| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Elderly patients with advanced stage previously untreated follicular lymphoma |
| Linfoma follicolare in stadio avanzato (pazienti anziani precedentemente non trattati) |
|
| 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 | HLT |
| E.1.2 | Classification code | 10016903 |
| E.1.2 | Term | Follicle centre lymphomas, follicular grade I, II, III |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 demonstrate a statistical benefit in complete remission rate (CR) of a brief chemoimmunotherapy with Rituximab-Bendamustine-Mitoxantrone regimen (4 courses) followed by Rituximab consolidation (4 weekly doses) in elderly patients with advanced stage follicular lymphoma in comparison to historical data in similar patient’s population |
| Dimostrare un beneficio statistico del tasso di remissione completa (CR), di una breve chemoimmunoterapia con rituximab-Bendamustina-mitoxantrone (4 cicli), seguita dal consolidamento con rituximab (4 dosi settimanali) nei pazienti anziani con linfoma follicolare in stadio avanzato, in confronto ai dati storici in una popolazione di pazienti in condizioni patologiche simili |
|
| E.2.2 | Secondary objectives of the trial |
| •To evaluate the efficacy of the Rituximab-Bendamustine-Mitoxantrone regimen to prolong 2-year progression-free survival (PFS) rate compared to historical standard treatment in elderly patients with advanced stage follicular lymphoma •To evaluate the rate of molecular response (Bcl2/IgH rearrangement) by qualitative and quantitative PCR after Rituximab-Bendamustine-Mitoxantrone, and its persistence over the follow-up period (Minimal residual disease kinetics) •To assess the predictive value of qualitative and quantitative PCR on PFS •To assess the toxicity/safety of this new combination in elderly patients •To evaluate overall survival of the patients treated with Rituximab-Bendamustine-Mitoxantrone association |
| • Valutare l'efficacia del regime rituximab-Bendamustina-mitoxantrone nel prorogare di 2 anni la sopravvivenza libera da progressione (PFS) rispetto al trattamento storico standard nei pazienti anziani con linfoma follicolare in stadio avanzato • Valutare il tasso di risposta molecolare (riarrangiamento Bcl2/IgH) attraverso PCR quantitativa e qualitativa dopo rituximab-Bendamustina-mitoxantrone, e la sua persistenza nel periodo di follow-up (cinetica della malattia minima residua ) • Valutare il valore predittivo della PCR qualitativa e quantitativa su PFS • Valutare la tossicita'/sicurezza di questa nuova associazione nei pazienti anziani • Valutare la sopravvivenza globale dei pazienti trattati con l'associazione rituximab-Bendamustine-mitoxantrone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Histological proven diagnosis of B-cell CD20+ follicular NHL, grade I, II and IIIa of WHO Classification 2. Untreated patients with the exception of prior limited radiotherapy 3. Stage III or IV who require therapy according to SIE and GELF criteria (see Appendix A) 4. Stage II with at least one of the following: a. Bulky disease (>7 cm) b. LDH >normal c. Systemic symptoms d. Beta2-Microglobulin >3 mg/l e. Extra-nodal involvement f. Active disease with rapid progression 5. Age from 65 to 80 years, geriatric score “FIT” (see Appendix B) 6. Life expectancy >6 months 7. ECOG performance status 0-2 (see Appendix C) 8. LVEF ≥45% or FS ≥37% 9. ANC ≥1 x 10^9/l and Platelets count ≥75 x 10^9/l, unless due to bone marrow involvement by follicular lymphoma 10. Creatinine up to 1.5 x ULN 11. Conjugated bilirubin up to 2 x ULN 12. Alkaline phosphatase and transaminases up to 2 x ULN 13. Sending of bone marrow sample for Bcl-2/IgH rearrangement evaluation 14. Written informed content |
| 1. Diagnosi istologica provata di cellule NHL follicolare B CD20+, di grado I, II e III secondo la classificazione WHO 2. Pazienti non trattati con l'eccezione della prima radioterapia 3. Fase III o IV, che necessitano di terapia in base ai criteri SIE e GELF (vedi Appendice A) 4. Fase II, con almeno una delle seguenti condizioni: a. Malattia bulky (> 7 cm) b. LDH> normale c. Sintomi sistemici d. Beta2-microglobulina> 3mg/l e. Coinvolgimento extranodale f. Malattia attiva in rapida progressione 5. Eta' da 65 a 80 anni, score geriatrico ''FIT'' (vedi Appendice B) 6. Aspettativa di vita> 6 mesi 7. Performance status ECOG 0-2 (vedi appendice C) 8. LVEF ≥ 45% o FS ≥ 37% 9. ANC ≥ 1 x 10^9/l, e conta piastrinica ≥ 75 x 10^9/l, senza coinvolgimento del midollo osseo. 10. Creatinina fino a 1,5xULN 11. Bilirubina coniugata fino a 2xULN 12. Fosfatasi alcalina e transaminasi fino a 2xULN 13. Invio di campioni di midollo osseo per la valutazione del riarrangiamento Bcl-2/IgH 14. Consenso informato scritto |
|
| E.4 | Principal exclusion criteria |
| 1. Men not agreeing to take adequate contraceptive precautions during and for at least 6 months after cessation of therapy 2. History of other malignancies within 3 years prior to study entry except for: adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage, localized prostate cancer treated surgically with curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with curative intent 3. Medical condition requiring long term use (>1 months) of systemic corticosteroids 4. Active bacterial, viral, or fungal infection requiring systemic therapy 5. Concurrent medical condition which might exclude administration of therapy 6. Cardiac insufficiency (NYHA grade III/IV; see Appendix D) 7. Myocardial infarction within 6 months of entry on study 8. Severe chronic obstructive pulmonary disease with hypoxemia 9. Severe diabetes mellitus difficult to control with adequate insulin therapy 10. Hypertension that is difficult to control 11. Impaired renal function with creatinine clearance <30 ml/min (see Appendix E) 12. HIV positivity 13. HBV positivity with the exception of patients HbsAg negative and Ab anti-Hbcore positive (these patients need to receive prophylaxis with Lamivudine) 14. HCV positivity with the exception of patients with no laboratory signs of active chronic hepatitis and HCV-RNA negativity 15. CNS involvement by lymphoma 16. Participation at the same time in another study in which investigational drugs are used 17. Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins 18. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent |
| 1. Persone che non accettano di prendere adeguate precauzioni contraccettive durante e per almeno 6 mesi dopo l'interruzione della terapia 2. Storia di altri tumori maligni nei 3 anni precedenti l'ingresso allo studio, tranne: carcinoma in situ della cervice uterina trattato in modo adeguato; cancro della pelle a cellule squamose o basali; carcinoma della prostata localizzato, di basso grado e stadio precoce trattato chirurgicamente con intenti curativi; buona prognosi DCIS del cancro alla mammella trattato con lumpectomia solo con intenti curativi 3. Condizioni mediche che richiedono l'uso a lungo termine (> 1 mese) di corticosteroidi sistemici 4. Infezioni batteriche, virali, o fungine attive che richiedono terapia sistemica 5. Condizione medica concomitante che possa escludere la somministrazione della terapia 6. Insufficienza cardiaca (classe NYHA III / IV; vedi Appendice D) 7. Infarto miocardico, entro 6 mesi dall'entrata nello studio 8. Grave malattia polmonare ostruttiva cronica con ipossiemia 9. Grave diabete mellito di difficile controllo con una terapia adeguata di insulina 10. Ipertensione di difficile controllo 11. Funzionalita' renale con clearance della creatinina <30 ml/min (vedi Appendice E) 12. HIV positivita' 13. HBV positivita' con l'eccezione dei pazienti HbsAg negativi e Ab anti-Hbcore positivo (questi pazienti devono ricevere la profilassi con Lamivudina) 14. HCV positivita' con l'eccezione dei pazienti senza segni di laboratorio epatite cronica attiva e HCV-RNA negativita' 15. Coinvolgimento del SNC 16. Partecipazione contemporanea ad un altro studio in cui sono utilizzati altri farmaci sperimentali 17. Nota ipersensibilita' o reazioni anafilattiche ad anticorpi murini o a proteine 18. Qualsiasi altra condizione medica o psicologica co-esistente che possa impedire la partecipazione allo studio o che comprometta la capacita' di dare il proprio consenso informato |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Tasso di remissione completa |
| Complete remission rate |
|
| 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 | 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 | 43 |
| 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
| |
| 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 | 66 |
| E.8.9.1 | In the Member State concerned days | 0 |
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