| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated intermediate-high risk according to the FLIPI2 stage II-IV follicular lymphoma requiring therapeutic intervention. |
| Pazienti con linfoma follicolare in stadio II-IV, a rischio intermedio-alto secondo il FLIPI2, non precedentemente trattati. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated intermediate-high risk according to the FLIPI2 stage II-IV follicular lymphoma requiring therapeutic intervention. |
| Pazienti con linfoma follicolare in stadio II-IV, a rischio intermedio-alto secondo il FLIPI2, non precedentemente trattati. |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061170 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 a PET and MRD response-based maintenance therapy is more effective in terms of Progression-Free Survival (PFS) than a standard maintenance therapy with Rituximab in patients with untreated, advanced, follicular lymphoma. |
| Valutare, in termini di Progression Free Survival (PFS), se una terapia di mantenimento basata sulla risposta alla PET e sulla valutazione della malattia minima residua è più efficace rispetto ad una terapia di mantenimento standard con Rituximab in pazienti con nuova diagnosi di linfoma follicolare in stadio avanzato. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy of maintenance with observation or pre-emptive Rituximab therapy administered on the basis of MRD status and the efficacy of a standard maintenance for 2 years in patients at low risk of progression after induction chemoimmunotherapy. To evaluate the efficacy of intensified maintenance with (90)Y Ibritumomab Tiuxetan followed by Rituximab maintenance therapy and the efficacy of a standard maintenance for 2 years in patients at high risk of progression after induction chemoimmunotherapy. To compare a response-based maintenance therapy with a standard maintenance therapy in terms of toxicity. To verify the predictive value of MRD detection. To perform a cross evaluation of the predictive value of MRD analysis and FDG-PET. |
| Valutare l’efficacia di un mantenimento con sola osservazione o con terapia pre-emptive con Rituximab Valutare l’efficacia di un mantenimento intensificato con (90)Y Ibritumomab Tiuxetan seguito da Rituximab e l’efficacia di un trattamento standard con Rituximab ogni 2 mesi per 2 anni in pazienti ad alto rischio di progressione dopo induzione standard con chemioimmunoterapia Valutare la tossicità di un mantenimento standard e di un mantenimento modulato in base alla risposta clinica e molecolare. Verificare il valore predittivo della valutazione della malattia minima residua su sangue midollare e periferico Eseguire una valutazione incrociata del valore predittivo dello stato della malattia minima residua (MMR) e della risposta determinata con la PET. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| • Histological diagnosis of B-Cell CD20+ Follicular Lymphoma (FL), grade I, II, IIIa according to the WHO 2008 classification • ECOG performance status 0-2 • Age ≥ 18 years • Ann Arbor stage II-IV • FLIPI2>0 • Presence of evaluable/measurable disease after diagnostic biopsy • At least one of the following criteria for defining active disease: - systemic symptoms - cytopenia due to bone marrow involvement - LDH> upper normal value - any nodal or extranodal tumor mass with a diameter >7cm - involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3cm - extranodal disease - rapidly progressive disease • Life expectancy > 6 months • Left ventricular ejection fraction (LVEF) 50% • Serum negativity for HIV • Serum negativity for HBsAg; HBcAb positive but HBV-DNA negative patients are allowed with mandatory Lamivudine prophylaxis. • Serum negativity for HCV, except for those patients without signs of active viral replication assessed by HCV-RNA copies • Serum creatinine < 2mg/dl , serum bilirubin < 1.5mg/dl, aspartate amino-transferase (AST/GOT) 2.5xUNV, alanine amino-transferase (ALT/GPT) 2.5xUNV, and alkaline phosphatase 4 times the upper limit of normal (unless the increase is attributed directly to the presence of tumour by the Investigator) • Patients with no previous treatment for the lymphoma with the exception of locoregional radiotherapy (IF-RT) • Adequate measure adoption to avoid pregnancy • Written informed consent given at time of registration • Patient must be accessible for treatment and follow up |
| • Diagnosi istologica di linfoma follicolare a cellule B, CD20+, di grado I, II, IIIa (sec.WHO 2008) • ECOG performance status 0-2 • Età ≥ 18 anni • Stadio II-IV, secondo Ann Arbor • FLIPI2>0 • Presenza di malattia misurabile e/o valutabile dopo biopsia diagnostica • Presenza di almeno uno dei seguenti criteri di malattia attiva: -sintomi sistemici B -citopenia conseguente ad infiltrazione midollare -LDH> valore normale -massa nodale o extranodale con diametro >7cm -coinvolgimento di 3 o più sedi nodali ognuna delle quali con diametro ≥ 3cm -malattia extranodale -rapida progressione della malattia • Aspettativa di vita > 6 mesi • Frazione di eiezione ventricolare (LVEF) 50% • Negatività sierica per HIV • Negatività sierica per HBsAg; i pazienti HBcAb positivi ma HBV-DNA negativi possono essere arruolati (la profilassi con lamivudina è obbligatoria). • Negatività sierica per HCV, eccetto per i pazienti senza segni di replicazione virale (HCV-RNA negativi) • Normale funzionalità epatica (bilirubina < 1.5mg/dl, aspartato amino-transferasi (AST/GOT) 2.5 volte il limite superiore normale, alanina amino-transferasi (ALT/GPT) 2.5 volte il limite superiore normale, fosfatasi alcalina 4 volte il limite superiore normale) e renale (creatinina < 2mg/dl). Sono ammessi valori superiori solo se tali alterazioni sono determinate dalla presenza del linfoma. • Nessun precedente trattamento per linfoma ad eccezione della radioterapia locoregionale (IF-RT) • Utilizzo di adeguati metodi contraccettivi in pazienti di età fertile, sia di sesso femminile che maschile • Consenso informato scritto prima della registrazione • Disponibilità del paziente ad essere seguito per tutte le fasi del trattamento chemioterapico e per il successivo follow-up |
|
| E.4 | Principal exclusion criteria |
| • Histological diagnosis of : -any lymphoma other than follicular lymphoma and all CD20 negative B-cell lymphomas -grade III b follicular lymphoma -evidence of transformation to high grade lymphoma • Ann Arbor stage I • Suspect or clinical evidence of CNS involvement by lymphoma • History of other malignancies within 5 years prior to study entry except for adequately treated carcinoma in situ of the cervix or 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 • Evidence of any severe active acute or chronic infection • Concurrent co-morbid medical condition which might exclude administration of full dose chemotherapy • Severe chronic obstructive pulmonary disease with hypoxemia • Severe diabetes mellitus difficult to control with adequate insulin therapy • Myocardial infarction within 6 months before study entry • Clinically significant secondary cardiovascular disease e.g. uncontrolled hypertension, (resting diastolic blood pressure >115 mmHg), uncontrolled multifocal cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA class III-IV • HbsAg-positive, HIV-positive, or HCVAb-positive patients • 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 • Follicular lymphoma, showing a negative baseline PET scan |
| • Diagnosi istologica di: -qualsiasi tipo di linfoma diverso da linfoma follicolare o linfoma CD20- -linfoma follicolare di grado IIIb -evidenza di trasformazione in linfoma ad alto grado • Stadio I secondo Ann Arbor • Coinvolgimento del sistema nervoso centrale da parte del linfoma • Storia di patologie tumorali nei 5 anni precedenti all’entrata nello studio, ad eccezione di: carcinoma in situ della cervice uterina, carcinoma basale o squamoso della cute, carcinoma prostatico localizzato trattato chirurgicamente con intento curativo e carcinoma duttale in situ trattato con lumpectomia • Evidenza di gravi infezioni acute o croniche • Patologie concomitanti che possono impedire la somministrazione dei farmaco a dose piena • Malattia polmonare ostruttiva cronica associate ad ipossiemia • Diabete mellito difficilmente controllabile con adeguata terapia insulinica • Infarto miocardico nei 6 mesi precedenti all’entrata nello studio • Patologia cardiaca secondaria clinicamente significativa (ipertensione non controllata (pressione diastolica >115 mmHg), aritmia cardiaca multifocale non controllata, angina pectoris sintomatica o scompenso cardiaco congestizio (NYHA classi III-IV) • Positività per HbsAg, HIV o HCVAb • Ipersensibilità nota o reazioni anafilattiche ad anticorpi o proteine murine • Altre condizioni mediche o psicologiche che possono interferire con la partecipazione del paziente allo studio clinico o compromettere la capacità di dare il proprio consenso • Linfoma follicolare con PET negativa all’esordio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) defined as the time from entry onto the study until lymphoma progression or death as a result of any cause. |
| la sopravvivenza libera da progressione (PFS) definita come l’intervallo di tempo dall’entrata nello studio fino a progressione del linfoma o alla morte per qualsiasi causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| the time from entry onto the study until lymphoma progression or death |
| l’intervallo di tempo dall’entrata nello studio fino a progressione del linfoma o alla morte |
|
| E.5.2 | Secondary end point(s) |
| overall survival (OS), overall response rate (ORR), duration of remission (DR) and event free survival (EFS). Molecular response evaluated by PCR assessment of Bcl2/IgH rearrangement |
| sopravvivenza globale (OS), risposta globale (ORR), durata di remissione (DR) e sopravvivenza libera da eventi (EFS). Risposta molecolare definita mediante valutazione del riarrangiamento genico Bcl-2/IgH |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of study |
| Fine dello studio |
|
| 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| 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 | 49 |
| 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
|
|
| 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 |
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