E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS |
Pazienti affetti da linfoma non-hodgkin linfoplasmocitico, morbo di Waldenstrom |
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E.1.1.1 | Medical condition in easily understood language |
NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS |
Pazienti affetti da linfoma non-hodgkin linfoplasmocitico, morbo di Waldenstrom |
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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 | 10047801 |
E.1.2 | Term | Waldenstrom's macroglobulinaemia |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This is a prospective, multicenter phase II trial designed to determine efficacy and safety of Bortezomib plus Rituximab plus Bendamustine in patients with relapsed/refractory Waldenstrom's Macroglobulinemia. Primary Objective is to assess whether the experimental treatment achieves an absolute increase of PFS rate from 50 to 65% at 18 months with respect to the standard treatment.
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Valutare l’efficacia e la sicurezza della chemioimmunoterapia in combinazione con Bortezomib, Rituximab e Bendamustina (BRB). Obiettivo principale: -determinare se il trattamento sperimentale BRB ottiene un aumento del tasso di PFS a 18 mesi dal 50 al 65% rispetto al trattamento standard.
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives are to asses: -Overall Response Rate (ORR) -Overall Survival (OS) -Toxicity |
Obiettivi secondari: - tasso di risposta globale (ORR) - la sopravvivenza globale (OS) - il profilo di tossicità |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Histological proven diagnosis of Lymphoplasmacytic/citoid lymphoma/Waldenstrom macroglobulinemia according to REAL/WHO Classification -Relapsed/refractory disease after receiving one line chemotherapy -Age >= 18 -Presence of at least one of the following criteria for the definition of active disease: Systemic symptoms or Hemoglobin less than 10 g/dL (due to lymphoma) or Platelets less than 100 x 109/L (due to lymphoma) or symptomatic splenomegaly or Bulky disease (>7 cm) or Hyperviscosity syndrome, peripheral neuropathy up to grade 1 (Waldenstrom's disease-related) , hemolytic anemia, and immune complex vasculitis -Life expectancy >6 months -ECOG performance status 0- 2 -LVEF ≥45% or FS ≥37% -Creatinine up to 1.5 x ULN -Conjugated bilirubin up to 2 x ULN -Alkaline phosphatase and transaminases up to 2 x ULN -Written informed content
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- Esame istologico (midollo osseo o biopsia linfonodale) comprovante la diagnosi di linfoma NHL indolente CD20 positivo sulla base della classificazione REAL/WHO: lymphoplasmacytic/citoid lymphoma/ Waldenstrom macroglobulinemia - Pazienti con malattia in recidiva/progressione dopo una iniziale risposta ad una prima linea di chemioterapia o con malattia resistente ad una linea chemioterapica - Età >= 18 anni - Presenza di almeno uno dei seguenti criteri per la definizione di malattia attiva: sintomi costituzionali e/o citopenia e/o organomegalia e/o sindrome da iperviscosità e/o malattia bulky - Aspettativa di vita > 6 mesi - ECOG performance status 0-2 - PMN >1 x109/l - Piastrine >50 x 109/l - Frazione d’eiezione cardiaca ≥37% - Creatinina non superiore a 1.5 volte i valori normali - Bilirubina non superiore a 2 volte i valori normali - Fosfatasi alcalina e transaminasi non superiori a 2 volte i valori normali -Comprensione e firma volontaria del consenso informato |
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E.4 | Principal exclusion criteria |
-Patients not agreeing to take adequate contraceptive precautions during and for at least 6 months after cessation of therapy -History of other malignancies within 3 years prior to study entry except for: adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage, localized prostate cancer treated surgically with curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with curative intent -Medical condition requiring long term use (>1 months) of systemic corticosteroids -Active bacterial, viral, or fungal infection requiring systemic therapy -Peripheral neuropathy of any grade >=2 -Concurrent medical condition which might exclude administration of therapy -Cardiac insufficiency (NYHA grade III/IV) -Myocardial infarction within 6 months of entry on study -Severe chronic obstructive pulmonary disease with hypoxemia -Severe diabetes mellitus difficult to control with adequate insulin therapy -Hypertension that is difficult to control -Impaired renal function with creatinine clearance <30 ml/min -HIV positivity -HBV positivity with the exception of patients HbsAg and HBV-DNA negative and Ab anti-HBcore positive (these patients need to receive prophylaxis with Lamivudine) -HCV positivity with the exception of patients with HCV RNA negative -Participation at the same time in another study in with investiogational drugs are used -Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins -Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent. -Women in pregnancy or breastfeeding
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- Uomini e donne in età fertile o donne potenzialmente in gravidanza, a meno di sterilità determinatachirurgicamente o che utilizzino adeguati metodi contraccettivi - Storia di altre neoplasie nei 3 anni precedenti all’arruolamento, ad eccezione del carcinoma in situ della cervice uterina adeguatamente trattato, carcinoma squamoso della pelle; carcinoma prostatico a basso grado, stadio iniziale, localizzato, trattato chirurgicamente a scopo eradicante; carcinoma duttale in situ della mammella a buona prognosi trattato con quadrantectomia a scopo eradicante - Condizioni mediche che richiedano terapia cronica con steroide (>1 mese) - Malattia attiva di HCV, HBV (nei pazienti con HbsAg e HBV-DNA negativi ma Ab anti-HBcore positivo obbligatoria la profilassi con Lamivudina) - HIV positività - Malattie attive batteriche virali o fungine che richiedano terapia sistemica - Neuropatia periferca di ogni grado > =2 - Altra condizione medica che potrebbe escludere la somministrazione della terapia - Insufficienza cardiaca (NYHA classi III/IV) - Infarto miocardico acuto entro 6 mesi dall’arruolamento nello studio - Severa malattia cronica ostruttiva polmonare con ipossiemia - Diabete mellito severo con difficoltà ad ottenere un adeguato controllo con insulina -Ipertensione difficile da controllare -Insufficienza renale con clearance della creatinina <30 ml/min -HIV positività -HBV positività con l'eccezione dei pazienti HbsAg e HBV-DNA negative e Ab anti-HBcore positivo (questi pazienti devono ricevere la profilassi con lamivudina) -HCV positività ad eccezione dei pazienti con HCV RNA negativi -Concomitante partecipazione ad un altro studio in cui sono utilizzati farmaci sperimentali -Nota ipersensibilità o reazioni anafilattiche ad anticorpi murini o proteici -Qualsiasi altra condizione medica o psicologica che possa compromettere la possibilità di fornire adeguato consenso informato
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is the asses progression free survival (PFS). PFS is measured from the beginning of therapy to the date of disease progression, relapse or death from any cause. Patients without any relapse at the end of the follow-up will be censored at their last assessment date. |
L'endpoint primario è la sopravvivenza libera da progressione (PFS). PFS è misurata dall'inizio della terapia alla data di progressione della malattia, recidiva o morte per qualsiasi causa.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Minimum follow up time required for all patients will be 2 years. |
Tempo minimo di follow-up richiesto per tutti i pazienti sarà di 2 anni. |
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E.5.2 | Secondary end point(s) |
Overall response rate (ORR): a patient is defined as a responder if he has a complete or very good partial or partial response. Overall survival (OS): measured from the beginning of therapy to the date of death from any cause. Patients alive at the time of the final analysis will be censored at the date of the last contact. Toxicity: severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events are defined according to “Common Terminology Criteria for Adverse Events” (CTCAE) |
Tasso di risposta globale (ORR): un paziente viene definito come responder se ha una risposta parziale o completa o parziale molto buona. La sopravvivenza globale (OS): misurata dall'inizio della terapia alla data di morte per qualsiasi causa. Pazienti vivi al momento dell'analisi finale saranno censurati alla data dell'ultimo contatto. Tossicità: grave, pericolosa per la vita, fatale (grado 3, 4 e 5) e / o eventi avversi gravi sono definite in base a "criteri terminologia comune per gli Eventi Avversi" (CTCAE) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Minimum follow up time required for all patients will be 2 years; 5 years for the toxicity. |
Tempo minimo di follow-up richiesto per tutti i pazienti sarà di 2 anni; 5 anni per la tossicità. |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 40 |
E.8.5 | The trial involves multiple Member States | No |
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
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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 | |
E.8.9.1 | In the Member State concerned days | |