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    EudraCT Number:2017-004628-31
    Sponsor's Protocol Code Number:FIL_V-RBAC
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-004628-31
    A.3Full title of the trial
    Rituximab, bendamustine and cytarabine followed by venetoclax (V-RBAC) in high-risk elderly patients with mantle cell lymphoma (MCL)
    Rituximab, bendamustina e citarabina seguiti da venetoclax (V-RBAC) in pazienti anziani, ad alto rischio con linfoma mantellare
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Venetoclax after chemotherapy R-BAC in high-risk elderly patients with mantle cell lymphoma
    Venetoclax dopo chemioterapia R-BAC in pazienti anziani affetti da linfoma mantellare
    A.4.1Sponsor's protocol code numberFIL_V-RBAC
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFondazione Italiana Linfomi ONLUS
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAbbVie S.r.l.
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione Italiana Linfomi ONLUS
    B.5.2Functional name of contact pointUffici studi FIL
    B.5.3 Address:
    B.5.3.1Street AddressVia Venezia, 16
    B.5.3.2Town/ cityAlessandria
    B.5.3.3Post code15121
    B.5.4Telephone number00390131206129
    B.5.5Fax number00390131263455
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Venclyxto
    D. of the Marketing Authorisation holderAbbVie Ltd
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1080
    D.3 Description of the IMP
    D.3.1Product nameVenclyxto
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product typeAntineoplastic agent
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mantle Cell Lymphoma in elderly patients
    Linfoma mantellare in pazienti anziani
    E.1.1.1Medical condition in easily understood language
    Mantle Cell Lymphoma in elderly patients
    Linfoma mantellare in pazienti anziani
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10026799
    E.1.2Term Mantle cell lymphoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary objectives of the trial
    Not applicable
    Non applicabile
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    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.
    E.3Principal 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
    E.4Principal 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)
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 months
    24 mesi
    E.5.2Secondary 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
    • 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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned40
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state130
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The protocol does not specify what will be the treatment or assistance for the subjects at the end of the participation in the study. Patients will be followed according to clinical practice.
    Il protocollo non specifica quale sarà il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio. I pazienti saranno seguiti secondo pratica clinica.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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