| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Childhood relapsed/refractory ALL |
| Leucemia linfoblastica acuta recidivata/refrattaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| malignancy that originates in the bone marrow cells from the lymphoid series |
| neoplasia maligna che origina nel midollo emopoietico da cellule della serie linfoide |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| 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 |
| Determine the antileukemic activity of combination chemotherapy including bortezomib as reinduction therapy in childhood relapsed/refractory ALL |
| Determinare l’attivita' antileucemica della chemioterapia combinata al bortezomib come terapia di reinduzione della remissione in bambini affetti da LLA (leucemia linfoblastica acuta) recidivata/refrattaria |
|
| E.2.2 | Secondary objectives of the trial |
| - Determine the feasibility and safety of combining bortezomib with conventional combination chemotherapy in children and adolescents with relapsed/refractory ALL - Evaluate bortezomib levels and proteasome inhibition in cerebrospinal fluid, bone marrow and peripheral blood in patients with relapsed/refractory ALL, and assess the relationship to the efficacy and toxicity of bortezomib |
| - Determinare la fattibilita' e la sicurezza del bortezomib in associazione alla chemioterapia tradizionale in bambini e adolescenti affetti da LLA recidivata/refrattaria - Valutare i livelli di bortezomib e l’inibizione del proteasoma nel liquor, nel midollo osseo e nel sangue periferico in pazienti con LLA redicivata/refrattaria, e valutare la relazione tra efficacia e tossicita' del bortezomib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| - Age between 6 months and 19 years - Patients with a second or subsequent relapsed ALL - Patients with first relapsed ALL after prior allogeneic stem cell transplantation in first complete remission - Patients with refractory first relapse of ALL, as defined by the ALL relapse protocol these patienst were enrolled in before - Circulating leukemic blasts of at least 100/ul peripheral blood (i.e. at least 0.1x109/l) - Patients must take adequate contraceptives when of childbearing potential - Written informed consent |
| - Eta' compresa fra 6 mesi e 19 anni - Pazienti con una LLA in seconda o successiva recidiva - Pazienti con una prima recidiva di LLA dopo un iniziale trapianto allogenico di cellule staminali emopoietiche effettuato in prima completa remissione - Pazienti in prima recidiva refrattaria di LLA cosi' come definita dal protocollo sulla LLA recidivata in cui i pazienti erano stati arruolati in precedenza - Blasti leucemici circolanti pari ad almeno 100/ul di sangue periferico (es. almeno 0.1x109/l) - I pazienti in eta' fertile devono assumere metodi contraccettivi adeguati - Consenso informato scritto |
|
| E.4 | Principal exclusion criteria |
| - Relapse not involving the bone marrow - Symptomatic CNS leukemia - Active uncontrolled infection - Performance status (Lansky or Karnofsky score) of 60% or less - Life expectancy of less than 6 weeks - Existing peripheral neuropathy NCI grade 2 or higher - Presence of acute diffuse infiltrative myocardial and/or pericardial disease - Clinical signs of cardiotoxicity - Previous allogeneic stem cell transplantation within 100 days - Pregnant or breastfeeding - Other contra-indications for chemotherapy, including no recovery from previous treatment - Previous exposure to bortezomib - Other experimental or conventional antileukemic treatment within 7 days from start of bortezomib - Allergy to boron and its metabolites - Concomitant anti-leukemic therapy other than according to this protocol |
| - Recidiva che non coinvolga il midollo osseo - Leucemia del SNC sintomatica - Infezione attiva non controllata - Scale di rendimento (score Lansky o Karnofsky) del 60% o inferiore - Aspettativa di vita inferiore a 6 settimane - Esistente neuropatia periferica di grado 2 o superiore - Presenza di una patologia miocardica e/o pericardica acuta diffusa ed infiltrativa - Segni clinici di cardiotossicita' - Precedente trapianto di cellule staminali allogeniche entro 100 giorni - Paziente in gravidanza o allattamento - Altre controindicazioni alla chemioterapia, incluso il non recupero da un precedente trattamento - Precedente esposizione al bortezomib - Altro trattamento antileucemico sperimentale o tradizionale entro 7 giorni dell’inizio del bortezomib - Allergia al boro e ai suoi metaboliti - Terapia antileucemica concomitante non conforme al protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute peripheral blood (PB) blast count on day 8 of treatment. Morphology will be centrally reviewed. |
| 1. Attivita' antileucemica del bortezomib aggiunto desametasone, a vincristina e a methotrexate intratecale, cosi' come stabilito dal conteggio dei blasti nel sangue periferico assoluto al giorno 8 del trattamento. La morfologia verra' sottoposta a revisione centralizzata. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| on day 8 of treatment |
| DOPO 8 GIORNI DALL'INIZIO DEL TRATTAMENTO |
|
| E.5.2 | Secondary end point(s) |
| Antileukemic activity of bortezomib when added to demathasone and vincristine and intrathecal methotrexate, as determined by the absolute bone marrow (BM) blast percentage on day 8, and BM and PB analysis on day 22 of treatment, in absolute numbers and expressed as an M1, M2 or M3 marrow (<5%, 5-15%, 15% or above respectively). Morphology will be centrally reviewed. |
| 1. Attività antileucemica del bortezomib aggiunto a desametasone, vincristina e methotraxate intratecale, definita come percentuale di blasti nel midollo osseo al giorno 8, nel midollo osseo e nel sangue periferico al giorno 22 del trattamento, espressi in numero assoluto e come M1, M2 o M3 (rispettivamente <5%, 5-15%, 15% o superiore). La morfologia sarà sottoposta a revisione centralizzata. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| blast percentage on day 8, and BM and PB analysis on day 22 of treatment |
| percentuale di blasti nel midollo osseo al giorno 8, nel midollo osseo e nel sangue periferico al giorno 22 del 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| stesso farmaco in tempi diversi |
| same drug at different times |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 24 |
| 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 | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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