E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria) |
Soggetti pediatrici (di età inferiore ai 18 anni) affetti da LLA da precursori delle cellule B in prima recidiva ad alto rischio (High-Risk, HR). |
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E.1.1.1 | Medical condition in easily understood language |
Acute Lymphoblastic Leukemia – a cancer of the blood and marrow |
Leucemia linfoblastica acuta – un cancro del sangue e del midollo |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066109 |
E.1.2 | Term | Precursor B-lymphoblastic leukemia acute |
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 event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy. |
Valutare la sopravvivenza libera da eventi (Event-Free Survival, EFS) in seguito a trattamento con
blinatumomab rispetto alla chemioterapia standard (SOC)
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of blinatumomab on overall survival (OS) when compared to SOC chemotherapy
• To evaluate reduction in minimal residual disease (MRD) after blinatumomab when compared to SOC chemotherapy
• To evaluate the safety of blinatumomab when compared to SOC chemotherapy
• To evaluate the safety of allogeneic hematopoietic stem cell transplantation (alloHSCT) after blinatumomab when compared to alloHSCT after SOC chemotherapy |
Valutare gli effetti di blinatumomab sulla sopravvivenza globale (Overall Survival, OS) rispetto alla chemioterapia standard
• Valutare la riduzione della malattia residua minima (Minimal Residual Disease, MRD) in seguito a trattamento con blinatumomab rispetto alla chemioterapia standard
• Valutare la sicurezza di blinatumomab rispetto alla chemioterapia standard
• Valutare la sicurezza del trapianto allogenico di cellule staminali ematopoietiche (Hematopoietic Stem Cell Transplantation, HSCT) in seguito a trattamento con blinatumomab rispetto all’HSCT allogenico in seguito a chemioterapia standard (SOC).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
* Subjects with Philadelphia (Ph-) chromosome negative high-risk (HR) first relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria)
* Subjects with M1 or M2 marrow (< 25% leukemic cells by cytomorphology) at the time of randomization
* Age > 28 days and < 18 years at the time of informed consent/assent
* Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated |
In questo studio saranno arruolati soggetti pediatrici di età >28 giorni e <18 anni affetti da LLA da
precursori delle cellule B in prima recidiva ad alto rischio (come definita dai criteri di International-Berlin-Frankfurt-Muenster Study Group [I-BFM SG]/IntReALL). Al momento della randomizzazione i soggetti avranno midollo osseo M1 o M2.
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E.4 | Principal exclusion criteria |
* Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy) Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment.
* Abnormal renal or hepatic function prior to start of treatment (day 1) as defined in the 20120215 protocol
a. Abnormal serum creatinine based on age/gender
b. Direct bilirubin > 1.5 mg/dl prior to start of treatment (unless related to Gilbert’s or Meulengracht disease)
* Peripheral neutrophils < 500/μl prior to start of treatment
* Peripheral platelets < 50,000/μl prior to start of treatment
* Currently receiving treatment in another investigational device or drug study, or less than 4 weeks since ending treatment on another investigational device or drug study(s). Other investigational procedures while participating in this study are excluded. Procedures required by IntReALL HR guidelines are allowed.
* Chemotherapy related toxicities that have not resolved to ≤ grade 2
* Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
* Known infection with HIV
* Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing
* Post-menarchal subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocol-required therapy and for at least 12 months thereafter
* Post-menarchal female subject who is not willing to practice true abstinence or use a highly effective form of contraception while receiving protocol-required therapy and for at least 12 months thereafter
* Sexually mature male subject who is not willing to practice true abstinence or use a condom while receiving protocol-required therapy and for at least 6 months thereafter
* Sexually mature male subject who is not willing to abstain from sperm donation while receiving protocol-required therapy and for at least 6 months thereafter
* Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject’s and investigator’s knowledge
* History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
* Placed into an institution due to juridical or regulatory ruling |
- Patologia a carico del CNS clinicamente rilevante che richiede trattamento (ad esempio epilessia instabile). I soggetti con ricaduta di CNS al momento della recidiva sono eleggibili se CNS è trattato con successo prima dell'arruolamento
- Funzione renale o epatica anormale prima dell'inizio del trattamento (giorno 1) come definito nel protocollo 20120215:
a. Livelli anormali di creatinina sierica in base all'età / genere
b. Bilirubina diretta > 1,5 mg / dl prima dell'inizio del trattamento (a meno che correlata alla malattia di Gilbert o Meulengracht)
- Neutrofili periferici < 500/μl prima dell’inizio del trattamento
- Piastrine periferiche < 50,000/μl prima dell’inizio del trattamento
- Il paziente attualmente riceve un altro trattamento con farmaco o dispositivo sperimentale, o lo ha ricevuto nelle ultime 4 settimane. Altre procedure in fase di sperimentazione durante la partecipazione a questo studio sono escluse. Sono permesse le procedure richieste dalle linee guida IntReALL HR.
- Tossicità correlate alla chemioterapia che non si sono risolte ad un grado ≤ 2.
- Sintomi e/o segni clinici e/o radiologici e/o segni ecografici che indicano un’infezione acuta o cronica incontrollata, qualsiasi altra malattia concomitante o condizione medica che potrebbe essere aggravata dal trattamento o potrebbe seriamente complicare
il rispetto del protocollo
- Infezione HIV conosciuta
- Ipersensitività conosciuta a immunoglobuline o qualsiasi prodotto o component da somministrare durante lo studio
- Soggetti femminili post-menarca incinte o in allattamento, o che hanno in progetto di rimanere incinte o allattare durante la terapia prevista dal protocollo e per almeno i 12 mesi successivi
- Soggetti femminili post-menarca non disposti a praticare l'astinenza o usare una forma di contraccezione ad alta efficacia durante la terapia e per almeno 12 mesi successivi
- Uomini sessualmente mature che non vogliono praticare l’astinenza o non intendono utilizzare il preservativo durante la terapia e per i 6 mesi successivi
- Uomini sessualmente maturi che non hanno intenzione di interrompere la donazione di sperma durante il trattamento o nei 6 mesi successivi
- Soggetti incapaci di completare tutte le visite o procedure previste dal protocollo, incluse le visite di follow up, e non in grado di rispettare tutte le procedure al meglio
- Storia o evidenza di altri disordini clinici significativi, condizioni o patologie (ad eccezione di quelle elencate sopra) che ad opinione dello sperimentatore o di un medico Amgen, se consultato, possono mettere a rischio la sicurezza del paziente o interferire con la valutazione dello studio, le sue procedure o il suo completamento.
- Soggetti confinati in istituti a seguito di sentenza giuridica
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. |
Dalla data di randomizzazione fino alla data di recidiva o midollo di tipo M2 dopo avere raggiunto una CR, un fallimentonella raggiunta della CR alla fine del trattamento, neoplasie secondarie o decesso dovuto a qualsiasi causa, la prima delle condizioni che si verifichi. |
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E.5.2 | Secondary end point(s) |
*OS
*MRD response
*Incidence of adverse events (both serious and non-serious), treatment-related adverse events, adverse events of interest, clinically significant changes in laboratory values
*Survival status at 100 days following HSCT
*Incidence of anti-blinatumomab antibody formation (blinatumomab arm only) |
OS
• Risposta MRD, definita come un livello di MRD <10-4 alla fine del trattamento con il/i prodotto/i
sperimentale/i
• Incidenza di eventi avversi (gravi e non gravi), eventi avversi correlati al trattamento, eventi avversi di interesse, alterazioni clinicamente significative dei valori di laboratorio
• Stato di sopravvivenza a 100 giorni dall’HSCT allogenico
• Incidenza della formazione di anticorpi anti-blinatumomab (solo gruppo trattato con blinatumomab)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
*OS: from time of randomization until the end of the study, or death, whatever comes first .
*MRD response: at the end of treatment with investigational product(s)
*Incidence of adverse events (both serious and non-serious), treatment-related adverse events, adverse events of interest, clinically significant changes in laboratory values : during the treatment period
*Survival status: at 100 days following alloHSCT
* Incidence of anti-blinatumomab antibody formation (blinatumomab arm only): during the whole study |
• OS: dalla randomizzazione alla fine dello studio, o decesso, la èprima che si verifichi
• Risposta MRD: alla fine del trattamento con il/i prodotto/i sperimentale/i
• Incidenza di eventi avversi (gravi e non gravi), eventi avversi correlati al trattamento, eventi avversi di interesse, alterazioni clinicamente significative dei valori di laboratorio: durante il periodo di trattamento
• Stato di sopravvivenza: a 100 giorni dall’HSCT allogenico
• Incidenza della formazione di anticorpi anti-blinatumomab (solo gruppo trattato con blinatumomab): durante l’intero 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Incidence of anti-blinatumomab antibody formation (blinatumomab arm only) |
Incidenza della formazione di anticorpi anti-blinatumomab (solo nel braccio blinatumomab) |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Czech Republic |
Denmark |
France |
Germany |
Israel |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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
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End of study (primary completion): when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint
End of Trial: when the last subject is assessed or receives an intervention for evaluation in the study; including follow-up assessments |
End of Study (completamento primario): quando l’ultimo soggetto è valutato o riceve un intervento per lo scopo della raccolta finale dei dati per l’endpoint primario
End of trial: quando l’ultimo soggetto è valutato o riceve un intervento per la valutazione dello studio; incluso le valutazioni di follow-up
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |