REC-ANZnuovo - Azienda AUSL Piacenza

EUDRACT:
A phase II multicentre open-label study
on allogeneic stem cell transplantation from
unrelated, cord-blood and family
haploidentical donors in patients
with active acute leukemia
Protocol Code:
GANDALF-01 (Gitmo Against Non-responding anD Acute Leukemia Failures)
Version:
N. 1 dated 05 Marzo 2013
EudraCT N°:
2012-004008-37
Promoter:
G.I.T.M.O. “Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali
emopoietiche e terapia Cellulare”
Writing Committee:
Fabio Ciceri (Principal Investigator)
Corrado Girmenia
Francesca Bonifazi
Andrea Bacigalupo
William Arcese
Nicoletta Sacchi
Sonia Mammoliti
Alessandro Rambaldi
Medical Statistical Unit:
Consorzio Mario Negri Sud
Information contained in this protocol is the property of GITMO and is confidential. Information may not be disclosed
to any third party without written authorization from him. This material may be disclosed and used by staff and
associates, as necessary. These persons should be told that this information is confidential. This document may not be
reproduced or stored in any form (i.e. electronic, printed, etc.), except as required by regulatory authorities, without
permission from GITMO.
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
CONTACTS
Dr Fabio Ciceri
Principal Investigator
(Centre coordinator)
Ospedale San Raffaele
Hematology and BMT Unit
Via Olgettina, 60. I-20132 Milan
Writing Committee:
Fabio Ciceri
Corrado Girmenia
Francesca Bonifazi
Andrea Bacigalupo
William Arcese
Nicoletta Sacchi
Sonia Mammoliti
Alessandro Rambaldi
Tel 02/26433903-4289
Fax 02/26434760
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
Dr Francesca Bonifazi
Coordinator
Clinical Trials Commission GITMO
Tel. 051/6363835
E-mail: [email protected]
Dr Sonia Mammoliti
Clinical Trials Office GITMO
Tel. 010/5553577/4423 Cell.329/8999529
Fax. 010/515491
E-mail: [email protected]
Dr Arianna Masciulli
Consorzio Mario Negri Sud
Data Management Center and Quality
Control
Tel1: 0872/570286
Tel2: 0872/570250
E-mail: [email protected]
Data Safety Monitoring Board (DSMB)
Renato Bassan
Marco Bregni
Roberto Crocchiolo
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
Data analsy Board (DAB)
Alberto Bosi
Luca Castagna
Fabio Ciceri
Giuseppe Milone
Laura Orlando
Arcangelo Prete
Alessandro Rambaldi
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
E-mail: [email protected]
Promotor GITMO
www.gitmo.it
Prof. Alessandro Rambaldi
President
Tel. 035/2673683
E-mail: [email protected]
Dr Barbara Bruno
GITMO Secreteriat
Tel. 010/5554423
E-mail: [email protected]
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
www.gitmo.net
2/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
ITALIAN SYNOPSYS
Titolo
Studio Multicentrico, di fase II, in aperto, sul trapianto allogenico di cellule staminali da
donatore non consanguineo, da cordone oppure da familiare aploidentico, in pazienti con
leucemia acuta attiva
Version
N. 1 del 05 Marzo 2013
EudraCT
Number: 2012-004008-37
Acronimo
Protocollo
GANDALF-01 (Gitmo Against Non-responding anD Acute Leukemia Failures)
Promotore
GITMO Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali emopoietiche e
terapia cellulare.
Centri
Partecipanti
Centri GITMO, ITALIA
Disegno
Prospettico, fase II, multicentrico, non-randomizzato, non controllato, in aperto.
Obiettivi
Obiettivo Primario
Aumentare la sopravvivenza globale nei pazienti con leucemia acuta attiva con un trapianto da
donatore non consanguineo (MUD), da sangue da cordone (CB) oppure da familiare
aploidentico (HAPLO).
Obiettivi Secondari
 Determinare la percentuale di identificazione di donatori compatibili in pazienti affetti da
leucemia acuta che hanno fallito l’induzione primaria (PIF) attivando una ricerca per
donatore alternativo
 Incidenza dell’attecchimento primario per i trapianti da MUD, CB o HAPLO
 Incidenza e severità della Graft-versus-Host Disease acuta (aGVHD) grado II-IV e
cronica (cGVHD) dopo trapianto MUD, CB o HAPLO
 Incidenza della non-relapse mortality (NRM) dopo trapianto MUD, CB o HAPLO
 Incidenza della ricaduta di leucemia dopo trapianto MUD, CB o HAPLO
 Sopravvivenza libera da progressione di malattia (PFS)
 Valutare l’impatto dell’outcome del mismatch HLA-DP1
 Valutare l’efficacia della Micafungina in profilassi primaria antimicotica
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
3/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
Endpoints
End-point primario
Sopravvivenza globale a 2 anni (a partire dall’arruolamento) di tutti i pazienti arruolati nello
studio (trapiantati e non).
End-Points secondari

Incidenza cumulativa della mortalità relata al trapianto (NRM)

Incidenza cumulativa di recidiva di leucemia dopo trapianto MUD, CB o HAPLO

Incidenza cumulativa e severità della aGVHD gradi II-IV e della cGvHD dopo
trapianto MUD, CB o HAPLO

Sopravvivenza libera da progressione di malattia di tutti i pazienti arruolati (trapiantati
e non)

Incidenza cumulativa dell’attecchimento primario dopo trapianto MUD, CB o HAPLO

Tasso di infezioni fungine invasive provate, probabili o possibili insorte entro il 100esimo
giorno dopo il trapianto

Tasso di infezioni fungine invasive provate, probabili o possibili insorte durante il
primo anno dal trapianto nonostante la strategia di profilassi antifungina impiegata

Qualità di Vita
Campione
80 pazienti trapiantati con donatore MUD, CB o HAPLO
Popolazione
in studio
Questo studio arruolerà pazienti con leucemia acuta attiva
Definizioni
Fallimento dell’Induzione Primaria (PIF): Un paziente che non ha raggiunto la prima
remissione completa dopo un ciclo di chemioterapia di induzione.
Recidiva chemioresistente: Un paziente che ha fallito il raggiungimento di una seconda o
successiva remissione completa dopo chemioterapia di salvataggio.
Recidiva non trattata: paziente con recidiva, la leucemia acuta richiede un trapianto
allogenico immediato.
Durata dello
studio
24 mesi di arruolamento più 2.5 anni di follow-up dall’ultimo paziente arruolato. Ciò
Selezione
Pazienti
Criteri di inclusione
consentirà di valutare due anni di follow-up dopo il trapianto in tutti i pazienti arruolati.

Diagnosi di PIF o recidiva chemioresistente nelle mieloidi acute e nelle leucemia
linfoblastiche

Attivazione alla ricerca per un donatore alternativo nel registro italiano IBMDR
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37

Età >18 <70

Indisponibilità di HLA-matched related donor (MRD)

Performance status : ECOG < 3

Consenso informato firmato

Aspettativa di vita non seriamente compromessa da malattie concomitanti
Criteri di esclusione
 Precedente trapianto allogenico (precedente trapianto autologo è accettato)
 Test di gravidanza positivo
 Qualsiasi infezione in fase attiva non controllata
Piano di
trattamento
Il trattamento sperimentale proposto dal protocollo è l’applicazione di una strategia
terapeutica di trapianto da donatore allogenico quale procedura potenzialmente curativa
in una popolazione di pazienti definita dallo stato di persistenza chemioresistente di
leucemia acuta. L’intervento terapeutico, e in particolare il regime di condizionamento e
la profilassi della GVHD, si avvalgono di un programma di trattamento farmacologico in
uso standard, secondo i seguenti regimi:
Regime di Condizionamento:

Thiotepa iv 5 mg/Kg die (dose totale (TD) 10 mg/kg) giorno -7 e giorno -6;

Busulfano iv 3,2 mg/kg/die (TD 9,6 mg/kg) come dosi singole nei giorni -5, -4, -3;

Fludarabina iv 50 mg/m2 (TD 150 mg/m2) nei giorni -5, -4, -3.
Profilassi per la GvHD e le malattie Linfoproliferative post Trapianto (PTLD)
Per il trapianto MUD:

Immunoglobulina anti-linfocitaria* (Thymoglobulin) 2 mg/kg i.v. nei giorni -4, -3, -2;

Ciclosporina 3 mg/kg/die i.v. dal giorno -1;

Metotrexate 15 mgi.v. giorno +1 e 10 mg i.v. nei giorni +3,+6 e +11;

Rituximab **
Per il trapianto da CB con procedura intraosseo:

Immunoglobulina anti-linfocitaria* (Thymoglobulin) 2 mg/kg i.v. nei giorni -4, -3, -2;

Ciclosporina 3 mg/kg/die i.v. dal giorno -1;

Micofenolato 15 mg/kg/ i.v. bid dal giorno -1 al giorno +30
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
5/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37

Rituximab **
Per il trapianto da CB senza procedura intraosseo:

Immunoglobulina anti-linfocitaria* (Thymoglobulin) 2 mg/kg i.v. nei giorni -4, -3 e 2;

Ciclosporina: 2 mg/kg/12 ore dal giorno -1 al giorno +1; 1.5 mg/kg/12 ore iv dal
girono +2 fino alla possibilità dell’assunzione orale; da 2.5 a 3 mg/kg/12 ore per os
con progressiva riduzione della dose iniziale dal giorno +90 con termine al giorno
+180 o prima se possibile;

6-Metilprednisolone 0.5 mg/kg al giorno, i.v. dal giorno +7 al giorno +14; 1 mg/kg/die
i.v. dal giorno +15 al giorno +28. La somministrazione sarà endovenovosa fino alla
possibilità dell’assunzione orale e la dose sarà scalata lentamente fino a terminarla
entro il giorno + 100;
* oppure Immunoglobulina anti-linfocitaria (ATG-Fresenius S) 10 mg/kg (TD 30 mg/kg) se
specificatamente autorizzato dalla propria azienda sanitaria.
**La profilassi per le Malattie Linfoproliferative post trapianto (PTLD) con Rituximab
vengono eseguiti in accordo alla pratica locale.
Per il trapianto APLO, è facoltà del Principal Investigator locale scegliere tra questi due
tipi di profilassi per la GvHD e le malattie Linfoproliferative post Trapianto (PTLD):
HAPLO 1:

Ciclosporina: 1,5 mg/kg/die i.v. dal giorno -1 al giorno +20,
3 mg/kg/die per os dal giorno +21 al giorno +180;

Micofenolato 15 mg/kg bid i.v. o per os dal giorno +1 al giorno +28;

Ciclofosfamide 50 mg/kg i.v. giorni +3 e +5;

MESNA: >80% della dose di ciclofosfamide suddivisa in 3 dosi dal giorno +3 al
giorno +7
HAPLO 2:

Ciclosporina: 0.75 mg/kg bid i.v. dal giorno -7 al giorno -2; 1.50 mg/kg bid i.v. dal
giorno -1 fino alla somministrazione orale; 5 mg/kg bid per os fino al giorno +180;

Micofenolato 500 mg bid per os dal giorno +7 al giorno +100;

Metotrexate 15 mg/m2/die i.v. il giorno +1, 10 mg/m2/die i.v. i giorni +3, +6 e +11;

Immunoglobulina anti-linfocitaria* (ATG-Fresenius S) 5 mg/kg i.v. dal giorno -5 al
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
6/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
giorno -2;

Basiliximab* 20 mg i.v. il giorno 0 (2 ore prima dell’infusione di midollo osseo) e 20
mg i.v. il giorno +4.
* se specificatamente autorizzato dall’azienda sanitaria in base alla pratica locale.
Profilassi Antifungina primaria
Micafungin 50 mg/die i.v. (1 mg/kg se <40 kg) dal giorno 0 all’attecchimento. Dopo
l’attecchimento proseguire la profilassi fungina in accordo alle pratiche locali.
Monitoraggi
o della
sicurezza dei
pazienti
Il Data Safety Monitoring Board (DSMB) in collaborazione con il comitato direttivo
effettuerà un monitoraggio periodico per garantire la sicurezza dei pazienti arruolati nello
studio. In particolare il DSMB controllerà il reports sulla sicurezza dei pazienti per la
valutazione degli eventi avversi gravi, il fallimento dell’attecchimento primario o secondario,
e la mortalità correlata (TRM) generati dal Data Management Center. I report saranno generati
ogni 30 pazienti arruolati che avranno completato 100 giorni di follow-up.
Disegno
Statistico
Popolazione in analisi
La popolazione in analisi sarà valutata tramite l’Intention to Treat (ITT). Tutti i pazienti
arruolati nello studio saranno inclusi nell'analisi ITT.
Calcolo del campione
Lo studio esplora la fattibilità, la sicurezza e l'efficacia del trapianto allogenico di cellule
staminali da donatore non consanguineo, da sangue da cordone e donatore aploidentico nella
popolazione di pazienti con leucemia acuta attiva al momento del trapianto. A causa della
mancanza di informazioni nella letteratura e l'assenza di opzioni terapeutiche alternative per
questa popolazione di pazienti, i criteri per la valutazione della dimensione del campione non
si riferiscono ad una formale calcolo di potenza statistica. Pertanto, il GITMO promuoverà
l’arruolamento di tutti i pazienti affetti da leucemia attiva candidabili ad un trapianto
allogenico in tutti i centri italiani con l'obiettivo di raccogliere variabili di outcome in
Intention to treatment nella coorte più ampia e più rappresentativa di questa specifica
popolazione di pazienti.
La scelta di effettuare 80 trapianti si basa su motivi di fattibilità, questa è la popolazione attesa
di pazienti con queste caratteristiche che andranno al trapianto nei principali centri trapianti
italiani in due anni. I dati di attività trapiantologica GITMO ci permettono di stimare un
accrual di circa 40 pazienti per anno, permettendo di terminare l’arruolamento in 24 mesi. I
criteri per definire la dimensione del campione non seguono quindi le stime di potenza
statistica per dimostrare differenze tra le opzioni di donatori alternativi.
Fine dello
studio
Lo studio terminerà quando sarà trapiantato l’80esimo paziente.
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
ENGLISH SYNOPSYS
Title
A phase II multicentre open-label study on allogeneic stem cell transplantation from
unrelated, cord-blood and family haploidentical donors in patients with active acute
leukemia
Version
Version n. 1 dated 05 March 2013
EudraCT
Number: 2012-004008-37
Protocol Code
GANDALF-01 (Gitmo Against Non-responding anD Acute Leukemia Failures)
Promoter
GITMO Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali emopoietiche
e terapia Cellulare.
Centres
Participating
GITMO centres, ITALY
Protocol
Design
Prospective, phase II, multicentre, non-randomised, uncontrolled, open label study
Objectives
Primary Objectives
To increase the overall survival of patients with active acute leukemia, undergoing
allogenic transplant after using either a Marrow Unrelated Donor (MUD) or a Cord Blood
(CB) unit or a family Haploidentical (Haplo) donor.
Secondary Objectives

To document the rate of success of identifying a suitable donor in patients with
Primary Induction Failure (PIF) acute leukemia activating the search of an
alternative donor

The incidence of primary engraftment of MUD, CB or haplo stem-cell
transplantation (SCT)

The incidence and severity of acute Graft-versus-Host Disease (aGVHD) II-IV and
chronic GvHD (cGvHD) following MUD, CB or haplo SCT

The incidence of non-relapse mortality (NRM) after MUD, CB or haplo SCT

The incidence of leukemia relapse after MUD, CB or haplo SCT

The progression-free survival (PFS)

To evaluate the impact an outcome of HLA-DP1 mismatches

To evaluate the efficacy of Mycafungin used an primary antifungal prophylaxis after
transplantation
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
8/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
Endpoints
The primary end-point
The overall survival at 2 years (from time of enrolment) of all patients enrolled in to the
study (either transplanted or not)
The Secondary End-Points

The cumulative incidence of non-relapse mortality (NRM) after MUD, CB or haplo
SCT

The cumulative incidence of leukemia relapse after MUD, CB or haplo SCT

The cumulative incidence and severity of aGVHD II-IV and cGvHD after MUD,
CB or haplo SCT

The PFS of all included patients (either transplanted or not)

The cumulative incidence of primary engraftment from MUD, CB or haplo SCT

The rate of proven, probable and possible invasive fungal diseases documented
within the first 100 days after transplantation

Rate of proven, probable and possible invasive fungal diseases documented during
the first year from transplant despite a tailored antifungal prophylaxis strategy.

Quality of Life
Sample size
80 patients transplanted with a MUD or a CB or Haplo donor
Study
Population
This study will enrol any patient with an active acute leukemia
Definitions
Primary induction Failure (PIF): is defined as inability to achieve first complete
remission after one cycle of induction chemotherapy.
Chemoresistant Relapse: A patient failing to achieve a second or subsequent complete
remission after a salvage chemotherapy.
Untreated Relapse: A patient with a relapsed, active acute leukemia selected for an
immediate allogeneic transplantation for any medical reason.
Study
duration
24 months of enrolment plus 2.5 year of follow-up for last patient enrolled. This will allow
Selection
criteria
Inclusion criteria
to evaluate 2-year follow-up post transplant in all patients enrolled.

Diagnosis of PIF or chemoresistant relapse in AML or ALL patients

Activation of an alternative donor search by the Italian Bone Marrow Donor
Registry (IBMDR)

Age >18<70
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37

Unavailability of a HLA-matched related donor (MRD)

Performance status : ECOG<3

Written and signed informed consent

Life expectancy not severely limited by concomitant illness.
Exclusion criteria
 Previous allogeneic transplant (autologous transplant is accepted)
 Positive pregnancy test
 Any active, uncontrolled infection.
Treatment
plan
The experimental treatment consists in the application of a therapeutic strategy of
allogeneic transplantation as a potential curative procedure in a population of
patients with chemoresistant acute leukemias. Therapeutic intervention, namely the
conditioning regimen as well as GVHD prophylaxis, are based on regimens currently
in standard use in the context of allogeneic transplantation:
Conditioning treatment:

Thiotepa i.v. 5 mg/kg/daily (total dose TD 10 mg/kg) day -7 and -6;

Busulfan i.v. 3,2 mg/kg/day (TD 9,6 mg/kg) as a single daily dose day -5, -4, -3;

Fludarabine i.v. 50 mg/m2 (TD 150 mg/m2) day -5, -4, -3.
GvHD and Post Transplant Linfoproliferative Disease (PTLD) prophylaxis
For MUD transplants:

Immunoglobulin anti-lymphocyt* (Thymoglobulin) i.v. 2 mg/kg day -4 -3 -2;

Cyclosporine 3 mg/kg/d i.v. from day -1;

Methotrexate 15 mg i.v. day 1, 10 mg i.v. day +3,+6, +11

Rituximab **
For CB transplants with Intrabone Procedure:

Immunoglobulin anti-lymphocyte* (Thymoglobulin) 2 mg/kg i.v. day -4, -3 and -2;

Cyclosporine 3 mg/kg/die i.v. from day -1;

Mycophenolate 15 mg/kg i.v. bid day -1 +30;

Rituximab**
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
10/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
For CB without intrabone procedure

Immunoglobulin anti-lymphocyte* (Thymoglobulin) 2 mg/kg i.v. day -4, -3 and -2;

Cyclosporine 2 mg/kg/12 hours on days –1 to +1; 1.5 mg/kg/12 hours i.v. from day
+2 to start of oral intake; 2.5 to 3 mg/kg/12 hours orally with progressive reduction
of dose starting on day +90 and discontinuation on day +180 or before if feasible

6-Metil Prednisolon 0,5 mg/kg/day i.v. from day + 7 to +14; 1 mg/kg/die i.v. from
day + 15 to +28 (i.v. administration until to oral feeding), Slow tapering and stop
within day + 100;
*or Immunoglobulin anti-lymphocyte (ATG-Fresenius S) 10 mg/kg (TD 30 mg/kg) if
specifically authorized by their local health authority.
**The Linfoproliferative Disease (PTLD) prophylaxis with Rituximab according to local
policy.
The local principal investigator may choose between two types of GvHD and Post
Transplant Linfoproliferative Disease (PTLD) prophylaxis:
HAPLO 1:

Cyclosporine 1,5 mg/kg/d i.v. day -1 to +20; 3 mg/kg/d per os from day +21 to +180

Mycophenolate 15 mg/kg bid i.v. or per os day +1 +28;

Cyclophosphamide 50 mg/kg i.v. day +3+5;

Mesna: >80% of the cyclophosphamide dose in 3 divided doses from day +3 daily
through day +7
HAPLO 2:
 Cyclosporine: 0.75 mg/kg bid i.v. from day -7 to -2; 1.5 mg/kg bid i.v. from day -1 up
to oral take; 5 mg/kg bid per os until day +180

Mycophenolate 500 mg bid per os from day +7 to +100;

Methotrexate 15 mg/ m2/d i.v. day +1 and 10 mg/m2/d i.v. days +3,+6, +11

Immunoglobulin anti-lymphocyte * (ATG-Fresenius S) 5 mg/kg i.v. from day -5 to -2

Basiliximab* 20 mg i.v. day 0 (2 h before bone marrow infusion) and 20 mg i.v. day +4
* if specifically authorized by local health authority according local practice.
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
11/16
A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
Primary antifungal prophylaxis
Micafungin 50 mg/die i.v. (1 mg/kg if <40 kg) day 0 to engraftment. After engraftment
continue antifungal prophylaxis according to local practice.
Safety
monitoring
The Data Safety Monitoring Board (DSMB) in collaboration with the Steering Committee
(SC) will make periodic monitoring to ensure the safety of patients enrolled in to the study.
In particular, DSMB will check the periodic safety reports of serious adverse events, the
primary or secondary graft failure and treated related mortality (TRM) data generated by
the Data Management Center. A safety report will be generated every 30 enrolled patients
completed 100 days of follow-up.
Statistical
Design
Population for analysis
The population for analysis in the trial will be the Intention to Treat (ITT) population. All
patients enrolled in the study will be included in the ITT analysis.
Sample size calculation
This study will explore the feasibility, safety and efficacy of allogeneic stem cell
transplantation from unrelated, cord-blood and haploidentical donor in patients with an
active leukemia. Due to the lack of detailed information from literature and the absence of
alternative curative options in this patient population, criteria for sample size assessment
do not refer to a formal statistical power calculation. Therefore, GITMO will promote
enrollment of all patients with active leukemia eligible to allogeneic SCT in all Italian
centres with the aim to collect outcome variables in ITT in the widest and most
representative cohort of this specific patient population.
The choice of 80 patients transplanted is based on feasibility reasons and the expected
patient population with these characteristics referred to the main Italian Transplant Centres
in two year. GITMO survey data on transplant activity points to an estimated accrual of 40
patients per year over a 24 months enrolment period. Criteria for defining sample size do
not follow statistical power estimates in order to demonstrate difference between the
alternative donor options.
End of study
The study will end when the 80th patient will be transplanted.
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
STUDY TREATMENT
TRIAL FLOW CHART
ELEGIBILITY:
An acute leukemia patient with PIF or chemoresistant
relapse activating an alternative donor search at the
Italian Bone Marrow Donor Registry (IBMDR)
ENROLLEMENT
DONOR WORK UP: identification of an alternative donor
(MUD, CB, HAPLO)
SI
NO
TRANSPLANT:
MUD / CBT / HAPLO
FOLLOW-UP for all patients
END 2,5 YEARS AFTER ENROLLMENT
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
Treatment schedule for MUD/CB/HAPLO
Days
Conditioning regimen
-7
Thiotepa iv 5 mg/Kg/d (TD 10 mg/kg) day -7 and -6
X
-6
-5
-4
-3
-2
-1
0
1 3 4 5 6 7
11
X
Busulfan iv 3,2 mg/kg/day (TD 9,6 mg/kg) as a single daily
dose day -5, -4, -3
Fludarabine iv 50 mg/m2 (TD 150 mg/m2) day -5, -4, -3
X
X
X
X
X
X
TRANSPLANT
X
Prophylaxis of GVHD and PTLD for MUD:
Immunoglobulin anti-lymphocyte* (Thymoglobulin) iv 2
mg/kg/d day -4, -3 and -2
Cyclosporine 3 mg/kg/day iv from day -1
X
X
X
X
X
Methotrexate 15 mg day +1; 10 mg day +3, +6, +11
Rituximab **
X X
Prophylaxis of GVHD and PTLD for CBT with Intrabone procedure:
Immunoglobulin anti-lymphocyte* (Thymoglobulin) 2
mg/kg/d iv day -4 -3 -2
Cyclosporine 3 mg/kg/d iv from day -1
X
X
Prophylaxis of GVHD and PTLD for CBT without intrabone procedure:
Immunoglobulin anti-lymphocyte* (Thymoglobulin)
2mg/kg/d iv day -4 -3 -2
X
X
X
X
X
X X X X X X X
X
X
X X X X X X X
X
X
X X X X X X X
X
Cyclosporine 2 mg/kg/12 h. on days -1 to +1; 1.5 mg/kg/12
hours i.v. from day +2 to start of oral intake; 2.5 to 3 mg/kg/12
h. per os with progressive reduction of dose starting on day +90
and discontinuation on day +180 or before if feasible.
6-Metil Prednisolon 0,5 mg/kg/day iv from day + 7 to +14; 1
mg/kg/die iv from day + 15 to +28 (iv administration until to
oral feeding), slow tapering and stop within day + 100
Prophylaxis of GVHD and PTLD for HAPLO 1:
Cyclosporine 1,5 mg/kg/d iv from day -1 +20,
3 mg/kg/d per os from day +21 to +180
Mycophenolate 15 mg/kg bid iv or per os day +1 +28
2
X
X
Mycophenolate 15 mg/kg bid iv day -1 +30
Rituximab**
Cyclophosphamide 50 mg/kg iv +3,+5
MESNA >80% of the Cyclophosphamide dose in 3 divided
doses from day +3 daily through day +7
Prophylaxis of GVHD and PTLD for HAPLO 2:
Cyclosporine 0,75 mg/kg bid iv from day -7 to -2; 1,5 mg/kg
bid at day -1 up to oral take, 5 mg/kg/bid per os until day +180
Mycophenolate 500 mg bid per os from day +7 to +100
X X X X X X X
X X
X
X
X X X X X X X
X X X X X X X
X
X
X X X X X X
X
X
X
X
X
X
X
X
X X X X X X X
X X
2
Methotrexate 15 mg/m iv day +1 and 10 mg/m day +3,+6,
+11
Immunoglobulin anti-lymphocyte (ATG Fresenius S) 5
mg/kg iv from day -5 to -2
Basiliximab*** 20 mg iv day 0 (2h before transplant), 20 mg
day +4
Primary antifungal prophylaxis:
Micafungin 50 mg/die (1 mg/kg if <40 kg) day 0 to
engraftment
X X
X
X
X
X
X
X
X
X
X X X X X X X
TD= total dose
*or Immunoglobulin anti-lymphocyte (ATG-Fresenius S) 10 mg/kg (TD 30 mg/kg) if request of the local principal investigator specifically
authorized by their local health authority.
** The Linfoproliferative disease (PTLD) prophylaxis with Rituximab according to local policy.
*** if request of the local principal investigator specifically authorized by their local health authority.
Sinossi studio Gandalf-01 Protocol – Versione 01 Dated 05 Marzo 2013
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
FLOW CHART OF ANTIFUNGAL PROPHYLAXIS STRATEGY
Patients eligible for primary antifungal prophylaxis:
 No yeast infection within 8 weeks of study entry
 No mould infection within 4 months of study entry
 No clinical and/or radiological signs of residual IFD regardless of the onset of infection*
From day 0 to engraftment:
Micafungin 50 mg/die
(1 mg/Kg for patients weighting <40 Kg)
From engraftment to day 100 recommended:
Fluconazole (i.v./oral) 400 mg/d
Patients with acute or chronic
GVHD requiring steroid treatment
Patients without GVHD after day
100 stop antifungal prophylaxis
Oral Posaconazole, 200 mg/8h**
*In patients not eligible for primary antifungal prophylaxis the secondary antifungal prophylaxis regimen will be
defined for each patient by the responsible physician based on the previous infectious history
**Patients with poor compliance with oral intake, or suspected (diarrhea, intestinal GVHD) or confirmed (by
therapeutic drug monitoring) reduced Posaconazole absorption, oral Posaconazole may be replaced with
intravenous micafungin.
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A phase II multicentre open-label study on allogeneic stem cell transplantation from unrelated, cord-blood and family haploidentical
donors in patients with active acute leukemia. EudraCT Number: 2012-004008-37
ASSESSMENT SCHEDULE
Baseline
Patients
undergoing
transplant
(if time from
During
Treatment
day -7 to
day +29
enrollment to
transplant is >
1 month)b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
screeninga
PROCEDURES
Informant Consent
Eligibility criteria
Diagnosis of PIF or chemoresistant relapse
acute myeloid and lymphoblastic leukemia
Complete medical history
Physical Examination1
Complete blood count2
Blasts count in the peripheral blood smear
Clinical laboratory evaluations3 and Urine
analysis
Blood group / Rh type
Infections markers4
Instrumental evaluation5
Cytologic, hystologic, cytogenetic and
molecular data: Peripheral Blood smear,
Bone marrow biopsy, Marrow karyotype
x
x
x
x
Evaluation of comorbidity score HCT-CI
x
x
x
x
x
x
HLA typing (A, B, Cw, DRB1, DQA1,
DQB, DPB1)
Bone marrow Aspiration6
Transplant
Antifungal drug prophylaxis
Recorded drugs and concomitant drugs
Assess/recorded SAE and AE see Definitions
Recorded the N° of platelet and erythrocyte
concentrates, G-CSF
Evaluation of aGVHD and/or cGVHD
Chimerism assessment in full PB
Immune
reconstitution
by
PB
immunophenotyping7
Quality of Life
Follow-up
Post
transplant:
Follow-up
for patients
all patients:
(patients
undergoing
transplant)
on day +30,
+60, +100,
+180, +365, +
540, +700 post
transplantc
on day +100,
+180, +365, +
540, +700 post
enrolment dayc
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x8
x8
a
All examinations (instrumental, bone marrow and blood) are accepted if they are performed to 30 days prior to study enrollment.
Instrumental and bone marrow examinations are accepted if they are performed to 30 days prior to transplant, hematological
exams must be performed within 10 days of transplantation.
c
Has accepted a range of variability of the date of the visit +/- 7 days.
1
Weight, height, body surface, ECOG PS.
2
Hemoglobin, Platelets, Leukocites, Neutrophils, Lymphocytes, Monocytes
3
PCR, VES, LDH, Total Protein, albumin, IgG, IgA, IgM, AST, ALT, GGT, ALP, Na+, K+, Ca++, BUN, uric acid, Total
Bilirubin, Direct Bilirubin, Glucose, creatinine, creatinine clearance, ferritin, Serum Iron, transferrin, transferring saturation,
INR, PTT, Antithrombin III, Serum pregnancy test (if applicable).
4
HBs-Ag, HBs-Ab, HBe-Ag, HBc-IgG, HBc-IgM, HBV-DNA, HCV-Ab, HCV-RNA, HIV-Ab, VZV-IgG, VZV-IgM, HSV1IgG, HSV1-IgM, EBV-IgG, EBV-IgM, EBV-DNA, CMV-IgG, CMV-IgM, Toxo-IgG, Toxo-IgM, HSV2-IgG, HSV2-IgM,
TPHA, Galactomannan detection.
5
Ecg, Ecocardiography and ultrasound evaluation of left ventricular FE, Chest x-ray, DLCO.
6
Including phenotypic, cytogenetics and molecular test of BM/PB for markers of disease.
7
Lymphocytes, CD3, CD4, CD8, CD20.
8
For patients undergoing to transplant only at +100 and + 700, for patients not undergoing to transplant only at +100 and +700.
b
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