E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse Large B-cells non-Hodgkin Lymphoma |
Linfoma diffuso a grandi cellule B |
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E.1.1.1 | Medical condition in easily understood language |
Elderly frail patients with Diffuse Large B-cells non-Hodgkin Lymphoma. |
Pazienti anziani con linfoma diffuso a grandi cellule B classificati fragili |
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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 | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025320 |
E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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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 efficacy and the safety of the R2 (Lenalidomide + Rituximab) combination in first line DLBCL patients not candidate for the standard R-CHOP (or R-CHOP like) treatments due to frail status. The efficacy will be measured as overall response rate (ORR, defined as complete plus partial remission rate). The safety will be measured as rate of the extra-hematologic adverse events of WHO grade 3-4 (NCI CTCAE 4.03) |
Valutare l’efficacia in termini di risposta globale (ORR) della combinazione Lenalidomide e Rituximab (R2) in prima linea in pazienti con DLBCL non candidabili al trattamento standard con R-CHOP (o R-CHOP like) perchè pazienti fragili. L’efficacia sarà misurata come tasso di risposta globale (ORR, definito come tasso di risposte complete e parziali). La tossicità sarà misurata come incidenza di eventi avversi extra-ematologici di grado 3-4 (NCI CTCAE 4.03) |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to better define the R2 efficacy and safety in terms of: - Complete Response Rate (CR), - Progression-Free Survival (PFS), - Overall Survival (OS), - Event-Free Survival (EFS), - Drop-out rate, - Rate of treatment discontinuation due to AE or treatment intolerance, - QoL assessement at baseline,4 months, 6 months and 12 months by EORTC-QLQ-C30 and FACT-Lym questionnaire. - Hematologic adverse events of any WHO grade (NCI CTCAE 4.03). |
Definire efficacia e tossicità di R2 in termini di: - Tasso di risposte complete (CRR), - Progression-Free Survival (PFS), - Overall Survival (OS), - Event-Free Survival (EFS), - Tasso di Drop-out, - Tasso di interruzioni del trattamento dovute ad eventi avversi o intolleranza al trattamento, - Valutazione sulla qualità della vita all’esordio, dopo 4, 6, 12 mesi con i questionari EORTC-QLQ-C30 e FACT-Lym, - Incidenza di eventi avversi ematologici di qualsiasi grado (NCI CTCAE 4.03) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomics Version: 2.0 Date: 26/06/2017 Title: Pharmacogenomics and pharmacokinetics of Lenalidomide in elderly frail patients evaluated in CGA with Diffuse Large B-cells non-Hodgkin Lymphoma. An ancillary study of the FIL_ReRi protocol.
Objectives: Primary Objective: To investigate the pharmacogenomics (PGx) of R2 (Lenalidomide + Rituximab) in first line DLBCL patients not candidate for the standard R-CHOP (or R-CHOP like) treatments due to the frailty. Secondary Objectives: - To evaluate the PK of R - To investigate any possible correlation among pharmacodynamics, pharmacogenomics and pharmacokinetics.
Life quality Version: 2.0 Date: 26/06/2017 Title: N/A. This is a secondary objective of the main study Objectives: QoL assessement at baseline,4 months, 6 months and 12 months by EORTC-QLQ-C30 and FACT-Lym questionnaire.
Other types of substudies Specify title, date and version of each substudy with relative objectives: Pharmacogenomics and pharmacokinetics of Lenalidomide in elderly frail patients evaluated in CGA with Diffuse Large B-cells non-Hodgkin Lymphoma. An ancillary study of the FIL_ReRi protocol. Version n. 2.0 date: June 26th 2017 Objectives: - To evaluate the PK of R - To investigate any possible correlation among pharmacodynamics, pharmacogenomics and pharmacokinetics.
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Farmacogenomica Versione: 2.0 Data: 26/06/2017 Titolo: Valutazione della farmacogenomica e farmacocinetica di Lenalidomide in pazienti anziani con Linfoma Diffuso a Grandi Cellule B classificati fragili secondo la Valutazione Geriatrica Multidimensionale (CGA). Studio ancillare al protocollo FIL_ReRi. Obiettivi: Obiettivo Primario: Indagare la farmacogenomica (PGx) della combinazione Lenalidomide e Rituximab (R2) in prima linea in pazienti con DLBCL non candidabili al trattamento standard con R-CHOP (o R-CHOP like) perchè pazienti fragili Obiettivi secondari: - Valutare la farmacocinetica (PK) della Lenalidomide - Valutare le possibili correlazioni tra farmacodinamica, farmacogenomica, farmacocinetica
Qualita' della vita Versione: 2.0 Data: 26/06/2017 Titolo: N/A. Si tratta di uno degli obiettivi secondari dello studio principale
Obiettivi: Valutazione sulla qualità della vita all’esordio, dopo 4, 6, 12 mesi con i questionari EORTC-QLQ-C30 e FACT-Lym,
Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Valutazione della farmacogenomica e farmacocinetica di Lenalidomide in pazienti anziani con Linfoma Diffuso a Grandi Cellule B classificati fragili secondo la Valutazione Geriatrica Multidimensionale (CGA). Studio ancillare al protocollo FIL_ReRi Versione 2.0 del 26/06/2017 Obiettivi: - Valutare la farmacocinetica (PK) della Lenalidomide - Valutare le possibili correlazioni tra farmacodinamica, farmacogenomica, farmacocinetica
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E.3 | Principal inclusion criteria |
1. Histologically proven CD20 positive Diffuse Large B-cell Lymphoma, according to WHO classification (local pathologist) 2. Age = 70 years 3. Previously untreated 4. CGA assessment performed before starting treatment 5. FRAIL patients defined as follows: Age >= 80 years (with UNFIT profile): ADL >= 5 residual functions and/or IADL >= 6 residual functions and/or CIRS: 0 comorbidity of grade 3-4 and 5-8 comorbidities of grade 2 Age < 80 (ONLY one of the following criteria): ADL <= 4 residual functions IADL <= 5 residual functions CIRS: 1 comorbidity of grade 3-4 or > 8 comorbidities of grade 2 6. Ann Arbor Stage I - IV 7. At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan 8. ECOG performance status of 0- 3 9. No active hepatitis C virus (HCV) infection. In case of HCV positivity HCV-RNA is required. Only patients with HCV-RNA negative are accepted. 10. Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows: - Hemoglobin > 10 g/dL - WBC > 2500/mmc with PMN > 1000/ mmc - Platelets count = 75000/mmc - Creatinine clearance = 10 mL/min 11. Ability and willingness to comply with the study protocol procedure 12. Life expectancy > 6 months 13. Patients must give written informed consent. 14. Male subjects must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following investigational product discontinuation, even if he has undergone a successful vasectomy.
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1. Conferma istologica di linfoma a grandi cellule B CD20 positivo, secondo la classificazione WHO 2008 (diagnosi del patologo locale) 2. Età = 70 anni 3. Pazienti non precedentemente trattati 4. Valutazione CGA eseguita prima dell’inizio del trattamento 5. Pazienti FRAIL definiti come segue: Età >= 80 anni (con profilo UNFIT): ADL >= 5 funzioni residue e/o IADL >= 6 funzioni residue e/o CIRS: 5-8 comorbidità di grado 2, nessuna di grado 3-4 Età < 80 (SOLO uno dei seguenti criteri): ADL <= 4 funzioni residue IADL <= 5 funzioni residue CIRS: 1 comorbidità di grado 3-4 o > 8 comorbidità di grado 2 6. Malattia di stadio I - IV secondo Ann Arbor 7. Almeno una lesione misurabile in 2 dimensioni perpendicolari con diametro maggiore > 1.5 cm in TAC 8. ECOG performance status 0- 3 9. Assenza di infezione attiva da HCV. In caso di HCV positività, è richiesto test HCV-RNA. Solo pazienti con HCV-RNA negativi sono eleggibili. 10. Normale funzionalità ematologica (se non alterata per infiltrazione midollare) definita come segue: - Emoglobina > 10 g/dL - Globuli bianchi > 2500/mmc con neutrofili > 1000/ mmc - Piastrine = 75000/mmc - Clearance della creatinina = 10 mL/min 11. Capacità e volontà di rispettare le procedure del protocollo 12. Aspettativa di vita > 6 mesi 13. Consenso informato scritto del paziente 14. I pazienti di sesso maschile, anche se resi chirurgicamente sterili (stato di post vasectomia) devono astenersi completamente dai rapporti o utilizzare un efficace contraccettivo di barriera (preservativo) durante rapporti con donne in gravidanza o donne potenzialmente fertili per tutta la durata dello studio, durante le interruzioni di dose e per almeno 28 giorni dalla fine del trattamento.
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E.4 | Principal exclusion criteria |
1. Histological diagnosis different from CD20 positive Diffuse Large B-cell Lymphoma are excluded. 2. Previous exposure to cytotoxic agents 3. Suspect or clinical evidence of CNS involvement by lymphoma 4. Contraindication to the use of Rituximab or of Lenalidomide 5. HBsAg positivity; HBsAg-negative patients with anti-HBc antibody can be enrolled if Hepatitis B Virus (HBV)-DNA are negative and antiviral treatment with Lamivudine or Tenofir is provided. 6. HIV positivity 7. Active herpes zoster infection; previously infected patients is accepted only with concomitant treatment with Valacyclovir 8. Any history of other malignancies within 5 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer 9. AST /ALT > 2 x UNL; bilirubin > 2 x UNL; serum creatinine > 2.5 mg /dL 10. Creatinine clearance < 10 mL/min 11. Evidence of any severe active acute or chronic infection 12. Severe cardiac dysfunction (NYHA grade III-IV) 13. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent 14. Absence of caregivers in non-autonomous patients |
1. Diagnosi istologica diversa da linfoma a grandi cellule B CD20 positivo 2. Precedente trattamento con agenti citotossici 3. Sospetto o evidenza clinica di coinvolgimento del SNC da parte del linfoma 4. Controindicazione all’uso di Rituximab o di Lenalidomide 5. Pazienti HBsAg positivi; pazienti HBcAb positivi possono essere inclusi solo se l’HBV-DNA è negativo e vengono trattati con Lamivudina o Tenofovir 6. Pazienti HIV positivi 7. Pazienti con herpes zoster attivo; possono essere inclusi pazienti che hanno precedentemente avuto l’herpes zoster solo se trattati con Valacyclovir 8. Pregresse neoplasie solide negli ultimi 5 anni, fatta eccezione per carcinoma basale o squamoso della cute attualmente in remissione o carcinoma in situ della cervice uterina 9. AST /ALT > 2 x UNL; bilirubina > 2 x UNL; creatinina sierica > 2.5 mg /dL 10. Clearance della creatinina < 10 mL/min 11. Evidenza di infezioni gravi acute o croniche 12. Insufficienza cardiaca severa (NYHA grado III-IV) 13. Qualsiasi altra condizione medica o psicologica coesistente che precluda la partecipazione allo studio o comprometta la capacità di dare il consenso informato. 14. Pazienti non autonomi senza una figura che li assista
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: overall response rate (ORR) Safety: clinical relevant toxicity, defined as the proportion of patients experiencing a grade 3 or greater non haematological toxicity.
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Efficacia: ORR (tasso di risposta globale) Sicurezza: tossicità rilevanti (non ematologiche di grado uguale o maggiore a 3) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: 48 months safety: 48 months |
Efficacia: 48 mesi Sicurezza: 48 mesi |
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E.5.2 | Secondary end point(s) |
Complete response rate (CR) ; Haematological toxicity of any WHO grade; Overall Survival (OS); Progression Free Survival (PFS); Event-Free Survival (EFS); Quality of Life (FACT-Lym and EORTC-QLQ-C39) |
Tasso di risposte complete (CR); Tossicità ematologiche di qualsiasi grado; Sopravvivenza globale (OS); Sopravvivenza libera da progressione (PFS); Event-Free Survival (EFS); Qualità della vita (FACT-Lym e EORTC-QLQ-C39) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
48 months; 48 months; 60months; 60 months; 60 months; 60 months |
48 mesi; 48 mesi; 60 mesi; 60 mesi; 60 mesi; 60 mesi |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 31 |
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 | 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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LVLS that means 12 months after the EoT. |
LVLS ossia 12 mesi dopo la fine del trattamento |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 60 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 60 |
E.8.9.2 | In all countries concerned by the trial days | 0 |