Abemaciclib and Letrozole in Patients with Estrogen Receptor-positive Rare Ovarian Cancer

Inclusion Criteria:

1. Voluntary written informed consent of the participant or their legally authorizedrepresentative has been obtained prior to any screening procedures.

2. Use of highly effective methods of birth control; defined as those that, alone or incombination, result in low failure rate (i.e., less than 1% per year) when usedconsistently and correctly; such as implants, injectables, combined oralcontraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexualintercourse during the entire period of risk associated with the Trial treatment(s))or commitment to a vasectomised partner.

3. Histological confirmation of diagnosis of low-grade serous (original diagnosis oflow-grade serous carcinoma or original diagnosis of serous borderline tumor withsubsequent diagnosis of low-grade serous carcinoma )or low-grade endometrioidcarcinoma of ovary, fallopian tube or peritoneum or granulosa-cell tumor of theadult type and ER positivity on immunohistochemistry. In order to prevent inclusionof patients with high-grade serous carcinoma, diagnosis of low-grade serouscarcinoma will be verified as part of screening review by a gynecologic pathologist.Tissue for confirmation can be from primary tumor or recurrence.

4. For Stage 1: only patients where platinum is still an option are eligible with nolimitations in prior chemotherapy regimens and a maximum of 2 prior endocrinetherapy regimens. For Stage 2: a further 20 patients where platinum is still anoption will be included, with no limitations in prior chemotherapy regimens and amaximum of 2 prior endocrine therapy regimens. Fifteen patients where platinum isnot an option are allowed with no limitations in prior chemotherapy regimens andmaximum of 2 prior endocrine therapy regimens. Patients cannot have receivedchemotherapy for platinum resistant or refractory disease.

5. Age > 18 years at time of study entry.

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

7. Patient must have recurrent, measurable disease by RECIST v1.1. Measurable diseaseis defined as at least one lesion that can be accurately measured in at least 1dimension (longest dimension to be recorded). Each lesion must be ≥10 mm whenmeasured by computed tomography (CT), magnetic resonance imaging (MRI), or calipermeasurement by clinical exam or must be ≥20 mm when measured by chest x-ray. Lymphnodes must be >15 mm in short axis when measured by CT or MRI.

8. Pre- and post-treatment tissue biopsy and ct-DNA blood sample are mandatory fortranslational studies. Tissue from an archival tissue sample or fresh tissueobtained from a core or excisional biopsy of a tumor lesion.

9. Patients who were previously treated with letrozole or another aromatase inhibitorare allowed, but capped at 10 patients in each cohort.

10. Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween end of radiotherapy and randomization.

11. Patients must not have remaining ovarian function. In women who have at least oneretained ovary, menopause must be confirmed with laboratory confirmation. Women whohave ovarian function are eligible but must be placed on hormonal suppression aftera negative serum or urine human chorionic gonadotropin (hCG) test.

12. Abnormal organ function is permitted. However, patients must have:

13. absolute neutrophil count ≥1500/mL

14. platelets ≥100.000/mL

15. hemoglobin ≥9 g/dL

16. estimated creatinine clearance ≥ 45 ml/min as calculated using the methodstandard for the institution

17. total serum bilirubin ≤1.5 X ULN

18. aspartate aminotransferase (AST/SGOT) and/or alanine aminotransferase (ALT/SGPT) ≤3 X ULN

19. alkaline phosphatase ≤2.5x ULN (or ≤5.0x ULN if liver or bone metastases)

Exclusion Criteria:

1. For Stage 1: patients where platinum is not an option and platinum refractorypatients are not allowed. For Stage 2: patients with platinum refractory disease arenot allowed. Patients who received chemotherapy must have recovered (CommonTerminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects ofchemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior torandomization. A washout period of at least 21 days is required between lastchemotherapy dose and randomization (provided the patient did not receiveradiotherapy).

2. The patient has serious preexisting medical condition(s) that would precludeparticipation in this study (for example, interstitial lung disease, severe dyspneaat rest or requiring oxygen therapy, severe renal impairment (e.g. estimatedcreatinine clearance <30 mL/min), history of major surgical resection involving thestomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or apreexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).

3. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to bepotent CYP3A4 inducers (for examples, see the Prohibited Concomitant Medicationssection).

4. Diagnosis of another malignancy within 3 years, except for adequately treated basalcell or squamous cell skin cancer, or carcinoma in situ of the cervix.

5. Patient cannot have previously received a prior cyclin dependent kinase inhibitor (CDKi).

6. Known Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV) infection.

7. Inability or unwillingness to swallow pills.

8. Patient has had major surgery within 14 days prior to starting study drug or has notrecovered from major side effects (tumor biopsy is not considered as major surgery).

9. Active infection requiring intravenous (IV) antibiotics or antifungals, or otheruncontrolled recurrent illness requiring hospitalization.

10. History of any of the following: syncope of cardiovascular etiology, ventriculararrhythmia of pathological origin (including, but not limited to, ventriculartachycardia and ventricular fibrillation), sudden cardiac arrest.

11. Prior hematopoietic stem cell or bone marrow transplantation.

12. Known history of brain metastasis(es) that may be considered active (screeningimaging of brain is not required unless there is clinical suspicion of brainmetastases). Patients with previously treated brain metastases may participateprovided that the lesions are stable (without evidence of progression for at least 12 weeks on imaging), there is no evidence of new or enlarging brain metastases.

13. Known abnormalities in coagulation such as bleeding diathesis, or treatment withanticoagulants precluding intramuscular injections of goserelin (if applicable).

14. Known or possible hypersensitivity to letrozole or abemaciclib or any of theirexcipients.

15. Pre/perimenopausal women with a known hypersensitivity to gnRH (gonadotropin-releasing hormone) agonists.

16. Patients who are pregnant or breastfeeding.

17. Participation in an interventional Trial with an investigational medicinal product (IMP) or device. The patient has received an experimental treatment in a clinicaltrial within the last 30 days or 5 half-lives, whichever is longer, prior torandomization, or is currently enrolled in any other type of medical research (forexample: medical device) judged by the sponsor not to be scientifically or medicallycompatible with this study.