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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Letrozole for Estrogen/Progesterone Receptor Positive Low-grade Serous Epithelial Ovarian Cancer: a Randomized Phase III Trial (LEPRE Trial)

Conditions
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Carcinoma, Ovarian Epithelial, Low Grade Serous Adenocarcinoma of Ovary

Intervention / Treatment
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* Drug: Letrozole tablets
* Drug: carboplatin AUC 5 and paclitaxel 175 mg/m2


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>Letrozole 2.5 mg daily, per os, until progression or up to 60 months, whichever comes first | Drug: Letrozole tablets<br>* ATC: L02BG04<br>|
| Active Comparator: Control arm<br>Carboplatin AUC 5 + Paclitaxel 175 mg/mq, IV, on day 1 every 21 days, for 6-8 cycles. | Drug: carboplatin AUC 5 and paclitaxel 175 mg/m2<br>* ATC: L01XA02 and ATC: L01CD01 respectively<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | the time from the date of randomization to the date of local or regional relapse, distant metastasis, or death from any cause, whichever comes first. Patients not recurred, not progressed or not died while on study or patients lost to f-up will be censored at their last disease assessment date. | 54 months up to 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | the percentage of patients with an objective response, i.e. patients who will experience a complete response (CR), or a partial response (PR) as determined by RECIST 1.1. Each patient will be assigned the best response ever recorded during the trial. | 54 months up to 84 months | 
| Predictive effect of ER and PgR (% expression) on response to letrozole in terms of PFS and ORR | the time from the date of randomization to the date of local or regional relapse, distant metastasis, or death from any cause, whichever comes first according to ER and PgR % expression. | 54 months up to 84 months | 
| Clinical Benefit (CB) | the percentage of patients who will experience a CR or PR or stable disease (SD). Each patient will be assigned the best response ever recorded during the trial. | 54 months up to 84 months | 
| Overall survival (OS) | the time from the date of randomization to the date of death from any cause. Patients not reported as having died at the end of the study will be censored at the date they were last known to be alive. | 54 months up to 84 months | 
| Safety (Adverse Events) | Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE | 54 months up to 84 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estrogen/progesteron receptor positive tumor, Letrozole, Aromatase Inhibitors