Letrozole for Estrogen/Progesterone Receptor Positive Low-grade Serous Epithelial Ovarian Cancer (LEPRE Trial)

This is an Italian, multicenter, randomized, open-label phase III trial which will evaluate if Letrozole is superior to standard adjuvant chemotherapy in patients with hormone receptor positive low-grade serous epithelial carcinoma of the ovary (LGSCO).The hypothesis is that letrozole will significantly prolong median progression free survival (PFS) compared with the standard chemotherapy treatment, namely carboplatin AUC 5 and paclitaxel 175 mg/m2.

Inclusion Criteria:I - 1. Age ≥ 18 years. I - 2. Newly diagnosed, low-grade serous carcinoma of the ovary including cancer of fallopian tube and peritoneum (invasive micropapillary serous carcinoma or invasive grade 1 serous carcinoma). This is to be confirmed via nuclear p53 immunohistochemistry testing by a central pathology review performed at the Coordinating Centre.I - 3. Immunohistochemically determined positivity (≥ 10%) for ER and/or PgR expression. This is to be confirmed by centralized review.I - 4. Patients must have undergone an upfront surgery with maximal cytoreductive effort, with either optimal or suboptimal residual disease status.I - 5. Stage III-IV according to 2018 FIGO classification. For proper staging:Patients must have undergone contrast-enhanced CT-scan of the chest, abdomen and pelvis within 28 days prior to randomization. If CT-scan is not recommended (e.g. for allergy to contrast agent) MRI or 18F-FDG PET/CT-scan are allowed.The imaging evaluation must be accompanied by an anamnestic and physical examination within 14 days prior to randomization.I - 6. Postmenopausal, defined as any of the following criteria:Patients who underwent bilateral salpingo-oophorectomy;Monolateral salpingo-oophorectomy, amenorrhea for 12 or more consecutive months and age ≥60 years;Monolateral salpingo-oophorectomy, amenorrhea for 12 or more consecutive months, age <60 years and FSH and serum estradiol levels within the laboratory's reference ranges for post-menopausal women.I - 7. Randomization must take place within 60 days of primary cytoreductive surgery.I - 8. Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0-1.I - 9. To be able to take oral medications.I - 10. Adequate bone marrow, hepatic and renal functions as defined below:Absolute neutrophil count (ANC) ≥ 1500/mm3Platelets ≥ 100,000/mm3Hemoglobin ≥ 10.0 g/dLTotal bilirubin ≤ 1.5 x Upper Limit of Normal (ULN)ALT and AST ≤ 3.0 x ULNAlkaline phosphatase ≤ 2.5 x ULNAlbumin ≥ 2.8 g/dLSerum creatinine ≤ 1.5 x ULN.I - 11. Written informed consent obtained prior to any study-specific procedure.Exclusion Criteria:E - 1. Other malignancy within the last 5 years, except for non-melanoma skin cancer adequately treated.E - 2. Neoadjuvant chemotherapy or radiotherapy for the treatment of this disease.E - 3. Previous hormonal therapy for the treatment of this disease.E - 4. Known hypersensitivity to letrozole or known hypersensitivity/intolerance to carboplatin/paclitaxel therapy.E - 5. Active or uncontrolled systemic infection.E - 6. Known central nervous system metastases.E - 7. Severe cardiac disease, such as myocardial infarction or unstable angina within 6 months prior to randomization.E - 8. New York Heart Association (NYHA) Class III or greater congestive heart failure.E - 9. Neuropathy grade 2 or higher.E - 10. History of fractures of the spine or femur not properly treated.E - 11. Known osteoporosis (dual-energy x-ray absorptiometry (DEXA) of the femoral neck T score of -2.5 or lower) not adequately treated with bisphosphonates or RANKL inhibitors.E - 12. Concomitant use of inducers of CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) which may reduce exposure to letrozole. Concomitant use of medicinal products with a narrow therapeutic index that are substrates for CYP2C19 (e.g. phenytoin, clopidrogel) that may have their systemic serum concentrations altered by letrozole.E - 13. Concurrent severe medical problems or any condition that would significantly limit full compliance with the study.