| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic triple negative breast cancer (TNBC) |
| Carcinoma mammario triplo negativo localmente avanzato o metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced or metastatic triple negative breast tumor |
| Tumore del seno triplo negativo localmente avanzato o metastatico |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| 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 | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the activity of the two study regimens (oral metronomic schedule of vinorelbine and combination of oral metronomic schedule of vinorelbine with fixed doses of capecitabine) in terms of proportion of patients alive and without disease progression after 12 weeks of maintenance therapy. |
| Valutare l’attività di due regimi terapeutici metronomici orali, vinorelbina in monoterapia e la combinazione di vinorelbina e capecitabina, in termini di percentuale di pazienti vivi e liberi da progressione dopo 12 settimane di terapia di mantenimento. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
- the two treatment regimens in terms of clinical benefit (CB), overall survival (OS) and progression free survival (PFS).
- the tolerability and safety profile of each treatment regimen.
Predefined subgroup analyses by clinical characteristics to assess the internal consistency of the results.
|
Valutare:
- I due regimi terapeutici in termini di beneficio clinico (clinical benefit - CB), sopravvivenza globale (overall survival - OS) e progressione libera da malattia (progression free survival - PFS).
- la tollerabilità e il profilo di sicurezza di ciascun regime di trattamento.
Effettuare analisi di sottogruppi predefiniti in base alle caratteristiche cliniche con lo scopo di stabilire la validità interna dei risultati.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all the following criteria to be eligible for study entry:
1. Female, aged = 18 years old;
2. Eastern Cooperative Oncology Group performance status (ECOG –PS) = 1;
3. Locally advanced or metastatic triple-negative breast cancer, i.e. HER2-negative status and ER and PgR negative status (as per local assessment);
4. Treatment with 1st line chemotherapy (with any drug excepted Bevacizumab-based regimens) as per clinical practice, and non-progressive when the treatment was terminated;
5. No more than 6 cycles of the previous chemotherapy;
6. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1);
7. Willingness and ability to comply with the study protocol as judged by the Investigator;
8. For women who are not postmenopausal (i.e., < 2 years after last menstruation) and who are sexually active: agreement to use an adequate method of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly) during the treatment period and for at least 6 months after the last dose of study drug;
9. Provision of a written informed consent signed prior to enrolment according to ICH/GCP.
|
Le pazienti dovranno soddisfare i seguenti criteri d’inclusione per poter essere considerate eleggibili per lo studio:
1. Donne di età superiore o uguale a 18 anni;
2. Eastern Cooperative Oncology Group performance status (ECOG –PS) = 1;
3. Carcinoma mammario triplo negativo localmente avanzato o metastatico (HER-2 e recettori estrogenici e progestinici negativi (valutazione effettuata presso ciascun centro sperimentale);
4. Trattamento di prima linea (con qualsiasi farmaco ad eccezione dei regimi a base di Bevacizumab) secondo la pratica clinica, e nessuna evidenza di progressione alla fine del trattamento;
5. Massimo sei cicli di chemioterapia precedente;
6. Almeno una lesione misurabile secondo criteri RECIST ver. 1.1;
7. Volontà e capacità di rispettare le procedure previste dallo studio, in base al giudizio clinico;
8. Per le donne in età fertile (< 2 anni dall’ultimo ciclo mestruale) e sessualmente attive: utilizzo di un adeguato metodo contraccettivo (contraccettivi orali, contraccettivi intrauterini, metodi contraccettivi di barriera in associazione con gel spermicidi) durante tutto il periodo di trattamento e per un minimo di 6 mesi dopo l’ultima somministrazione del trattamento in studio;
9. Consenso informato scritto, firmato prima di intraprendere qualsiasi procedura legata allo studio, in accordo con ICH/GCP.
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|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from study entry:
1. Previous treatment with vinorelbine or capecitabine;
2. 1st line therapy with a bevacizumab-based regimen;
3. Presence of brain metastases;
4. Any other investigational drug or any anti-cancer treatment (except for radiotherapy, if the treatment field does not include the liver);
5. Inadequate bone marrow, hepatic or renal function including the following:
a. absolute neutrophils count of < 1.5 cells x 109/L, platelet count < 100 cells x 109/L, or hemoglobin < 8 g/L;
b. serum total bilirubin >1.5 × institution upper limit of normal [ULN], aspartate aminotransferase and alanine aminotransferase >2.5 × ULN, or >5 × ULN for patients with liver metastases, alkaline phosphatase >2.5 × ULN, or >5 × ULN for patients with liver metastases, or >10 × ULN for patients with bone metastases;
c. serum creatinine concentration >1.5 × ULN, creatinine clearance <50 mL/min calculated according to Cockcroft-Gault equation, and coagulation parameters international normalized ratio >1.5;
6. With the exception of basal cell carcinoma or cervical cancer in situ, history of another malignancy, unless in remission for 5 years or more and judged of negligible potential of relapse;
7. Known dihydropyrimidine dehydrogenase deficiency;
8. Treatment with sorivudine or its chemically related analogues, such as brivudine, within 4 weeks prior to randomization;
9. Evidence of any significant clinical disorder or concurrent illness or laboratory finding that, at the judgment of the Investigator, contra-indicate the inclusion of the patient in the study;
10. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures;
11. Unable to swallow tablets;
12. Previous significant surgical resection of stomach or small bowel
13. Patients requiring long-term oxygen therapy
14. Known hypersensitivity to any excipients of oral vinorelbine, oral capecitabine and to fluoropyrimidine.
|
Le pazienti che presentino uno o più dei seguenti criteri sono escluse dalla partecipazione allo studio:
1. Precedente trattamento con VNR o CAPE;
2. Prima linea di terapia con regimi a base di bevacizumab;
3. Presenza di metastasi cerebrali;
4. Terapia concomitante con altri agenti sperimentali o altri trattamenti antitumorali (ad eccezione della radioterapia, se il campo di applicazione non include il fegato);
5. Inadeguata funzionalità midollare, epatica o renale, comprendenti:
a. Conta assoluta di neutrofili < 1.5 x 109/L, piastrine < 100 x 109/L, o emoglobina < 8 g/L;
b. Bilirubina sierica totale >1.5 × limite superiore di normalità [ULN], aspartato amminotrasferasi e alanina amminotrasferasi >2.5 × ULN, o >5 × ULN per pazienti con metastasi epatiche, fosfatasi alcalina >2.5 × ULN, o >5 × ULN per pazienti con metastasi epatiche, o >10 × ULN per pazienti con metastasi ossee;
c. Concentrazione di creatinina sierica >1.5 × ULN, creatinine clearance <50 mL/min calcolata secondo la formula di Cockcroft-Gault, e parametri di coagulazione (INR) >1.5;
6. Con l’eccezione del carcinoma a cellule basali e cancro in situ della cervice uterina, anamnesi positiva per altre neoplasie maligne a meno che siano in remissione negli ultimi 5 anni o più e con un potenziale trascurabile di recidiva secondo il giudizio clinico;
7. Noto deficit dell’enzima diidropirimidina deidrogenasi;
8. Trattamento con sorivudina o analoghi, come brivudina, durante le quattro settimane precedenti la randomizzazione;
9. Disordini psichiatrici o stato mentale alterato che precludano la comprensione del consenso informato e/o il completamento delle valutazioni e delle procedure necessarie per lo studio;
10. Incapacità di deglutire compresse e capsule;
11. Precedente resezione chirurgica significativa dello stomaco o dell’intestino tenue;
12. Necessità di terapia prolungata con ossigeno;
13. Nota ipersensibilità ai farmaci VNR, CAPE e fluoropirimidine e agli eccipienti.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients alive and without progression after 12 weeks of maintenance therapy (PFS12w). |
| Percentuale di pazienti vivi e liberi da progressione dopo 12 settimane di terapia di mantenimento (PFS12w). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 weeks of maintenance therapy (PFS12w). |
| A 12 settimane dalla data di inizio della terapia di mantenimento (PFS12w) in studio. |
|
| E.5.2 | Secondary end point(s) |
| PFS, calculated in each patient as the time from the date of treatment start to the date of first progression or death from any cause, whichever comes first. Subjects not having progressed or died by the end of the study will be censored at the last disease assessment date OS, calculated for each patient as the time from the date of treatment start 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. Clinical Benefit, defined as proportion of patients with CR+PR+SD and without grade 3-4 adverse events after 12 weeks of maintenance treatment. Maximum toxicity grade experienced by each patient for each specific toxicity; frequency of patients experiencing adverse events that are recorded as grade 3-5 (also grade 2 for neurotoxicity); adverse events will be graded according to NCI CTC AE, version 4.03. Type and frequency of serious adverse reactions. |
| PFS, calcolata per ogni paziente come il tempo trascorso dalla data di inizio del trattamento alla data di prima progressione o morte per ogni causa, a seconda di quale evento si verifica per primo. Le pazienti non in progressione o vive alla data dell’analisi saranno censorizzate alla data dell’ultima valutazione di malattia. OS, calcolata per ogni paziente come il tempo trascorso dalla data di inizio del trattamento alla data di morte per ogni causa. Le pazienti che risultano essere vive alla data dell’analisi saranno censorizzate alla data dell’ultima valutazione di malattia. CB, definita come la percentuale di pazienti con CR+PR+SD che non hanno sperimentato eventi avversi di grado 3-4 dopo 12 settimane di terapia di mantenimento. Grado massimo di tossicità registrato per ogni paziente e per singolo tipo di tossicità; proporzione di pazienti con eventi avversi di grado 3-5 (grado 2 per la neurotossicità); gli eventi avversi saranno riportati in accordo a NCI CTC AE, versione 4.03. Tipo e frequenza di reazioni avverse serie. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| PFS: at the date of first progression or death from any cause, whichever comes first. Subjects not having progressed or died by the end of the study will be censored at the last disease assessment date . OS: at 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. Clinical Benefit: after 12 weeks of maintenance treatment. Safety of the study treatments will be evaluated during the study, throughout the treatment period and including the follow-up period (30 days after the last dose of study treatment). |
| Sopravvivenza libera da progressione (PFS) verrà rilevata alla data di prima progressione o morte per ogni causa, a seconda di quale evento si verifica per primo. Le pazienti non in progressione o vive alla data dell’analisi saranno censorizzate alla data dell’ultima valutazione di malattia. Sopravvivenza globale (OS) verrà rilevata alla data di morte per ogni causa. Le pazienti che risultano essere vive alla data dell’analisi saranno censorizzate alla data dell’ultima valutazione di malattia. Beneficio clinico verrà rilevato dopo 12 settimane di terapia di mantenimento. La sicurezza e la tollerabilità dei trattamenti in studio verranno valutate durante tutta la durata della sperimentazione. |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| If both the schedules will show the required minimum proportion of non-progressing patients, the stu |
| Se per entrambi i regimi di trattamento si raggiungesse il numero minimo richiesto di pazienti liber |
|
| 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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