic therapy for metastatic LGEEC (including checkpoint inhibitor, hormone therapy, or chemotherapy). Prior external beam radiotherapy, brachytherapy, and/or surgery for localized disease is allowed and is not counted as a line of therapy.
• •6. Phase 1 (Dose escalation cohorts): Have either measurable or non- measurable disease.
• •OR Phase 2a (Dose expansion cohort): Have measurable disease outside the radiated field.
• •7. Local mismatch repair (MMR) immunohistochemistry (IHC) results available (both deficient mismatch repair (dMMR) and mismatch repair protein (MMRP) deficiency (MMRp) patients are eligible, and will be documented for research purposes).
• •8. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• •9. Tissue for estrogen/progesterone receptor status and molecular classification (paraffin embedded or fresh biopsy if unavailable).
• •10. Have adequate organ function as indicated by the following:
• •1. Absolute neutrophil count (ANC) ≥1.0×109/L
• •2. Platelets ≥100×109/L
• •3. Hemoglobin ≥9.0 g/dL
• •4. International Normalized Ratio (INR) ≤1.5
• •5. Serum creatinine ≤1.5 times ULN, or estimated creatinine clearance (calculated according to normal institutional practice) greater than 50 milliliters (ml)/min
• •6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) below 3.0×the upper limit of normal (ULN) (or ALT and AST ≤5×ULN if liver metastases are present).
• •7. Total serum bilirubin \<1.5×ULN; or total bilirubin ≤3.0×ULN with direct bilirubin within normal range of the central laboratory in participants with well documented Gilbert's Syndrome.
• •11. Have baseline corrected QT (QTc) interval \<470 msec.
• •12. Are able to swallow oral medications.
• •13. Have a life expectancy of at least 12 weeks
• •14. Sex and Contraceptive/Barrier Requirements
• •a) Are postmenopausal, defined as: i) Patient's last menstrual period occurred more than 12 months prior to screening without any alternative medical cause, and ii) Patient's postmenopausal status is confirmed by screening serum follicle-stimulating hormone concentration of \>40 milli-International unit/ml (mIU/mL); or iii) Patient has undergone surgical sterilization (bilateral oophorectomy and/or hysterectomy) OR b) Must have a negative pregnancy test at screening and upon study entry (Cycle 1 Day 1) if not postmenopausal and c) Contraceptive use must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies if not postmenopausal.
• •Patients under 55 years with intact ovaries will undergo hormonal verification.
• •15. Are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.