Clinical Trials Register

Summary
EudraCT Number:	2011-001534-42
Sponsor's Protocol Code Number:	TrRaMM4Gy
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-001534-42

A.3

Full title of the trial

Treosulfan and 4 Gy TBI based conditioning with Rapamycin-based GvHD prophylaxis for allogeneic stem cell transplantation in patients with haematological malignancies

Condizionamento a base di Treosulfano e TBI 4Gy e profilassi per la GVHD con Rapamicina nel trapianto allo genico in pazienti con patologie neoplastiche ematologiche.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical study in which are enrolled patients with malignant hematologic diseases for which there is no indication for allogeneic bone marrow transplantation, and for whom a suitable donor has been identified (fully compatible or partially compatible).

Studio clinico nel quale vengono arruolati pazienti affetti da malattie ematologiche maligne, per i quali ci sia indicazione a trapianto di midollo osseo allogenico, e per i quali sia stato individuato un donatore idoneo (totalmente compatibile o parzialmente compatibile).

A.4.1

Sponsor's protocol code number

TrRaMM4Gy

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	FONDAZIONE CENTRO S. RAFFAELE DEL MONTE TABOR
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MEDAC
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	FRESENIUS BIOTECH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione San Raffaele
B.5.2	Functional name of contact point	EMATOLOGIA e TMO
B.5.3	Address:
B.5.3.1	Street Address	via Olgettina, 60
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0226433903
B.5.5	Fax number	0226434760
B.5.6	E-mail	ciceri.fabio@hsr.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	FLUDARA*EV 5FL 50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GENZYME Srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	fludarabina
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	natura chimica
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OVASTAT
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDAC
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	treosulfano
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	natura chimica
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ATG FRESENIUS S
D.2.1.1.2	Name of the Marketing Authorisation holder	FRESENIUS
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Anti-thymocyte globulin (ATG)
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	MABTHERA*EV 1FL 50ML 500MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	anticorpo monoclonale
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	RAPAMUNE*30CPR RIV 2MG
D.2.1.1.2	Name of the Marketing Authorisation holder	WYETH LEDERLE SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sirolimus
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	natura chimica
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	MYFORTIC*250CPR RIV 360MG
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	acido micofenolico
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	360
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	natura chimica

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pediatric and adult patients (aged from 1 to 70 years) with hematologic malignancies (leukemia, myeloma, lymphoma), candidates for allogeneic transplantation from HLA-identical or HLA-mismatched family is from the register.

Pazienti pediatrici e adulti (età compresa da 1 a 70 anni) affetti da patologie maligne ematologiche (leucemia, mieloma, linfoma), candidati a trapianto allogenico da donatore HLA-identico o HLA- mismatched sia familiare che da registro.

E.1.1.1

Medical condition in easily understood language

Pediatric and adult patients (aged 1 to 70 years) suffering from blood cancer (leukemia, lymphoma, etc..) to be undergoing bone marrow transplantation.

Pazienti pediatrici e adulti (età compresa da 1 a 70 anni) affetti da tumori del sangue (leucemie, linfomi etc.) che dovranno essere sottoposti a trapianto di midollo osseo.

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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	10001756
E.1.2	Term	Allogenic bone marrow transplantation therapy
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of progression free survival (PFS) at 365 days

Valutazione della “progression free survival (PFS)” ad un anno post-trapianto.

E.2.2

Secondary objectives of the trial

Efficacy
- Evaluation of engraftment
- Evaluation of relapse incidence (RI)
- Documentation of donor chimerism on day +28 and +100
Safety
- Evaluation of incidence of non-relapse mortality (NRM) on day +28,
day +100 and +360
- Evaluation of cumulative incidence and severity of acute and
chronic graft vs. host disease (GvHD).
- EBV reactivation
End of total follow up for OS, PFS, RI, NRM, cGvHD =
365 days after transplantation of the last patient included

Efficacia · Valutazione dell’ ”engrafment” · Valutazione del chimerismo al giorno +28 e +100 post-trapianto. Sicurezza · Valutazione dell’incidenza della “non-relapse mortality (NRM)” al giorno +28, +100 e +360 posttrapianto. · Valutazione della incidenza cumulativa e della severità della “Graft vs Host Disease” (GvHD). · Riattivazione EBV

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:01
Date:2011/01/01
Title:Substudy to evaluate the pharmacokinetics of ATG Fresenius.
Objectives:assess the concentration of rabbit IgG specific, corresponding to biological activity against human T-lymphocytes, and compared this to levels of specific IgG have lost their activity against T lymphocytes

FARMACOCINETICA/FARMACODINAMICA:
Vers:01
Data:2011/01/01
Titolo:Sottostudio per la valutazione della farmacocinetica del farmaco ATG Fresenius.
Obiettivi:valutare la concentrazione di IgG di coniglio specifiche, corrispondenti all’attività biologica umana contro i linfociti T, e comparare questo ai livelli di IgG non specifiche che hanno perso l’attività contro i linfociti T.

E.3

Principal inclusion criteria

Patients with hematological malignancies such as
- acute myeloid leukaemia -AML- in CR1 except “low-risk
cases” defined by: t(15;17); t(8;21); inv 16; normal cytogenetics
at diagnosis with FLT3-ITD negative and NPM-1 positive (with
any high-risk clinical criteria).
- any AML beyond CR1
- acute lymphoblast leukaemia -ALL- in CR1 only if at “high
risk” defined by cytogenetics as t(9;22), t(4;11), or for
persistence of minimal residual disease (MRD) after
consolidation.
- any ALL beyond CR1
- chronic myeloid leukaemia -CML- in chronic phase (CP) or
accelerated phase (AP) intolerant/not responsive to TKinhibitors,
in blastic phase (BP)
- myeloproliferative neoplasia –MPD-
- myelodysplastic syndrome -MDS- with intermediate or high
risk International Prognostic Scoring System (IPSS)
- diffuse large cell lymphoma –DLCL- with a chemosensitive
relapse or beyond CR1
- lymphoblastic and Burkitt lymphoma with a chemosensitive
relapse or beyond CR1
- mantle cell lymphoma –MCL- with a chemosensitive relapse
or beyond CR1
- follicular lymphoma –FCL- with a chemosensitive relapse or
beyond CR2
- Hodgkin lymphoma -HD- with a chemosensitive relapse or
beyond CR1
- chronic lymphocytic leukaemia –CLL- at “poor risk” in CR1 or
with a chemosensitive relapse
- T-cell non Hodgkin lymphoma –T-NHL- in CR1 or beyond
- multiple myeloma –MM- at high risk for cytogenetics or ISS
stage 3 in CR1 following high dose chemotherapy
- MM at any relapse/progression, except refractory disease
· ECOG > 2
· Age < 70 years
· Adequate contraception in female patients of child-bearing
potential.
· Written informed consent
· Availability of one of the following:
· A matched related or unrelated donor (MRD or MUD)
· A mismatched related donor (MMRD) sharing at least one full
haplotype (MMRD)
· An unrelated donor satisfying the minimum criteria of a 5/6
antigen match at HLA-A, -B and -DRB1 (MMUD)
· A single cord blood unit (CBU) with a cellularity as follows:
6/6 TNC > 3x10e7/kg*
5/6 TNC > 4x10e7/kg*
4/6 TNC > 5x10e7/kg*
· If a single CBU doesn’t reach the target dose, then two CBUs are
preferred.
* This values are intented at the moment of collection.

Pazienti con malattie neoplastiche ematologiche: Indice Karnofsky > 80 %
- Età minore di 70 anni Adeguata contraccezione nei pazienti di sesso femminile in età fertile. Consenso informato -Disponibilità di un donatore: • Familiare o non familiare identico (MRD or MUD) • Un donatore familiare parzialmente compatibile che condivida almeno un aplotipo completo (MMRD) • Un donatore non familiare con una compatibilità HLA 5 su 6, definita dai seguenti markers: A, B e DRB1 (MMUD). • Singola unità cordonale (CBU) con le seguenti caratteristiche: - 6/6 TNC > 3x10e7/kg* - 5/6 TNC > 4x10e7/kg* - 4/6 TNC > 5x10e7/kg*

E.4

Principal exclusion criteria

1. A hematopoietic cell transplantation-specific comorbidity index
(Sorror et al Appendix B) > 4
2. Active non-controlled infectious disease at the moment of inclusion
3. Active HBV or HCV infection
4. Impaired liver function (Bilirubin > 2.0 x upper normal limit;
Transaminases > 3.0 x upper normal limit)
5. Impaired renal function (Creatinine-clearance < 60 ml/min; Serum
Creatinine > 1.5 x upper normal limit).
6. Pleural effusion or ascites > 1.0 L
7. Pregnancy or lactation
8. Known hypersensitivity to treosulfan and/or fludarabine and/or
rapamycin
9. Non-co-operative behaviour or non-compliance
10. Psychiatric diseases or conditions that might impair the ability to give
informed consent

Indice di comorbidità specifico per trapianto di cellule ematopoietiche >4 (HTC-CI Sorror et al. Appendice B) Infezioni non controllate al momento dell’inclusione. Epatite attiva Epatopatia (bilirubina > 2 volte il valore di norma, transaminasi >3 volte il valore di norma) all’inclusione. Alterata funzionalità renale (clearance creatinina < 60ml/min, creatina sierica > 1.5 volte valore di norma) al momento dell’inclusione. Versamento pleurico o ascite > 1.0 L Gravidanza o allattamento Ipersensibilità al treosulfano e/o alla fludarabina e/o alla rapamicina note. Non-compliance. Malattie psichiatriche e impossibilità di esprimere consenso informato.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) within 1 year after transplantation is measured from time of start of HSCT (= day -7) to time of progression event. Progression events are defined as relapse of disease in patients in CR at the moment of transplant and progressive desease in the others. Relapse is defined according to “WHO diagnostic criteria”. Progressive diseases is defined as increasing of 25% of the bulk of disease parameters (blast for leukemia, lymphonodes diameters for lymphoma, monoclonal paraprotein in MM).

Sopravvivenza libera da progressione (PFS) entro 1 anno dal trapianto è misurata dal tempo di inizio di HSCT (= giorno -7) a tempo di progressione della manifestazione. Eventi di progressione sono definiti come recidiva della malattia nei pazienti in CR al momento del trapianto e le malattia progressiva negli altri. Relapse è definito in base a "criteri diagnostici WHO". Malattie progressive è definita come aumento del 25% della maggior parte dei parametri di malattia (blastica della leucemia, linfonodi diametri per il linfoma, paraproteina monoclonale in mm).

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year

1 anno

E.5.2

Secondary end point(s)

Efficacy - Engraftment Is defined as neutrophil ≥ 500*109/L, Hemoglobin ≥ 8 gr/L, Platelets ≥ 20000*10^9/L without transfusion or growth factor administration for consecutively three days. - Relapse incidence (RI) Is defined as reappearance of disease according to “WHO diagnostic criteria” until at the end of total follow-up. - Donor chimerism course ≥ 95% on day +28, +100 Safety - Non-relapse mortality (NRM) until 365 days after transplant - Acute graft vs. host disease (aGvHD) until 100 days after trasplant of any grade. - Grade of acute graft vs. host disease (aGvHD), according to the “Consensus Conference on Acute GVHD Grading” until 100 days after trasplant. - Chronic graft vs. host disease (cGvHD) by 100 days after trasplant to the end of follow up. - Grade of chronic graft vs. host disease (aGvHD), according to “National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: Diagnosis and staging working group” report by 100 days after trasplant to the end of follow up. - EBV reactivation expressed like positive PCR, exceeding 50 copies/105 cells, in the three different treatment arms until 365 days after transplant.

Efficacia - Engraftment è definito come neutrofili ≥ 500 * 109 / L, emoglobina ≥ 8 gr / L, piastrine ≥ 20.000 * 10 ^ 9 / L, senza trasfusione o la somministrazione fattore di crescita per consecutivamente tre giorni. - incidenza Relapse (RI) è definito come ricomparsa della malattia in base a "criteri diagnostici WHO" fino alla fine del follow-up totale. - Corso di chimerismo del donatore ≥ 95% giorno 28, 100 di sicurezza - non recidiva mortalità (NRM) fino a 365 giorni dopo il trapianto - graft vs host disease acuta (aGvHD) fino a 100 giorni dopo TRAPIANTO di qualunque grado. - Grado di graft vs host disease acuta (aGvHD), secondo la "Consensus Conference sulla GVHD acuta di classificazione" fino a 100 giorni dopo TRAPIANTO. - graft vs host disease cronica (cGVHD) di 100 giorni dopo TRAPIANTO alla fine del follow-up. - Grado di graft vs host disease cronica (aGvHD), secondo il "National Institutes of Health progetto di sviluppo di un consenso sui criteri per la sperimentazione clinica in malattia cronica di graft-versus-host: Diagnosi e stadiazione del gruppo di lavoro", relazione di 100 giorni dopo il TRAPIANTO di alla fine del follow up. - riattivazione EBV espresso come PCR positivo, superiore a 50 copies/105 cellule, nei tre bracci di trattamento diverso fino a 365 giorni dopo il trapianto.

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year

1 anno

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised