E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Indolent Non-Hodgkin Lymphoma (iNHL) |
linfoma non Hodgkin indolente |
|
E.1.1.1 | Medical condition in easily understood language |
Blood cancer |
Cancro del sangue |
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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 | HLT |
E.1.2 | Classification code | 10029621 |
E.1.2 | Term | Non-Hodgkin's lymphomas unspecified histology indolent |
E.1.2 | System Organ Class | 100000004851 |
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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 |
The primary objective of this study is to evaluate whether the addition of ibrutinib to bendamustine and rituximab (BR) combination or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination will result in prolongation of PFS compared with either BR or R-CHOP alone in subjects with previously treated iNHL (FL or MZL). |
L’obiettivo primario di questo studio è stabilire se l’aggiunta dell’Ibrutinib all’associazione bendamustina e rituximab (BR) o all’associazione rituximab, ciclofosfamide, doxorubicina, vincristina e prednisone (R-CHOP) determinerà il prolungamento della sopravvivenza libera da progressione (PFS) rispetto al solo regime BR o il solo regime R-CHOP in soggetti con linfoma non Hodgkin indolente (iNHL) (linfoma follicolare o linfoma della zona marginale) precedentemente trattato. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare treatment groups in terms of the following:
overall survival (OS)
complete response rate (CR)
overall response rate ORR (CR+PR)
duration of response (DOR)
patient-reported lymphoma symptoms and concerns as measured by the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
safety of ibrutinib when combined with BR or R-CHOP |
Gli obiettivi secondari sono i confronti tra i gruppi di trattamento in termini di
- sopravvivenza globale
- percentuale di risposta completa (CR)
- percentuale di risposta globale (ORR: CR + risposta parziale [PR])
- durata della risposta (DOR)
- sintomi e problemi correlati al linfoma riferiti dal paziente misurati dalla sottoscala Lym del questionario per la valutazione funzionale della terapia oncologica per il linfoma (FACT-Lym)
- sicurezza dell’Ibrutinib in associazione al regime BR o al regime R-CHOP
|
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically confirmed diagnosis of B-cell indolent Non-Hodgkin lymphoma with histological subtype limited to follicular lymphoma or marginal zone lymphoma
- At least 1 prior treatment with a CD20 antibody combination chemotherapy regimen
- Disease that has relapsed or was refractory after prior chemoimmunotherapy
- At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma 2007
- Eastern Cooperative Oncology Group performance status grade 0 or 1
- Laboratory values within protocol-defined parameters
- Agrees to protocol-defined use of effective contraception
- Men must agree not to donate sperm during and after the study for 6 months after the last dose of bendamustine, 12 months after the last dose of rituximab, or 3 months after the last dose of study medication, whichever is later
- Women of childbearing potential must have a negative serum or urine
pregnancy test at screening |
Diagnosi di linfoma non Hodgkin indolente a cellule B confermata dall’esame istologico, con sottotipo istologico limitato al linfoma follicolare o al linfoma della zona marginale
- Almeno 1 precedente trattamento con un regime chemioterapico associato contenente un anticorpo anti-CD20.
-Malattia recidivante o refrattaria dopo la precedente chemio-immunoterapia.
-Almeno una sede misurabile della malattia secondo i criteri di risposta revisionati per il linfoma maligno (Cheson 2007)
-Performance status ECOG (Eastern Cooperative Oncology Group) di grado 0 o 1.
-Valori di laboratorio compresi nei range del protocollo
-Consenso all’utilizzo di metodi contraccettivi definiti in protocollo
-Gli uomini devono anche acconsentire a non donare lo sperma durante e dopo lo studio. Per gli uomini, queste restrizioni valgono per 6 mesi dopo l’ultima dose di bendamustina, 12 mesi dopo l’ultima dose di rituximab o 3 mesi dopo l’ultima dose di farmaco sperimentale, a seconda dell’evento che si verifica per ultimo.
- Le donne in età fertile devono presentare un test di gravidanza negativo sul siero o sulle urine allo screening
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E.4 | Principal exclusion criteria |
-Prior treatment according to protocol-defined criteria
-Unable to receive background chemotherapy based on prior treatment history and cardiac function
-Known central nervous system lymphoma
-Diagnosed or treated for malignancy other than indolent Non-Hodgkin lymphoma
-History of stroke or intracranial hemorrhage within 6 months prior to randomization
-Requires anticoagulation with warfarin or equivalent Vitamin K antagonists or treatment with strong CYP3A4/5 inhibitors
-Clinically significant cardiovascular disease
-Known history of human immunodeficiency virus or active infection with hepatitis C or B or any uncontrolled active systemic infection requiring intravenous antibiotics
-Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the participant’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
-Women who are pregnant or breastfeeding |
-Precedente trattamento conforme ai criteri definiti in protocollo
-Impossibilità di ricevere il regime chemioterapico di background a causa della storia di trattamento precedente e della funzione cardiaca.
-Linfoma del sistema nervoso centrale noto.
-Diagnosi di o terapia per tumore maligno diverso dal linfoma non Hodgkin indolente
-Storia di ictus o emorragia intracranica entro i 6 mesi precedenti la randomizzazione
-Necessità di terapia anticoagulante con warfarin o antagonisti equivalenti della vitamina K o con forti inibitori del CYP3A4/5
-Malattia cardiovascolare clinicamente significativa
-Nota storia di infezione da virus dell’immunodeficienza umana o infezione attiva da virus dell’epatite C o B (HBV) o di qualsiasi infezione sistemica attiva non controllata che richieda antibiotici per via endovenosa.
-Qualsiasi malattia, condizione medica o disfunzione di un sistema organico potenzialmente letale che, secondo lo sperimentatore, potrebbe compromettere la sicurezza del soggetto, interferire con l’assorbimento o il metabolismo delle capsule di Ibrutinib o mettere inutilmente a rischio gli esiti dello studio.
-Donne in gravidanza o in allattamento |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival |
Sopravvivenza senza progressione di malattia |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 7 years after the first participant is randomized |
Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente |
|
E.5.2 | Secondary end point(s) |
Overall survival
1/ Overall survival
2/ Complete response rate
3/ Overall response rate
4/ Duration of response
5/ Participants with change in patient-reported lymphoma symptoms and concerns as measured by the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
6/ Number of participants affected by adverse events by MedDRA system organ class (SOC) and Preferred term (PT) |
1/Sopravvivenza globale
2/Percentuale di risposta completa
3/Percentuale di risposta globale
4/Durata della risposta
5/Sintomi e problemi correlati al linfoma riferiti dal paziente misurati dalla sottoscala Lym del questionario per la valutazione funzionale della terapia oncologica per il linfoma (FACT-Lym)
6/Numero dei pazienti affetti da evento avverso secondo la classificazione MedDRA (SOC) e Preferred Term (PT)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/ Up to approximately 7 years after the first participant is randomized
2/ Up to approximately 7 years after the first participant is randomized
3/ Up to approximately 7 years after the first participant is randomized
4/ Up to approximately 7 years after the first participant is randomized
5/ Up to approximately 7 years after the first participant is randomized
6/ Up to 30 days after the last dose of study medication |
1/Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente
2/ Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente
3/ Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente
4/ Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente
5/ Approssimativamente fino a 7 anni dopo la randomizzazione del primo paziente
6/ Fino a 30 giorni dopo l’assunzione dell’ultima dose di farmaco in 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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 |
Biomarker analysis |
Analisi dei biomarcatori |
|
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 | 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 | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
China |
France |
Germany |
Israel |
Italy |
Japan |
Poland |
Russian Federation |
Ukraine |
Korea, Republic of |
Spain |
Sweden |
Turkey |
United Kingdom |
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
|
Per protocol, the end of the trial is defined as the time when 50% of subjects have died. |
Per protocollo, il termine dello studio è al raggiungimento del decesso del 50% dei soggetti |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |