| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with diffuse large B cell lymphoma (DLBCL) with low risk profile according to age-adjusted IPI (0 with bulky or 1) |
Pazienti con Linfoma diffuso a grandi cellule B (DLBCL)con IPI=0-1 a profilo clinico sfavorevole
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Patient with diffuse large B cell lymphoma (DLBCL) with low risk profile according to age-adjusted IPI (0 with bulky or 1) |
| Patient with diffuse large B cell lymphoma (DLBCL) with low risk profile according to age-adjusted IPI (0 with bulky or 1) |
|
| 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 | 17.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10012819 |
| E.1.2 | Term | Diffuse large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
| Evaluate if a chemoimmunotherapy R-CHOP-14 or R-CHOP-21 +/- consolidation RT on positive PET-TC residual mass improves the prognosis in terms of 2years PFS in comparison to an historical population control treated with R-CHOP and RT on bulky disease independently of PET-TC evaluation. |
Valutare se una chemioimmunoterapia R-CHOP-14 o RCHOP-
21 +/- una radioterapia di consolidamento sulla massa residua PET-TC positiva
determini un miglioramento della prognosi (PFS a due anni) rispetto ad un confronto
storico in pazienti trattati con R-CHOP e radioterapia eseguita sulla malattia bulky
indipendentemente dalla valutazione PET-TC. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of a consolidation RT involved-field on single residual PET-positive area after 6 R-CHOP-14 or R-CHOP-21 cycles in terms of overall response rate (ORR = complete + partial remission: CR +PR) improvement according to standard international response criteria (Cheson 2007);
To evaluate the ORR after 4 and 6 R-CHOP-14 or R-CHOP-21 cycles; To explore the predictive role of the early PET after 2 R-CHOP-14 or R-CHOP-21 cycles in terms of 2-year PFS (descriptive analysis based on available data). |
Valutare l’efficacia di una radioterapia di consolidamento involved-field sulla sede unica di malattia residua positiva all’esame PET dopo 6 cicli di RCHOP-14 o R-CHOP-21 in termini di miglioramento della risposta clinica (risposta globale = parziale + completa sec criteri di Cheson et al 2007- v. allegato G); Valutare la percentuale di risposte globali dopo i primi 4 cicli e i 6 cicli totali di chemioterapia R-CHOP-14 o R-CHOP-21; Valutare il ruolo predittivo della PET precoce dopo 2 cicli in termini di FFS a due anni (analisi a
carattere esplorativo sui casi raccolti). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age 18-80 years
Patients aged > 70 years with FIT profile according to VGM
Histological diagnosis of DLBCL (CD20+), follicular lymphoma grade IIIB, T-cell rich large B cell lymphoma
aaIPI=1 +/- bulky and aaIPI=0 with bulky (>7.5 cm)
ECOG-PS < 3 unless due to lymphoma
Ventricular ejection fraction ≥ 50%
Biochemical, renal and hepatic tests within normal range
Negative HIV and HBV tests. In case of HBcAb positive and HBsAb +/-, which is indicative of a past infection (occult carriers) the subject can be included, but antiviral prophylaxis with lamivudine must be given from the beginning of treatment until 12 months after treatment completion. Anti-HCV positive patients can be included in the absence of viral replication (HVR-RNA absent or less than 500 copies/ml.
Written informed consent
Life-expectancy > 3 months
|
Età 18-80 anni;
Pazienti di età > 70 anni1 con profilo “fit” secondo VGM (vedi appendice M);
Istologia: Linfoma diffuso a grandi cellule B (CD20+), linfoma follicolare grado IIIB, linfoma a grandi cellule B di tipo T-cell rich;
Age-adjusted IPI =1+/- bulky e IPI= 0 con bulky (malattia bulky definita come dimensione >7,5 cm in uno dei diametri misurabili);
PS < 3 se non dovuto al linfoma;
Frazione di eiezione cardiaca ≥ 50%;
Normale funzionalità epatica, renale, polmonare;
Markers virali HIV e HBV negativi;
Possono essere inclusi pazienti anti-HBc positivi, HBsAg negativi, anti-HBs+/- (portatori occulti) con valori di HBV-DNA inferiori a 2.000 UI/ml, pazienti anti-HCV positivi in assenza di replicazione virale (HCV-RNA assente o inferiore a 500 copie/ml);
Consenso informato;
Aspettativa di vita > 3 mesi.
|
|
| E.4 | Principal exclusion criteria |
CD20 negative B-cell lymphoma;
Lymphoblastic lymphoma or Burkitt’s lymphoma;
Primary Mediastinal B-cell Lymphoma;
Grade I, II, IIIa Follicular Lymphoma, Lymphocytic/Lymphoplasmacytic, Marginal, Mantle Lymphoma;
T cell Lymphoma (any histotype);
Patients aged > 80 years and < 18 years;
Age-adjusted IPI= 0 (with no bulky disease);
PS > 3 if not related to lymphoma;
Patient already treated with chemotherapy, RT, immunotherapy (with the exception of therapies specified in the study protocol);
Creatinine >1.4 mg/dl or creatinine clearance <60 ml/min;
AST/ALT or Bilirubin >2.5 times normal limit, unless the alteration is due to lymphoma;
Clinically significant cardiopathies or cardiovascular disease (e.g. uncontrolled hypertension, uncontrolled multifocal cardiac arrhythmias);
Ventricular ejection fraction < 50%;
Pulmonary pathologies (e.g. BPCO, pulmonary fibrosis, TBC etc);
Concurrent thrombohemolytic disease;
HIV positivity;
Positive serology for HBV (HBsAg+) and HCV positivity in presence of replication marks;
CNS localization disease;
Malignancy during last 3 years, except from carcinoma in situ of the cervix, basal cell skin carcinoma or early stage prostate cancer or DCIS (good prognosis) treated only with surgery;
Inability of the patient to give her/his informed consent;
Drug addiction or alcoholism;
Pregnancy or breast-feeding women.
|
Linfoma CD20 negativo
Linfoma linfoblastico, linfoma di tipo Burkitt o linfoma a grandi cellule con aspetti tipo
Burkitt
Linfoma a grandi cellule B primitivo del mediastino
Linfoma di tipo follicolare grado I, II, IIIA, linfocitico/linfoplasmocitico, marginale e
mantellare.
Linfoma a cellule T (ogni istotipo)
DLBCL primitivo cutaneo e osseo.
DLBCL a esordio extranodale per la quale è in corso protocollo dedicato (es testicolo,
sistema nervoso centrale)
Età > 80 e < 18 anni (vedi criteri di inclusione)
Age-adjusted IPI= 0 in assenza di malattia bulky
PS > 3 (se non dovuto al linfoma)
Paziente già trattato con chemioterapia, radioterapia o immunoterapia ad eccezione della
prefase di terapia specificata nello studio (vedi dopo).
Insufficienza renale intesa come creatinina >1.4 mg/dl o clearance creatininica <60 ml/min.
AST/ALT o bilirubina >2.5 volte la norma, a meno che l’alterazione non sia dovuta al
linfoma.
Cardiopatia clinicamente significativa: es. ipertensione arteriosa grave non controllata,
aritmie cardiache multifocali non controllate, cardiopatia ischemica sintomatica o scompenso
cardiaco congestizio classe NYHA classe III-IV, infarto miocardico acuto pregresso.
Frazione di eiezione ventricolare < 50% (vedi appendice B).
Diabete mellito scompensato non controllabile con terapia insulinica.
Patologia polmonare importante con compromissione della funzionalità (BPCO, fibrosi
polmonare, TBC etc)
Malattia tromboembolica concomitante.
Positività dei markers virali HIV.
Infezione da epatite B in atto (HBsAg positivi) e HCV positivi con replicazione virale
Localizzazione di malattia al Sistema Nervoso Centrale (SNC)
Neoplasia negli ultimi 3 anni, ad eccezione di carcinoma in situ collo utero e basalioma
cutaneo o carcinoma della prostata in stadio precoce localizzato trattato con exeresi
chirurgica o brachiterapia con intento curativo, DCIS a buona prognosi mammario trattato
con sola chirurgia.
Stato psichico che interferisca con la capacità del paziente di comprendere il programma
terapeutico e/o di dare il proprio consenso informato.
Tossicodipendenza o alcolismo
Gravidanza o allattamento
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as no response after the first 4 cycles or 6 cycles of immunochemotherapy or progression disease after consolidation RT or at any time of therapy, relapse or death from any cause. The PFS includes all patients and its duration is calculated from the date of initiation of therapy to the date of occurrence of any of the events or date of last follow-up, in the absence of such events. |
PFS, definita come non risposta
dopo i primi 4 cicli o i 6 cicli totali di chemio-immunoterapia o la progressione di
malattia dopo la radioterapia di consolidamento o in qualunque momento della terapia,
ricaduta o morte da qualunque causa. La PFS include tutti i pazienti e la sua durata è
calcolata dalla data dell’inizio della terapia alla data di comparsa di uno degli eventi o
alla data di ultimo follow-up, in assenza di tali eventi. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| OS, defining the event as death from any cause. OS includes all patients and the duration is calculated from the initiation of therapy to the date of death or of last follow up. |
Overall Survival (OS), definendo l’evento come la morte da qualunque causa. La OS
include tutti i pazienti e la sua durata è calcolata dalla data dell’inizio della terapia alla data
di morte o ultimo follow-up vivo.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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