| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with a low-grade serous epithelial carcinoma of the ovary (LGSCO) including cancer of fallopian tube and peritoneum, FIGO III-IV stage and with ER+ and/or PgR+ after primary surgery are eligible. |
| Pazienti con un carcinoma epiteliale sieroso di basso grado (LGSCO) dell’ovaio o del peritoneo, stadio FIGO III-IV e con recettori ER e/o PgR positivi dopo intervento chirurgico primario. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Estrogen/Progesterone Receptor positive low-grade serous Epithelial ovarian cancer. |
| Pazienti affette da carcinoma ovarico epiteliale sieroso di basso grado positivo ai recettori degli Estrogeni e/o del Progesterone. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070907 |
| E.1.2 | Term | Ovarian cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070908 |
| E.1.2 | Term | Ovarian cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective 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 positive for estrogen and/or progesterone receptors. |
| Determinare se letrozolo è superiore alla chemioterapia standard in termini di sopravvivenza libera da progressione di malattia (PFS) in pazienti con carcinoma ovarico epiteliale sieroso di basso grado (LGSCO) avanzato e recettori per estrogeni e/o progesterone positivi. |
|
| E.2.2 | Secondary objectives of the trial |
• 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, 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 MENQOL;
• to evaluate the impact of letrozole compared with standard chemotherapy on patients’ musculoskeletal pain evaluated by BPI-SF;
• to describe the OS according to randomization arm.
• to evaluate the safety of letrozole compared with standard chemotherapy. |
• valutare la risposta del tumore al letrozolo rispetto alla chemioterapia standard in termini di tasso di risposta oggettiva (ORR);
• verificare l’effetto predittivo di ER e PgR sulla risposta al letrozolo in termini di PFS e ORR;
• valutare la possibile associazione negativa tra l’effetto del letrozolo e l’indice di proliferazione Ki67 in termini di PFS e ORR;
• valutare l'impatto del letrozolo rispetto alla chemioterapia standard sulla qualità della vita correlata alla salute delle pazienti, misurata tramite il questionario MENQOL;
• valutare l'impatto del letrozolo rispetto alla chemioterapia standard sul dolore muscolo-scheletrico delle pazienti, misurato tramite il questionario BIP-SF;
• descrivere la sopravvivenza globale (OS) in base al braccio di randomizzazione.
• valutare la sicurezza del letrozolo rispetto alla chemioterapia standard. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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 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.
6. Postmenopausal status (>12 consecutive months without menstruation) or patients who have undergone a bilateral salpingo-oophorectomy.
7. Randomization must take place 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. |
1. Età = 18 anni.
2. Carcinoma sieroso di basso grado dell'ovaio o del peritoneo (carcinoma sieroso micropapillare invasivo o carcinoma sieroso di grado 1 invasivo) di nuova diagnosi, confermata da una revisione patologica centralizzata presso il Centro Coordinatore.
3. Positività dei recettori ER e/o PgR (=10%) determinata con analisi immunoistochimica e confermata dalla revisione centralizzata presso il Centro Coordinatore.
4. Le pazienti devono aver effettuato un intervento di chirurgia citoriduttiva primaria, con residuo di malattia ottimale o non ottimale.
5. Stadio III-IV secondo la classificazione FIGO 2018.
6. Stato postmenopausale (Oltre 12 mesi consecutivi senza mestruazioni) o pazienti che hanno effettuato una salpingo-ovariectomia bilaterale.
7. La randomizzazione deve avvenire entro 60 giorni dalla chirurgia citoriduttiva primaria.
8. Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0-1.
9. Pazienti in grado di assumere farmaci orali.
10. Pazienti con adeguate funzioni del midollo osseo, epatiche e renali come definito di seguito:
- Conta assoluta dei neutrofili (ANC) = 1500/mm3
- Piastrine = 100.000/mm3
- Emoglobina = 10,0 g/dL
- Bilirubina totale = 1,5 x Limite superiore della norma (ULN)
- ALT e AST = 3,0 x ULN
- Fosfatasi alcalina = 2,5 x ULN
- Albumina = 2,8 g/dL
- Creatinina sierica = 1,5 x ULN.
11. Consenso informato scritto ottenuto prima di qualsiasi procedura specifica dello studio. |
|
| E.4 | Principal exclusion criteria |
1. 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 (T score of -2.5 or lower) not adequately treated with bisphosphonates or RANKL inhibitors (A dual-energy x-ray absorptiometry (DEXA) of the femoral neck is recommended).
12. Concurrent severe medical problems or any condition that would significantly limit full compliance with the study. |
1. Altri tumori maligni negli ultimi 5 anni, ad eccezione del carcinoma cutaneo non melanoma adeguatamente trattato.
2. Chemioterapia neoadiuvante o radioterapia per il trattamento di questa malattia.
3. Precedente terapia ormonale per il trattamento di questa malattia.
4. Ipersensibilità nota al letrozolo o ipersensibilità/intolleranza nota alla terapia con carboplatino-paclitaxel.
5. Infezione sistemica attiva o incontrollata.
6. Metastasi del sistema nervoso centrale.
7. Malattia cardiaca grave, come infarto miocardico o angina instabile entro 6 mesi prima della randomizzazione.
8. Insufficienza cardiaca congestizia di classe III o maggiore secondo la classificazione della New York Heart Association (NYHA).
9. Neuropatia di grado 2 o superiore.
10. Storia di fratture della colonna vertebrale o del femore non adeguatamente trattate.
11. Pazienti con osteoporosi nota (T score di -2,5 o inferiore) non adeguatamente trattata con bifosfonati o inibitori di RANKL.
12. Problemi medici gravi concomitanti o qualsiasi condizione che possa significativamente limitare la piena adesione allo studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS, defined for each patient as 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. |
| L'end point primario è la sopravvivenza libera da malattia (PFS), definito come il tempo dalla randomizzazione alla data in cui si verifica una progressione locale o regionale (secondo i criteri RECIST v 1.1), metastasi o morte per qualsiasi causa, a seconda di quale si verifica prima. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments should be performed by radiological assessment and CA-125 every 6 months until PD. |
| La valutazione della malattia sarà effettuata tramite CA 125 e TAC total body ogni 6 mesi fino a progressione. |
|
| E.5.2 | Secondary end point(s) |
| Objective Response Rate (ORR), defined as the percentage of patients with an objective response determined by a complete response (CR) or a partial response (PR) as determined by RECIST 1.1.; Clinical Benefit (CB), defined as the percentage of patients who will experience a CR or PR or stable disease (SD).; OS, defined for each patient as the time from the date of randomization to the date of death from any cause.; Health-related QoL assessed by the Menopause Quality of Life questionnaire (MENQOL) questionnaire.; Musculoskeletal Pain assessed by BPI-SF questionnaire. |
| La risposta obiettiva è definita come percentuale di pazienti con risposta completa (CR) o risposta parziale (PR) determinata tramite RECIST v1.1.; Beneficio clinico, definito come percentuale di pazienti con risposta completa, parziale o malattia stabile.; Sopravvivenza, definito come il tempo dalla randomizzazione alla data in cui si verifica la morte per qualsiasi causa.; Valutazione della qualità di vita correlata alla salute tramite la somministrazione del questionario MENQOL (qualità di vita in menopausa).; Valtazione del dolore muscoloscheletrico tramite la somministrazione del questionario BPI-SF. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments should be performed by radiological assessment and CA-125 every 6 months until PD.; Tumor assessments should be performed by radiological assessment and CA-125 every 6 months until PD.; Tumor assessments should be performed by radiological assessment and CA-125 every 6 months until PD.; The evaluation will be performed at visit at 3 months and at disease progression (Both arms).; The evaluation will be performed at visit at 3 months and at disease progression (Both arms). |
| La valutazione della malattia sarà effettuata tramite CA 125 e TAC total body ogni 6 mesi fino a progressione.; La valutazione della malattia sarà effettuata tramite CA 125 e TAC total body ogni 6 mesi fino a progressione.; La valutazione della malattia sarà effettuata tramite CA 125 e TAC total body ogni 6 mesi fino a progressione.; La valutazione verrà effettuata alla visita dopo 3 mesi e in caso di progressione della malattia per entrambi i bracci di trattamento.; La valutazione verrà effettuata alla visita dopo 3 mesi e in caso di progressione della malattia per entrambi i bracci di trattamento. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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