E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with lymphomas (any histology) relapsed after high dose chemotherapy and in complete remission or partial remission after the last CT line |
Pazienti con linfoma (qualsiasi istologia) ricaduti dopo la chemioterapia ad alte dosi con supporto di cellule staminali autologhe e in remissione completa o parziale dopo l’ultima chemioterapia |
|
E.1.1.1 | Medical condition in easily understood language |
poor prognosis lymphomas |
linfoma a cattiva prognosi |
|
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 | 10003908 |
E.1.2 | Term | B-cell small lymphocytic lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10003899 |
E.1.2 | Term | B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10008958 |
E.1.2 | Term | Chronic lymphocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10020206 |
E.1.2 | Term | Hodgkin's disease |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10034623 |
E.1.2 | Term | Peripheral T-cell lymphoma unspecified |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the activity, taking into account an excess of toxicity, of the procedure of T-replete BM infused after a reduced intensity conditioning (RIC) regimen and post-transplantation Cy, in patients with poor prognosis lymphoproliferative diseases. |
Valutare in pazienti con linfoma a prognosi infausta l’efficacia e la sicurezza della procedura di infusione di midollo T-repleto dopo un condizionamento di intensità ridotta (RIC) e con l’uso di ciclofosfamide post-trapianto, |
|
E.2.2 | Secondary objectives of the trial |
To further evaluate the efficacy and safety of the procedure |
Valutare ulteriormente l’efficacia e la sicurezza della procedura |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
PATIENT-RELATED CRITERIA
1. Age 18-70 years old
2. Karnofsky performance score ≥ 80%
3. HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, DRB1, and DQB1 loci. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant.
4. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1
5. Patients with lymphomas (any histology) relapsed after high dose chemotherapy and in complete remission or partial remission after the last CT line.
a. Hodgkin’s lymphoma.
Patients refractory to at least 2 CT lines, and included in tandem auto-allo program.
b. Diffuse large B cell lymphoma
Refractory to second line salvage chemotherapy (patients in partial remission, stable disease or progressive). These patients have to be in partial remission or complete remission after last CT line, including high dose chemotherapy (auto-allo program).
Transformed low grade lymphomas
c. Peripheral T cell lymphoma
Patients failing to achieve a complete remission after first line CT.
d. Low grade lymphomas (follicular and non follicular)
Patients refractory to first R-CT line.
Patients failing at least 2 lines CT - The duration of last remission should be < 1 year
e. Chronic lymphatic leukemia.
Patients with refractory or relapsing (response duration < 1 year) disease after R-Fludarabine CT
f. Mantle cell lymphoma.
Patients relapsing or refractory after first line conventional CT.
6. Absence of HLA identical sibling and 10/10 unrelated donor
7. Patients with adequate physical function as measured by:
Hearth FEV fraction ≥ 40%;
Total bilirubin ≤ 2.5 mg/dl, ALT, AST, and alkaline phosphatase all ≤ 5 x upper limit of normal (ULN);
Creatinine clearance or GFR by Cockroft-Gault formula ≥ 50 mL/min/1.73m2;
FEV1,FVC, DLCO ≥ 50% predicted
DONOR SELECTION CRITERIA
1. Donors must be HLA-haploidentical first-degree relatives of the patient. Eligible donors include biological parents, siblings, or children, or half-siblings.
2. Age ≥ 18 years.
3. Donors must meet the selection criteria as defined by JACIE
4. Absence of DSA (donor specific antibody against HLA antigens) |
CRITERI CORRELATI AL PAZIENTE
1. Età tra 18 e 70 anni
2. Karnofsky performance score > 80%
3. Tipizzazione HLA
La tipizzazione HLA sarà eseguita ad alta risoluzione (livello allelico 4 digits) per i loci HLA-A, -B, Cw, DRB1, e DQB1. Il match minimo richiesto è di 5/10. La ricerca di un donatore volontario non è richiesta per un paziente eleggibile per questo protocollo se la situazione clinica necessita di avere a disposizione un donatore in tempi rapidi.
4. Il donatore ed il ricevente devono essere identici almeno per un allele in ognuno dei seguenti loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.
5. Pazienti con linfoma (qualsiasi istologia) ricaduti dopo la chemioterapia ad alte dosi con supporto di cellule staminali autologhe e in remissione completa o parziale dopo l’ultima chemioterapia.
a. Linfoma di Hodgkin.
Pazienti refrattari ad alemeno 2 linee di chemioterapia, ed in inclusi in un programma auto-allo.
b. Linfoma a grandi cellule B
Pazienti con malattia refrattaria alla terapia di salvataggio (remissione parziale, malattia stabile o in progressione) dopo valutazione PET. I pazienti devono essere in remissione completa o parziale dopo l’ultima chemioterapia, che può comprendere una chemioterapia ad alte dosi (programma auto-allo).
Linfoma a grandi cellule B trasformati da un linfoma di basso grado.
c. Linfoma a cellule T periferiche
Pazienti che non ottengono la remissione completa dopo la chemioterapia di prima linea.
d. Linfomi di basso grado (follicolari e non)
Pazienti refrattari alla terapia di prima linea con rituximab
Pazienti che sono in recidiva dopo almeno 2 linee di chemioterapia e la durata dell’ultima remissione é < ad 1 anno
e. Leucemia linfatica cronica.
Pazienti refrattari o in ricaduta (durata della risposta < 1 anno) dopo chemioterapia con rituximab e analogo delle purine.
f. Linfoma mantellare.
Pazienti in ricaduta o refrattari alla terapia di prima linea (senza chemioterapia ad alte dosi).
6. Assenza di un donatore HLA identico nella fratria o nel registro dei donatori (10/10).
7. Pazienti con adeguata funzionalità fisica misurata con:
Frazione d’eiezione cardiaca > 40%
Bilirubina totale ≤ 2.5 mg/dl, ALT, AST, e FA ≤ 5 x il limite superiore della normale
Clearance creatinina o GFR calcolata con la formula di Cockroft-Gault > 50 mL/min/1.73m2;
FEV1,FVC,DLCO > 50% del valore teorico
CRITERI DI SEZIONE DEL DONATORE
Il donatore deve essere un parente di primo grado. La sorgente di cellule staminali è il midollo osseo, prelevato in anestesia generale, non crio-preservato salvo in casi discussi con il PI dello studio.
1. I donatori eleggibili includono i fratelli/fratellastri, genitori, figli, cugini di primo grado
2. Età ≥ 18 anni.
3. Criteri di selezione secondo lo standard JACIE
4. Assenza nel paziente di anticorpi anti HLA del donatore |
|
E.4 | Principal exclusion criteria |
1. Presence of HLA-matched, related donor (HLA-A, -B, -DRB1)
2. Presence of matched unrelated donor (10/10), available on time.
3. Pregnancy or breast-feeding.
4. Evidence of HIV infection or known HIV positive serology.
5. Current uncontrolled bacterial, viral or fungal infection
6. Evidence of progression of clinical symptoms or radiologic findings.
7. Prior allogeneic hematopoietic stem cell transplant.
8. CNS lymphoma localization |
1. Presenza di un donatore HLA identico familiare (HLA-A, -B, -DRB1)
2. Presenza di un donatore non correlato HLA compatibile (10/10), disponibile in tempo utile.
3. Gravidanza o allattamento
4. Evidenza di infezione HIV o sierologia positiva HIV nota.
5. Presenza di infezioni batteriche, virali o fungine non controllate
6. Evidenza di progressione da sintomi clinici o riscontri radiologici
7. Precedente trapianto allogenico con cellule staminali ematopoietiche.
8. Localizzazione del linfoma nel SNC |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1-year progression free survival (PFS) |
sopravvivenza libera da progressione a un anno (progression free survival, PFS) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 year from the treatment |
un anno dal trattamento |
|
E.5.2 | Secondary end point(s) |
• Neutrophil and platelet recovery
• Incidence of graft failure
• Cumulative incidence of acute and chronic GVHD
• Incidence of infections
• Cumulative incidence of relapse/progression
• Treatment related mortality (TRM)
• Immunological reconstitution |
• Attecchimento dei neutrofili e delle piastrine
• Incidenza di rigetto
• Incidenza cumulativa di GVHD acuta e cronica
• Incidenza di infezioni batteriche, virali, fungine
• Incidenza cumulativa di recidiva
• Non relapse related mortality (NRM)
• Ricostituzione immunologica |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
controls with different frequencies in the interval between transplantation and the 1-year follow-up visit, according to clinical practice |
controlli effettuati con differenti cadenze nel periodo fra il trapianto e la visita di follow-up a 1 anno, secondo pratica clinica |
|
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
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
|
LVLS where LV = follow-up visit one year after last patient's enrolment |
LVLS dove per ultima visita (LV) si intende la visita di follow-up a un anno dall'arruolamento dell'ultimo paziente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |