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.

Primary objective:

To determine if letrozole is superior to standard chemotherapy in terms of progression-free survival (PFS) in the first line treatment of patients with advanced low-grade serous epithelial ovarian carcinoma positive for estrogen and/or progesterone receptors.

Secondary objectives:

* to evaluate the response of tumor to letrozole compared with standard chemotherapy in terms of objective response rate (ORR);
* to test the predictive effect of ER and PgR on response to letrozole in terms of PFS and ORR;
* to evaluate the possible negative association between the effect of letrozole, in terms of PFS and ORR, and the proliferative index Ki67;
* to evaluate the impact of letrozole compared with the impact of standard chemotherapy on patients' health related quality of life evaluated by Menopausal Quality of Life Questionnaire (MENQOL);
* to evaluate the impact of letrozole compared with standard chemotherapy on patients' musculoskeletal pain evaluated by Brief Pain Inventory - Short Form (BPISF);
* to evaluate the effect on overall survival (OS). As most patients will recur and will be switched to chemotherapy and vice versa, OS is not expected to be significantly different;
* to evaluate the safety of letrozole compared with standard chemotherapy according to CTCAE v 5.0.

Translational objectives:

* to characterize the mutational profile and gene expression of the disease by NGS (next-generation sequencing) methodology on tissue samples;
* to evaluate the circulating tumor DNA (ctDNA) on liquid biopsies as a tool to monitor the disease response.

Eligibility Criteria:
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/mm3
* Platelets ≥ 100,000/mm3
* Hemoglobin ≥ 10.0 g/dL
* Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN)
* ALT and AST ≤ 3.0 x ULN
* Alkaline phosphatase ≤ 2.5 x ULN
* Albumin ≥ 2.8 g/dL
* Serum 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.