Phase III Randomized Trial of Letrozole Versus Carboplatin and Paclitaxel in Estrogen/Progesterone Receptor-Positive Low-Grade Serous Ovarian Carcinoma
- Trial ID
- 2024-516874-31-00
- Protocol
- 10UCS2018
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase III trial is to determine if **letrozole** is superior to standard chemotherapy in terms of progression-free survival (PFS) in patients with advanced low-grade serous epithelial ovarian carcinoma that is positive for estrogen and/or progesterone receptors. This is clinically relevant as it may offer a more effective treatment option for this specific patient population, potentially improving their prognosis and quality of life.
Secondary objectives include:
- Evaluating the tumor response to letrozole compared with standard chemotherapy in terms of objective response rate (ORR).
- Testing the predictive effect of estrogen receptor (ER) and progesterone receptor (PgR) on response to letrozole in terms of PFS and ORR.
- Assessing the possible negative association between the effect of letrozole, in terms of PFS and ORR, and the proliferative index Ki67.
- Evaluating the impact of letrozole compared with standard chemotherapy on patients' health-related quality of life, assessed by the MENQOL questionnaire.
- Evaluating the impact of letrozole compared with standard chemotherapy on patients' musculoskeletal pain, assessed by the BPI-SF questionnaire.
- Describing overall survival (OS) according to the randomization arm.
- Evaluating the safety of letrozole compared with standard chemotherapy.
Participants
The clinical trial involves **female** participants diagnosed with **low-grade serous epithelial carcinoma of the ovary**, including cancer of the fallopian tube and peritoneum, at FIGO stages III-IV. The study population is exclusively female, with an age requirement of 18 years and older, and includes postmenopausal women. Participants must have undergone primary surgery with maximal cytoreductive effort and exhibit positivity for estrogen and/or progesterone receptors, confirmed through centralized review. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group performance status of 0-1 and must be capable of taking oral medications. Adequate bone marrow, hepatic, and renal functions are necessary for inclusion. The sponsor has not provided the total number of participants in the study. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The selection process ensures that participants have undergone appropriate imaging evaluations and meet specific health criteria to ensure a comprehensive baseline assessment.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **letrozole** compared to standard chemotherapy in patients with advanced low-grade serous epithelial ovarian carcinoma. The primary objective is to assess progression-free survival (PFS) in patients positive for estrogen and/or progesterone receptors. The trial is expected to run until December 31, 2028, with recruitment starting on March 1, 2023. Participants will be involved in the study for a maximum treatment period of 60 days for letrozole, while the comparator treatments, **carboplatin** and **paclitaxel**, have a maximum treatment period of 8 days each.
The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, diagnosis, and previous surgical interventions. This visit includes a comprehensive evaluation, including imaging and laboratory tests, to establish a baseline. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and adverse events. These visits will include physical examinations, laboratory assessments, and imaging studies as necessary. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the primary and secondary endpoints.
Participant involvement is expected to last up to 60 days, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is defined as the time from randomization to local or regional relapse, distant metastasis, or death from any cause. Secondary endpoints include the Objective Response Rate (ORR), determined by complete or partial response as per RECIST 1.1 criteria. The trial's design ensures rigorous assessment of the investigational product's efficacy and safety, contributing valuable data to the treatment landscape for low-grade serous epithelial ovarian carcinoma.
Treatment
The clinical trial involves the administration of **Letrozole**, marketed under the name Letrix 2.5 mg, in the form of **film-coated tablets**. The active substance, letrozole, is a chemical compound classified under the ATC code L02BG04. The medication is administered orally with a maximum daily dose of 2,500 micrograms. The treatment period for letrozole is set at a maximum of 60 days. Letrozole is being evaluated for its efficacy in improving progression-free survival in patients with advanced low-grade serous epithelial ovarian carcinoma that is positive for estrogen and/or progesterone receptors.
In addition to letrozole, the trial includes the use of **Carboplatin** as a comparator treatment. Carboplatin is administered via **intravenous use** and is classified under the ATC code L01XA02. The maximum daily dose for carboplatin is 450 mg/m², with a treatment period not exceeding 8 weeks. This chemotherapeutic agent is used as part of the standard chemotherapy regimen against which letrozole's efficacy is being compared.
Another comparator treatment in the trial is **Paclitaxel**, which is also administered through **intravenous administration**. Paclitaxel is classified under the ATC code L01CD01 and has a maximum daily dose of 175 mg/m². Similar to carboplatin, the treatment period for paclitaxel is limited to 8 weeks. Paclitaxel serves as a standard chemotherapeutic agent in the study, providing a basis for comparison with the experimental letrozole treatment.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**. PFS is defined as the time from the date of randomization to the date of local or regional relapse, distant metastasis, or death from any cause, whichever occurs first. This endpoint will provide a measure of the time patients remain free from disease progression or death, offering insight into the effectiveness of the treatment regimen.
Secondary efficacy will be evaluated using the **Objective Response Rate (ORR)**, which is the percentage of patients who achieve an objective response, defined as either a complete response (CR) or a partial response (PR) according to RECIST 1.1 criteria. This will help determine the proportion of patients who experience a significant reduction in tumor size.
The trial will compare the efficacy of letrozole against standard chemotherapy in patients with advanced low-grade serous epithelial ovarian carcinoma that is positive for estrogen and/or progesterone receptors. The assessments will be conducted at specified intervals throughout the trial to monitor and analyze the efficacy outcomes. The data collected will be analyzed to determine the superiority of letrozole in improving PFS compared to the standard chemotherapy regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years. 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. 3. Immunohistochemically determined positivity (≥ 10%) for PgR and/or ER expression. This is to be confirmed by centralized review. 4. Patients must have undergone an upfront surgery with maximal cytoreductive effort, with either optimal or suboptimal residual disease status. 5. Stage III-IV according to 2018 FIGO classification. Furthermore, for a proper baseline evaluation 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. 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 plus FSH and serum estradiol levels within the laboratory’s reference ranges for postmenopausal women. 7. Randomization must take place within 90 days (preferably within 60 days) of primary cytoreductive surgery. 8. Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0-1. 9. To be able to take oral medications 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. 11. Written informed consent obtained prior to any study-specific procedure.
Exclusion Criteria
- Other malignancy within the last 5 years, except for non-melanoma skin cancer adequately treated. 2. Neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 3. Previous hormonal therapy for the treatment of this disease. 4. Known hypersensitivity to letrozole or known hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 5. Active or uncontrolled systemic infection. 6. Known central nervous system metastases. 7. Severe cardiac disease, such as myocardial infarction or unstable angina within 6 months prior to randomization. 8. New York Heart Association (NYHA) Class III or greater congestive heart failure. 9. Neuropathy grade 2 or higher. 10. History of fractures of the spine or femur not properly treated. 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. 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. 13. Concurrent severe medical problems or any condition that would significantly limit full compliance with the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Yet Recruiting | 01 Mar 2023 | 10 |
 Italy | Recruiting | 01 Mar 2023 | 132 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Letrix 2,5 mg compresse rivestite con film. | Test | COMPRESSE RIVESTITE CON FILM | ORAL USE | 2500 | 60 | PRD4495155 |
CARBOPLATIN | Comparator | PHF00230MIG | INTRAVENOUS USE | 450 | 8 | SCP10337134 |
PACLITAXEL | Comparator | PHF00230MIG | INTRAVENOUS ADMINISTRATION | 175 | 8 | SCP129816 |