| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and adolescents, 1-20 years, with CML or relapsed Philadelphia positive ALL resistant or intolerant to imatinib or second or subsequent relapse of other ALL or AML |
| Bambini e adolescenti da 1 a 20 anni affetti da leucemia mieloide cronica (CML) o da leucemia linfoblastica acuta (ALL) philadelphia positiva recidivata e resistenti o intolleranti all'imatinib, o da seconde o successive recidive di altre ALL o leucemia mieloide acuta (AML). |
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| 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 | 14.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10024324 |
| E.1.2 | Term | Leukaemias |
| 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 establish, by stratum using a dose-finding design, a recommended dose of dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia |
| Identificare la dose consigliata di dasatinib (BMS-354825) in bambini o adolescenti affetti da leucemia recidivata o refrattaria, usando un disegno che ricerca la dose migliore nei differenti strati. |
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| E.2.2 | Secondary objectives of the trial |
| To determine the adverse events and identify any dose-limiting toxicities of dasatinib in children and adolescents with CML in CP (Ph+; Stratum 1) or advanced leukemias (Strata 2/3 e 4 aggregated) 2) To estimate, by stratum, the rates of morphologic (major hematologic response; MaHR), cytogenetic (major cytogenetic response; MCyR; strata 1 e 2/3 only), and molecular (qPCR; subjects with MCyR only, 1 e 2/3 only) response to dasatinib 3) To describe, by stratum, time to response, response duration, progression-free survival, and survival in children and adolescents with relapsed or refractory leukemia treated with dasatinib 4) To estimate, as a function of dasatinib dose, plasma and (if applicable) cerebrospinal fluid pharmacokinetic parameters of dasatinib 5) Describe spectrum of mutations in BCR-ABL gene (strata 1 and 2/3) and in FLT and KIT genes (stratum 4) at baseline and at the end of treatment and explore role of mutations as predictor of response. |
| 1)Det.gli eventi avversi e identificare le dosi limite di tossicità di dasatinib in bambini e adolescenti con leucemia mieloide cronica(CML)in CP(philadelphia positiva;strato 1)o leucemie in fasi avanzate(Strati 2/3 e 4 aggregati);2)Identificare,negli strati,la percentuale di risp morfologica(risp ematologia maggiore;MaHR),citogenetica(Maggiore risp citogenetica;MCyR;solo strati 1 e 2/3),e molecolare(qPCR;solo nei paz con MCyR,solo 1 e 2/3)al dasatinib;3)Valut,negli strati,il tempo di risp,la durata della risp,la sopravvivenza libera da progressione,e la sopravvivenza in bambini e adolescenti con leucemia recidivata o refrattaria trattata con dasatinib;4)Det.i parametri farmacocinetici di dasatinib nel plasma e nel liquido cerebrospinale(se applicabile),in funzione della dose di dasatinib;5)Descrivere lo spettro di mutazioni nel gene BCR-ABL(strato 1 e 2/3)e nei geni FLT3e KIT(strato 4)al baseline ed alla fine del tratt ed esplorare il ruolo delle mutazioni come predittori di risp. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Diagnosis (see § 3.2.1 for definitions of resistance and intolerance): Stratum 1: Ph+ chronic myeloid leukemia in chronic phase with resistant or progressive disease during, or intolerance to, imatinib, including: i) failure to achieve, or loss of, complete hematologic response after ≥ 3 months of imatinib ii) failure to achieve major cytogenetic response [minor or equal to 35% Ph+ metaphases] after ≥ 6 months or complete cytogenetic response [0% Ph+ metaphases] after ≥ 12 months of imatinib iii) recurrence of Ph+ clone with ≥ 35% abnormal metaphases after prior major cytogenetic response to imatinib iv) increase in BCR-ABL signal by quantitative PCR of ≥ 1 logs, confirmed at ≥ 6 week interval [must be discussed with Principal Investigator]. [Note: subjects enrolled in Stratum 1 should have an ongoing search for an identical HLA donor while on study]. Stratum 2/3: i) Ph+ advanced phase CML (accelerated phase (AP), myeloid blast phase (MBP), lymphoid blast phase (LBP)) resistant to imatinib; or ii) Relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ALL) after imatinib; iii) Ph+ acute myeloid leukemia in second or subsequent relapse [≥ 25% blasts in bone marrow] after prior imatinib. Note: for strata 1 and 2/3 it is not required that imatinib be the most recent treatment. In addition, biopsy-proven isolated extramedullary leukemia, i.e. with negative BM, is permitted for all strata after discussion with Prinicipal Investigator. Stratum 4: Ph-negative acute leukemia, any cytopathologic subtype, in second or subsequent relapse [≥ 25% blasts in bone marrow] or refractory after 2 or more induction regimens and for whom no therapy of greater curative potential is available. Age major or equal to 1 and < 21 years. Lansky or Karnofsky scale > 60 (see Appendix 1). Life expectancy > 3 weeks. Serum Ca2+ levels above institutional lower limit of normal; Na, K, Mg, Phos, AST, ALT, and Bilirubin ≤ Grade 1, and BUN and Creatinine ≤ Grade 2. No organ toxicity ≥ Grade 2 (except alopecia), and recovered from acute toxicity of previous therapy 7. Able to comply with scheduled follow-up at one of the ITCC-leukemia centers involved in this study. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medication. WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 3 months after the study in such a manner that the risk of pregnancy is minimized. Written informed consent from subject, or from parents or legal guardians for minor subjects, according to local law and regulation. |
| Diagnosi di (vedere § 3.2.1 per le definizioni di resistenza ed intolleranza): Strato 1: leucemia mieloide cronica (CML) Ph+ in fase cronica resistente o intollerante all'imatinib o che va in progressione durante il trattamento con imatinib, comprendente i) pazienti che non hanno raggiunto la risposta ematologia completa o l'hanno persa dopo 3 mesi di trattamento con imatinib ii) pazienti che non hanno raggiunto la risposta citogenetica maggiore (metafasi positive ≤ 35%) dopo 6 mesi o la risposta citogenetica completa (0% di metafasi positive) dopo 12 mesi di trattamento con imatinib iii) ricomparsa di cloni philadelphia positivi con piu` del 35% di metafasi anormali dopo precedenti maggiori risposte citogenetiche all'imatinib iv) incremento del segnale BCR-ABL tramite PCR quantitativa di 1 o piu` ceppi, confermata ad un intervallo di almeno 6 settimane (deve essere discusso con il Principal Investigator). Nota: i soggetti arruolati nello strato 1 dovrebbero cercare un donatore HLA identico durante lo studio). Strato 2/3: i) CML Ph+ in fase accelerata (AP), mieloide blastica (MBP) o linfoide blastica (LBP) resistente all'imatinib o ii) ALL Ph+ in prima o successive recidive dopo precedente trattamento con imatinib iii) AML Ph+ in seconda o successive recidive (≥ 25% di blasti nel midollo osseo) dopo precedente trattamento con imatinib. Nota: per gli strati 1 e 2/3: non e` richiesto che imatinib sia il trattamento piu` recente. In aggiunta, biopsy-proven isolated extramedullary laeukemia, i.e. with negatine BM, is permitted for all strata after discussion with Principal Investigator. Strato 4: Leucemia acuta Ph-, qualsiasi sottotipo citopatologico, in seconda o successive recidive (≥ 25% di blasti nel midollo osseo) o refrattario dopo due anni o piu` di regimi di induzione e per cui non sono disponibili trattamenti di maggiore potenziale curativo. Eta` dei pazienti: minore o uguale ad 1 e ‹ 21 anni. Scala di Lansky o di Karnofsky inferiore o uguale a 60. Aspettativa di vita superiore a 3 settimane. Nessuna tossicita` degli organi ≥ grado 2 (eccetto alopecia) e senza evidenza di tossicita` acute derivanti da terapie precedenti. Pazienti in grado di partecipare ai follow-up programmati in uno dei centri coinvolti in questo studio. Pazienti di sesso femminile in eta` fertile con test di gravidanza negativo entro le 72 ore prima dell'inizio del trattamento con il farmaco in studio. Firma del consenso informato da parte del soggetto, dei parenti o dei tutori legali per i minorenni, in base alla legge locale. |
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| E.4 | Principal exclusion criteria |
| Subjects for whom potentially-curative therapy is available, including electing immediate stem-cell transplantation 2. Extramedullary leukemia, specifically with a) symptomatic CNS involvement or b) isolated extramedullary disease, with < 5% blasts in marrow 3. Any serious uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy, including a) Ongoing uncontrolled infection b) Not recovered from acute toxicity of previous therapy c) Clinically-significant disorder of platelet function (e.g. von Willebrand's disease) or ongoing gastrointestinal bleeding d) Clinically-significant cardiovascular disease, congenital long QT syndrome, history of ventricular arrhythmias or heart block, or prolonged QTc interval > 450 ms (Fridericia correction) on baseline electrocardiogram 4. Expected non-compliance or unable to have regular follow-up due to psychological, social, familial or geographic reasons 5. Subjects who have received: a) Any investigational agent or any other anti-cancer agent within 14 days prior to treatment start. Exception: 6-mercaptopurine or 6-thioguanine may be given up to 2 days before entry, if required. For concomitant use of corticosteroids or hydroxyurea, see §6.6. b) Any prior therapy with dasatinib [BMS-354825] 6. Subjects requiring ongoing medications which a) irreversibly inhibit platelet function, or anticoagulants [see §6.4.1]. (Does not apply to low-dose heparin for prophylaxis or to heparin flushes for i.v. lines) b) have a known risk of causing QTc prolongation 7. WOCBP with a positive pregnancy test prior to study drug administration, or who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 3 months after the study, or who are pregnant or breastfeeding 8. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. |
| Pazienti per cui sono disponibili terapie potenzialmente curative compreso il trapianto delle cellule staminali Leucemia extramidollare con - coinvolgimento sintomatico del CNS - isolata malattia extramidollare con presenza di oltre il 5% di blasti nel midollo osseo Qualsiasi disturbo non controllato che puo` danneggiare la possibilita` del paziente di ricevere la terapia sperimentale. Pazienti che hanno ricevuto terapie contro il cancro entro 14 giorni dall'inizio del trattamento col farmaco in studio fatto salvo alcune eccezioni elencate nel protocollo. Pazienti che hanno precedentemente assunto dasatinib Pazienti che devono costantemente essere trattati con farmaci che inibiscono la funzionalita` piastrinica o anticoagulanti. Pazienti che sono a rischio di prolungamento delQTc |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety/Toxicity: safety and tolerability of dasatinib will be reported for all treated subjects. Adverse events will be assessed continuously and graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Safety analysis will include frequency, severity and relatedness of all AEs, abnormal laboratory values, use of concomitant medications, and dose interruptions of reductions. Efficacy: Efficacy will be assessed by stratum, for all patients, with any disease evaluation after treatment start. Hematologic, cytogenetic and molecular responses will be recorded. |
| La sicurezza e la tollerabilita` del dasatinib verranno considerati per tutti i pazienti trattati. Gli eventi avversi saranno valutati continuamente in accordo con gli NCI Common Terminology Criteria for Adverse Events (CTCAE) versione3.0. Le analisi di safety includeranno la frequenza, la serieta` e la correlazione di tutti gli AEs, valori anormali di laboratorio, l`uso di terapie concomitanti e le interruzioni o riduzioni di dose. L`efficacia verra` valutata nei diversi strati per tutti i pazienti con qualsiasi tipo di patologia dopo l`inizio del trattamento. |
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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 | 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Descrizione dello spettro delle mutazioni al livello di base ed alla fine del trattamento. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| 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) | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | 5 |
| 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 | 5 |
| 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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