| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
| Leucemia linfocitica cronica |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the white blood cells (leukocytes) which grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells. |
| Proliferazione abnorme di un particolare tipo di cellule presenti nel sangue(Linfociti),con conseguente accumulo in varie parti del corpo. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
| To evaluate the efficacy of the FCO2 front-line treatment in terms of CR rate (2008 revised guidelines). |
| Valutare l’efficacia del trattamento di prima scelta FCO2in termini di percentuale di remissione completa (linee guida IWCLL 2008). |
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| E.2.2 | Secondary objectives of the trial |
- the overall response rate (ORR) of the FCO2 front-line treatment;
- the Progression-free survival (PFS);
- the Time to a new treatment (TTT);
- the Overall survival (OS);
- the toxicity of the FCO2 front-line treatment;
- the toxicity of the FCO2 front-line treatment in terms of grade 3-4 granulocytopenia;
- the outcome (response, PFS, TTT, OS) according to clinical and biologic variables (age; size of nodes, 2-microglobulin, lymphocyte count, stage, IgVH, p53, FISH, NOTCH1, SF3B1, BIRC3, ZAP-70, CD38, CD49d, FLCs, FDG-uptake, nodal histology).
|
Gli obiettivi secondari sono:
- Risposta globale del trattamento di prima linea con FCO2.
- Sopravvivenza libera da progressione di malattia.
- Tempo ad un nuovo trattamento.
- Sopravvivenza globale.
- Tossicità del trattamento di prima linea con FCO2
- Tossicità in termini di termini di granulocitopenia di grado 3-4;
- L’outcome (percentuale globale di risposte, sopravvivenza libera da progressione di malattia, tempo ad un nuovo trattamento, sopravvivenza globale)secondo le variabili cliniche e biologiche (età, dimensione dei linfonodi, 2-microglobulina, conta dei linfociti, IgVH, p53, FISH, NOTCH 1, SF3B1,BIRCS3,ZAP-70, CD38, CD49d, FLCs, FDG-uptake, istologia dei linfonodi).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- B-cell CLL diagnosis by 2008 revised IWCLL criteria.
- Treatment requirement according to the 2008 revised IWCLL criteria.
- No previous treatment.
- Age > 18 year and ≤ 65 years.
- ECOG performance status of 0-1 at study entry and CIRS score ≤6.
- Adequate renal function (creatinine clearance≥60 ml/min estimated using the Cockcroft-Gault equation) .
- For male and female subjects of childbearing potential, agreement to use effective contraception.
- Signed written informed consent according to ICH/EU/GCP and national local laws.
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-Diagnosi di B-LLC secondo i criteri IWCLL (2008).
- Requisiti per il trattamento secondo i criteri IWCLL (2008).
- Assenza di precedente trattamento.
- Età >18 anni e ≤ 65 anni.
- ECOG performance status 0-1 all’entrata nello studio e CIRS score ≤6.
- Adeguata funzionalità renale (clearance della creatinina ≥60 ml/min stimata mediante equazione di Cockcroft-Gault).
- Per i soggetti maschi e per le femmine potenzialmente fertili, consenso all’uso di una contraccezione efficace.
- Consenso informato scritto secondo le ICH/EU/GCP e la normativa locale nazionale.
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| E.4 | Principal exclusion criteria |
- Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease and/or laboratory abnormality which in the opinion of the investigator may represent a risk for the patient and/or that would prevent the subject from signing the informed consent form.
- Pregnant or lactating females.
- Known positive serology for HIV.
- Positive serology for Hepatitis B (HBV) defined as a positive test for HBsAg and HBV-DNA.
- HCV-RNA positive.
- Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection, tuberculosis and active hepatitis.
- History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months.
- Known presence of alcohol and/or drug abuse.
- Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to the inclusion in the study, congestive heart failure (NYHA III-IV), arrhythmia unless controlled by therapy.≥ grade 2 neuropathy; history of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
- Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
- One or more laboratory abnormalities:
1. Calculated creatinine clearance (Cockroft-Gault)<60mL/min.
2. Absolute granulocyte count <1500/µL not disease related.
3. Platelet count < 75000/µL not disease related.
4. GOT, GPT, GT, alkaline phosphatase > 1,5 x upper limit of normal value unless due to disease involvement); serum bilirubin >1.5mg/dL, subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones)
- Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrolment, whichever is longer, or currently participating in any other interventional clinical study
- Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
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- Condizione medica concomitante significativa e non controllata dal trattamento relativa a, ma non esclusiva a, patologie renali, epatiche, gastrointestinali, endocrine, polmonari, neurologiche, cerebrali o psichiatriche e/o anormalità di laboratorio, che secondo il giudizio dello sperimentatore possano rappresentare un rischio per il paziente o tali da impedire al paziente di firmare il consenso informato in maniera adeguata.
- Donne in gravidanza o in allattamento.
- Conosciuta sierologia positiva per HIV.
- Sierologia positiva per l’epatite B (HBV), definita come test positivo per HBsAg e HBV-DNA.
- Positività a HCV-RNA.
- Patologie infettive croniche in corso che richiedano un trattamento con antibiotici sistemici, antifungini, o antivirali includenti, ma non limitate a, un’infezione renale cronica, un’infezione toracica cronica, tubercolosi ed epatite attiva.
- Storia di tubercolosi negli ultimi cinque anni o una recente esposizione alla tubercolosi entro i 6 mesi precedenti alla valutazione del paziente.
- Noto abuso di alcool o sostanze stupefacenti.
- Patologia cardiaca clinicamente significativa, comprendente un’ angina instabile, l’ infarto acuto del miocardio entro i sei mesi precedenti alla valutazione del paziente , scompenso cardiaco congestizio (NYHA III-IV), aritmia non controllata dalla terapia, neuropatia ≥ grado 2, storia di una patologia cerebrovascolare significativa negli ultimi sei mesi, evento cerebrovascolare in atto sequele di evento cerebrovascolare.
- Trombocitopenia o anemia emolitica autoimmune non controllate dalla terapia..
- Una o più anomalie di laboratorio tra le seguenti:
1. Clearance della creatinina calcolata (Cockroft-Gault)<60mL/min.
2. Conta assoluta dei granulociti <1500/µL non correlabile alla patologia.
3. Conta piastrinica < 75000/µL non correlabile alla patologia.
4. GOT, GPT, GT, fosfatasi alcalina > 1,5 x ULN a meno che non giudicate come dovute all’interessamento dalla patologia); bilirubina sierica >1.5mg/dL, epatopatia o patologia delle vie biliari in (con l’eccezione della sindrome di Gilbert, calcolosi biliare asintomatica)
- Precedente trattamento con un qualsiasi farmaco non in commercio o terapia sperimentale che sia stata assunta entro le cinque emivite terminali del prodotto o entro le quattro settimane precedenti l’arruolamento, considerando tra i 2l l’intervallo di maggiore durata, oppure, pazienti che partecipino contemporaneamente ad un altro studio di tipo interventistico.
- Altra neoplasia pregressa o in atto. Sono eleggibili al trattamento pazienti in remissione da una neoplasia da almeno cinque anni o che abbiano avuto la completa resezione di una neoplasia cutanea che non sia un melanoma oppure che abbiano subito la resezione completa di un carcinoma in situ.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The complete response (CR) rate after FCO2 front-line treatment |
| La percentuale di remissione completa dopo il trattamento in studio |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 months from the last study drug administration |
| 2 mesi dall'ultima somministrazione del farmaco in studio |
|
| E.5.2 | Secondary end point(s) |
- Overall Response (OR) rate after FCO2 front-line treatment.
- Progression-free survival (PFS) calculated from the date of first treatment dose - induction phase - until the date of the first documentation of progressive disease or until death (whatever the cause), whichever occurs first. Patients still alive and known to be progression free will be censored at the moment of last follow-up.
- Time to a new CLL treatment (TTT) will be calculated from the date of last treatment dose until date of a new treatment received for CLL, where death occurred before the new treatment will be considered as competing risk. Patients still alive without receiving a new treatment will be censored at the time of the last follow-up.
- Overall survival (OS): defined as the time interval between the date of first treatment dose - induction phase- and the date of death for any cause; patients still alive will be censored at the moment of last follow-up
- Toxicity of treatment according the last NCI criteria.
- Outcome of patients (response, PFS OS) according to clinical and biologic variables (age; size of nodes, 2-microglobulin, lymphocyte count, stage, IgVH, p53, FISH, NOTCH1, SF3B1, BIRC3, ZAP-70, CD38, FLCs).
|
Risposta globale del trattamento di prima linea con FCO2.
- Sopravvivenza libera da progressione di malattia.
- Tempo ad un nuovo trattamento.
- Sopravvivenza globale.
- Tossicità del trattamento di prima linea con FCO2
- Tossicità in termini di termini di granulocitopenia di grado 3-4;
- L’outcome (percentuale globale di risposte, sopravvivenza libera da progressione di malattia, tempo ad un nuovo trattamento, sopravvivenza globale)secondo le variabili cliniche e biologiche (età, dimensione dei linfonodi, 2-microglobulina, conta dei linfociti, IgVH, p53, FISH, ZAP-70,NOTCH1, SF3B1, BIRC3, CD38, CD49d, FLCs, FDG-uptake, istologia dei linfonodi).
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the study |
| Alla fine dello studio |
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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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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 | 33 |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 50 |
| E.8.9.1 | In the Member State concerned days | |
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