E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mantle Cell Lymphoma in elderly patients |
Linfoma mantellare in pazienti anziani |
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E.1.1.1 | Medical condition in easily understood language |
Mantle Cell Lymphoma in elderly patients |
Linfoma mantellare in pazienti anziani |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10026799 |
E.1.2 | Term | Mantle cell lymphoma NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate whether the addition of venetoclax after R-BAC to HR patients with MCL, as defined above, improves the results of the standard R-BAC, in terms of PFS. |
1. Valutare se l'aggiunta di venetoclax dopo la chemioterapia R-BAC in pazienti HR migliori i risultati della terapia standard R-BAC, in termini di sopravvivenza libera da progressione (PFS).
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E.2.2 | Secondary objectives of the trial |
Not applicable |
Non applicabile |
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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 |
Definition of risk profile, molecular minimal residual disease determination (RQ PCR), molecular minimal residual disease determination (cytometry), pathologic review. These sub-studies are included in the main study (v. 1_november 16th, 2017). The planned analyzes for biological studies are part of a necessary aspect of the main study. Therefore they are unavoidable from it.
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Definizione del profilo di rischio, quantificazione della malattia minima residua attraverso RQ PCR, quantificazione della malattia minima residua mediante citometria a flusso, revisione della diagnosi. Si tratta di sottostudi inclusi nello studio principale. Le analisi previste per gli studi biologici fanno parte di un aspetto necessario dello studio principale e pertanto sono imprescindibili da esso. |
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E.3 | Principal inclusion criteria |
1. Previously untreated patients with MCL aged ≥65 years if they are FIT according to the geriatric CGA assessment. 2. age ≤64 years not eliglible to high-dose chemotherapy plus transplantation, FIT or UNFIT according to the geriatric CGA assessment. 3. Measurable nodal or extranodal disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions. 4. ECOG performance status ≤2. 5. Positivity for cyclin D1 and/or SOX11 [the latter being mandatory in cases lacking cyclin D1- or t(11;14)-negative]. 6. Adequate renal function (Creatinine clearance >50 mL/min), with preserved diuresis. 7. Adequate liver function: alanine aminotransferase (ALT)/aspartate aminotransferase (AST) <2.5 x upper limit of normal (ULN) value, total bilirubin <1.5 x ULN, unless directly attributable to the patient’s tumor or to congenital causes. 8. Hepatitis B core antibody (HBcAb) positive/HBsAg negative/HBV-DNA negative patients may be enrolled if correct antiviral prophylaxis is administered at least 2 weeks before initiating protocol treatment. 9. Written informed consent. |
1. Pazienti non precedentemente trattati con MCL di età ≥ 65 se FIT in base alla valutazione geriatrica CGA 2. Pazienti con età ≤ 64 non elegibili a chemioterapia ad alte dosi seguita da trapianto, FIT o UNFIT in base alla valutazione geriatrica CGA 3. Malattia nodale o extranodale misurabile con diametro di lunghezza ≥ 1.5 cm e misurabile su due dimensioni perpendicolari 4. Performance status ECOG ≤ 2. 5. Positività per ciclina D1 e/o SOX11 [quest’ultimo è obbligatorio nei casi in cui manca la ciclina D1 o in caso di negatività t(11;14)] 6. Appropriata funzionalità renale (creatinine clearance >50 mL/min), con diuresi normale 7. Appropriata funzinalità epatica: ALT/AST <2.5 volte superiore al valore normale (ULN), total bilirubin <1.5 volte ULN, a meno che direttamente attribuibile al tumore o a condizioni congenite del paziente 8. Pazienti positivi per anticorpi anti-core dell’epatite B (HBcAb), pazienti negativi per HBsAg e HBV-DNA possono essere arruolati se effettuano una corretta profilassi antivirale almeno nelle ultime 2 settimane prima dell’inizio del trattamento in protocollo 9. Firma del consenso informato |
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E.4 | Principal exclusion criteria |
1. Human immunodeficiency virus (HIV) positive. 2. Previous treatment for lymphoma. 3. Disease confined to the bone marrow/peripheral blood/spleen, without any other nodal or extranodal involvement. 4. In-situ MCL. 5. Medical conditions or organ injuries that could interfere with administration of therapy. 6. Active bacterial, viral, or fungal infection requiring systemic therapy. 7. Seizure disorders requiring anticonvulsant therapy. 8. Severe chronic obstructive pulmonary disease with hypoxiemia. 9. History of severe cardiac disease: New York Heart Association (NYHA) functional class III-IV, myocardial infarction within 6 months, ventricular tachyarrhythmias, dilatative cardiomyopathy, or unstable angina. 10. Uncontrolled diabetes mellitus. 11. Active secondary malignancy. 12. Known hypersensitivity or anaphylactic reactions to murine antibodies and proteins, to Bendamustine or mannitol. 13. Major surgery within 4 weeks of study Day 1. 14. HBsAg+ 15. HCVAb+ patients with active viral replication (HCV-RNA+ with AST>2 x normal limit) 16. Any co-existing medical or psychological condition that would preclude participation in the study or compromise the patient’s ability to give informed consent, or that may affect the interpretation of the results, or render the patient at high risk from treatment complications. 17. CNS involvement 18. Chronic treatment with strong or moderate CYP3A inhibitors (e.g. ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole) |
1. Pazienti HIV positivi 2. Pazienti precedentemente trattati per il linfoma 3. Malattia confinata a livello del midollo osseo/sangue periferico/milza senza alcun altro coinvolgimento nodale o extranodale 4. MCL in-situ 5. Condizioni mediche o lesioni d'organo che potrebbero interferire con la somministrazione della terapia 6. Infezioni batterica, virale o fungina attiva che richiedono una terapia sistemica 7. Disturbi convulsivi che richiedono una terapia anticonvulsivante 8. Grave malattia polmonare cronica ostruttiva con ipossiemia 9. Pregressa malattia cardiaca grave: di classe III-IV della scala New York Heart Association (NYHA), infarto del miocardio nei 6 mesi precedenti, tachiaritmie ventricolari, cardiomiopatia dilatativa o angina instabile 10. Diabete mellito non controllato dalla terapia insulinica sottocute 11. Tumore maligno secondario attivo 12. Note reazioni di ipersensibilità o reazioni anafilattiche agli anticorpi e proteine murine, alla bendamustina o mannitolo 13. Importanti operazioni chirurgiche nelle 4 settimane precedenti all’inzio della terapia dello studio 14. HBsAg+ 15. Pazienti HCVAb+ con replicazione virale attiva (HCV-RNA+ con AST>2 volte il limite normale) 16. Qualsiasi condizione medica e/o psicologica che potrebbe precludere la partecipazione allo studio, compromettere la capacità del paziente a dare il consenso informato, influire sull’interpretazione dei risultati o aumentare il rischio di complicazioni nel trattamento 17. Coinvolgimento del CNS 18. Trattamento cronico con inibitori CYP3A moderati o forti (ketoconazolo, ritonavir, claritromicina, itraconazolo, voriconazolo) |
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E.5 End points |
E.5.1 | Primary end point(s) |
2-years progression-free survival (PFS) of the HR patients from date of enrollment |
PFS a 2 anni dalla data di arruolamento, in pazienti HR. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• The proportion of molecular response (analyzed in the labs of the FIL-MRD Network) • The progression-free survival (PFS) of all enrolled patients, and of different subgroups (i.e TP53 mutated patients) • The overall survival (OS) • The duration of responses (DoR) • The proportion of complete remission (CR) before and after venetoclax in the HR group and/or in the LR not responding to R-BAC. • The proportion of patients that complete the expected treatment schedule • The safety of venetoclax when administered as consolidation or maintenance after R-BAC
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• Proporzione della risposta molecolare (analizzato nei laboratori del FIL-MRD network) • PFS di tutti i pazienti arruolati e del sottogruppo HR • Sopravvivenza globale (OS) • Durata della risposta (DoR) • Proporzione di CR prima e dopo la somministrazione di venetoclax nel gruppo HR e nel gruppo LR non responsivo a R-BAC. • Proporzione di pazienti che completano il trattamento previsto • Sicurezza del farmaco venetoclax
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• 10 and 30 months • 24 months • 54 months • 24 months • 6 and 10 months • 30 months • 10 and 30 months |
• 10 e 30 mesi • 24 mesi • 54 mesi • 24 mesi • 6 e 10 mesi • 30 mesi • 10 e 30 mesi • 24 months • 54 months • 24 months • 6 e 10 mesi months • 30 months • 10 e 30 months |
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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 | 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) | 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 | 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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |