E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory Waldenstrom’s Macroglobulinemia |
Macroglobulinemia di Waldenström recidivante o refrattaria |
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E.1.1.1 | Medical condition in easily understood language |
Leukemia or Lymphoma |
Leucemia o linfoma |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047804 |
E.1.2 | Term | Waldenstrom's macroglobulinaemia recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 the effect of the addition of ibrutinib to rituximab on progression-free survival (PFS) assessed by an independent review committee (IRC) in subjects with previously treated Waldenstrom’s Macroglobulinemia WM.
Efficacy evaluations will be based on the modified Consensus Response Criteria from the VIth International Workshop for WM (NCCN 2014). |
Analizzare l'effetto dell'aggiunta di ibrutinib a rituximab sulla sopravvivenza libera da progressione (PFS) valutata da un comitato etico indipendente (IRC) in soggetti con macroglobulinemia di Waldenström (WM) già trattata in precedenza.
Le valutazioni dell’efficacia saranno basate sui criteri di risposta di consenso modificati
del 6° Workshop Internazionale sulla WM (NCCN 2014).
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E.2.2 | Secondary objectives of the trial |
Efficacy
To compare the treatment arms in terms of the following:
• Overall Response Rate (ORR) assessed by IRC (≥ PR; according to the modified VIth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) [NCCN 2014] criteria).
• Hematological improvement measured by hemoglobin.
• Time to next treatment (TTnT).Overall survival (OS).
Safety
• To evaluate the safety and tolerability of ibrutinib when combined with rituximab therapy compared to rituximab in combination with placebo. |
Confrontare i bracci di trattamento in termini di:
• Tasso di risposta complessiva (ORR) valutato dall'IRC (≥PR; secondo i criteri modificati del 6° Workshop Internazionale sulla macroglobulinemia di Waldenström (IWWM, International Workshop on Waldenstrom's Macroglobulinemia) [NCCN 2014]).
• Miglioramento ematologico misurato attraverso l'emoglobina.
• Tempo al trattamento successivo (TTnT). Sopravvivenza complessiva (OS).
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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 |
An open-label ibrutinib substudy (Arm C) is included to further investigate the safety and efficacy of ibrutinib monotherapy in subjects with WM who would otherwise be excluded from the randomized study because they are considered refractory to the last prior rituximab containing therapy.
PFS, ORR, hematological improvement measured by hemoglobin, TTnT, FACTAn, OS and other efficacy parameters as well as safety analyses will be summarized descriptively for Arm C. No comparator analysis will be done with Arms A or B. |
È incluso un studio secondario di ibrutinib in aperto (Braccio C) per valutare ulteriormente la sicurezza e l’efficacia della monoterapia con ibrutinib in soggetti con WM che sarebbero altrimenti esclusi dallo studio randomizzato, in quanto considerati refrattari all’ultima precedente terapia contenente rituximab. PFS, ORR, miglioramento ematologico misurato dall'emoglobina, TTnT, FACT-An, OS e altri parametri di efficacia unitamente alle analisi di sicurezza saranno riassunti in maniera descrittiva per il Braccio C. Nessuna analisi comparativa sarà effettuata con i Bracci A o B. |
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E.3 | Principal inclusion criteria |
For the Randomized Study (Arm A and Arm B):
- Previously treated for Waldenstrom’s macroglobulinemia and have either documented disease progression or had no response (stable disease) to the most recent treatment regimen.
- Centrally confirmed clinicopathological diagnosis of WM in accordance with the consensus panel of the Second International Workshop on WM (Owen 2003).
- Measurable disease defined as serum monoclonal IgM >0.5 g/dL.
- Symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003).
- Adequate hematologic function.
- Adequate hepatic and renal function.
- PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN.
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Ethical/Other
For the Open-label Substudy Treatment Arm C:
To be enrolled in the substudy, each potential subject must meet all of the inclusion criteria defined in Protocol Section 4.1.1 (Arm A & Arm B). IN ADDITION, the following criterion must be met:
1. Disease that is refractory to the last prior rituximab-containing therapy defined as either
• Relapse after the last rituximab-containing therapy <12 months since last dose of rituximab,
OR
• Failure to achieve at least a MR after the last rituximab-containing therapy. |
Per lo studio randomizzato (Braccio A e Braccio B):
- Soggetti che hanno precedentemente ricevuto un trattamento per la macroglobulinemia di Waldenström e mostrano una progressione della malattia documentata oppure un'assenza di risposta (malattia stabile) al regime di trattamento più recente.
- Diagnosi clinico-patologica di WM confermata centralmente in accordo con il gruppo di consenso del Secondo Workshop Internazionale sulla WM (Owen 2003).
- Malattia misurabile definita come concentrazione di IgM monoclonale sierica >0,5 g/dl.
- Malattia sintomatica che risponde ad almeno 1 delle raccomandazioni del Secondo Workshop Internazionale sulla Macroglobulinemia di Waldenström per la richiesta di trattamento (Kyle 2003).
- Funzione ematologica adeguata.
- Funzione epatica e renale adeguata.
- PT/INR ≤ 1,5 x ULN e PTT (aPTT) ≤ 1,5 x ULN.
- Performance status secondo ECOG (Eastern Cooperative Oncology Group) ≤ 2. Etici/Di altro genere
Per il braccio di trattamento C dello studio secondario in aperto:
Per essere arruolato nello studio secondario, ogni potenziale soggetto deve rispondere a tutti i criteri di inclusione definiti nel paragrafo 4.1.1 del protocollo (Braccio A e Braccio B). INOLTRE, devono essere soddisfatti i seguenti criteri:
1. Malattia refrattaria all'ultima precedente terapia contenente rituximab, definita come
• Recidiva dopo l'ultima terapia contenente rituximab <12 mesi dall'ultima dose di rituximab,
OPPURE
• Mancato conseguimento di almeno una risposta molecolare (MR) dopo l'ultima terapia contenente rituximab.
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E.4 | Principal exclusion criteria |
- Known involvement of the central nervous system by WM.
- Disease that is refractory to the last prior rituximab-containing therapy defined as either
• Relapse after the last rituximab-containing therapy <12 months since last dose of
rituximab,
OR
• Failure to achieve at least a MR after the last rituximab-containing therapy.
If the subject meets this exclusion criterion and therefore is excluded from the main randomized study, participation in the non randomized substudy (Arm C) may be considered (Section 4.2)
- Rituximab treatment within the last 12 months before the first dose of study drug.
- Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab.
- Prior exposure to ibrutinib or other BTK inhibitors.
- Received any WM-related therapy (eg, chemotherapy, immunotherapy, investigational drug) ≤30 days prior to first administration of study treatment.
- Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia.
- History of stroke or intracranial hemorrhage within 12 months prior to enrollment.
- Known history of infection with human immunodeficiency virus (HIV).
- History of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) .
- Any uncontrolled active systemic infection.
- Major surgery (as defined in Section 6.2.2) within 4 weeks of first dose of study drug.
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
- Significant screening electrocardiogram (ECG) abnormalities.
- Currently active, clinically significant cardiovascular disease.
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function.
- Concomitant use of warfarin or other Vitamin K antagonists.
- Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
The exclusion criteria for the substudy are identical to those of the main randomized study as described in Protocol Section 4.1.2, EXCEPT for criteria 2, 3, and 4, which are related to prior rituximab use and do not apply for the substudy Arm C. |
- Interessamento noto del sistema nervoso centrale da parte della WM.
- Malattia refrattaria all'ultima precedente terapia contenente rituximab, definita come
• Recidiva dopo l'ultima terapia contenente rituximab <12 mesi dall'ultima dose di
rituximab, OPPURE
• Mancato conseguimento di almeno una risposta molecolare (MR) dopo l'ultima terapia contenente rituximab.
Se il soggetto risponde a questo criterio di esclusione ed è quindi escluso dallo studio randomizzato principale, può essere considerata la sua partecipazione allo studio secondario non randomizzato (Braccio C) (paragrafo 4.2)
- Trattamento con rituximab nei 12 mesi precedenti la prima dose del farmaco in studio.
- Nota anafilassi o ipersensibilità mediata da IgE alle proteine murine o a qualsiasi componente di rituximab.
- Precedente esposizione a ibrutinib o altri inibitori di BTK.
- Assunzione di qualsiasi terapia associata alla WM (per es. chemioterapia, immunoterapia, farmaco sperimentale) nei ≤30 giorni precedenti la prima somministrazione del trattamento in studio.
- Disordini emocoagulativi noti (per es. malattia di von Willebrand) o emofilia.
- Storia di ictus o emorragia intracranica nei 12 mesi precedenti l'arruolamento.
- Storia nota di infezione da virus dell'immunodeficienza umana (HIV).
- Storia di infezione in atto o cronica da virus dell'epatite C (HCV) o virus dell’epatite B (HBV)
Qualsiasi infezione sistemica in atto non controllata.
- Intervento di chirurgia maggiore (come definito nel paragrafo 6.2.2) nelle 4 settimane precedenti la prima dose del farmaco in studio.
- Qualsiasi malattia potenzialmente mortale, condizione medica o disfunzione organica che, a parere dello sperimentatore, possa compromettere la sicurezza del soggetto o esporre gli esiti dello studio a un rischio eccessivo.
- Significative anomalie elettrocardiografiche (ECG) allo screening.
- Malattia cardiovascolare clinicamente significativa in atto.
- Incapacità di ingerire capsule o sindrome da malassorbimento, malattia con significativo impatto sulla funzione gastrointestinale.
- Concomitante utilizzo di warfarin o altri antagonisti della vitamina K.
- Richiesta di trattamento con un potente inibitore del citocromo P450 (CYP) 3A.
I criteri di esclusione dello studio secondario sono identici a quelli dello studio randomizzato principale, come descritto nel paragrafo 4.1.2 del protocollo, ECCETTO per i criteri 2, 3 e 4 che sono associati al precedente utilizzo di rituximab e non si applicano al Braccio C dello studio secondario
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) assessed by an independent review
committee (IRC), which is defined as duration from the date of
randomization to the date of disease progression or death, whichever is first reported, assessed according to the modified VIth IWWM (NCCN 2014) criteria. |
Sopravvivenza libera da progressione (PFS) valutata da un comitato etico indipendente (IRC), che è definita come la durata dalla data di randomizzazione alla data di progressione della malattia o del decesso, a seconda di quale evento si verifichi per primo, valutata secondo i criteri modificati del 6° IWWM (NCCN 2014) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Refer to protocol section 10.6.1. |
Vedere il paragrafo 10.6.1 del protocollo. |
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E.5.2 | Secondary end point(s) |
Multiplicity adjustment will be made in a sequential hierarchical manner based on a closed testing procedure as outlined in protocol section 10.8 (interim analysis) to control the overall type 1 error.
- Overall response rate (ORR) defined as the proportion of subjects who achieve Partial response (PR) or better according to the modified VIth IWWM (NCCN 2014) criteria as assessed by IRC.
- Hematological improvement as measured by change from baseline hemoglobin level.
- Time-to-next treatment (TTnT) as measured from the date of randomization to the start date of any subsequent WM treatment.
- Overall survival (OS) as measured from the date of randomization to the date of the subject’s death from any cause. |
Sarà effettuato un aggiustamento di molteplicità in maniera gerarchica sequenziale sulla base di una procedura di test chiuso (Closed Testing) come definito nel paragrafo 10.8 del protocollo (analisi ad interim) per il controllo dell'errore complessivo di tipo 1. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Refer to protocol section 10.6.2. |
Vedere il paragrafo 10.6.2 del protocollo |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Canada |
Australia |
United States |
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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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The end of study will occur approximately 3 years after the last subject is randomized, or the Sponsor terminates the study, whichever comes first.
At the time of the study closure, a survival sweep will be conducted. All subjects who are on study and not known to have died prior to the survival sweep will be contacted at that time. |
Lo studio si concluderà circa 3 anni dopo la randomizzazione dell'ultimo soggetto o al termine dello studio deciso dallo sponsor, a seconda di quale di questi eventi si verifichi per primo.
Al momento della chiusura dello studio, sarà effettuata un'esplorazione dei dati di sopravvivenza. A quel punto, tutti i soggetti che sono nello studio e non risultano essere deceduti prima dell'esplorazione dei dati di sopravvivenza saranno contattati.
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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 | 4 |
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 | 4 |
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 |