Clinical Trials Register

Summary
EudraCT Number:	2010-022052-23
Sponsor's Protocol Code Number:	ProtocolCodeGITMO-MF2010
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:	2011-09-19
Trial 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-022052-23

A.3

Full title of the trial

Prospective, phase II randomized study to compare busulfan-fludarabine reduced-intensity conditioning (RIC) with thiotepa-fludarabine RIC regimen prior to allogeneic transplantation of hematopoietic cells for the treatment of myelofibrosis

Studio prospettico, di fase II randomizzato, di confronto tra Condizionamento a ridotta intensita' (RIC) con busulfano-fludarabina e regime di condizionamento con thiotepa-fludarabine prima di trapianto allogenico di cellule ematopoietiche nel trattamento della mielofibrosi.

A.3.1

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

Studio clinico per confrontare due regimi di condizionamento: busulfano-fludarabina e regime di condizionamento con thiotepa-fludarabine prima di trapianto allogenico nel trattamento della mielofibrosi.

A.4.1

Sponsor's protocol code number

ProtocolCodeGITMO-MF2010

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	GITMO GRUPPO ITALIANO TRAPIANTO DI MIDOLLO OSSEO,CELLULE STAMINALI EMOPOIETICHE E TERAPIA CELLULARE - ONLUS
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	pierre fabre
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	gitmo
B.5.2	Functional name of contact point	coordinatrice sperimentazioni
B.5.3	Address:
B.5.3.1	Street Address	ao san martino largo benzi 10 padiglione 6
B.5.3.2	Town/ city	genova
B.5.3.3	Post code	16132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0105554423
B.5.5	Fax number	0105556789
B.5.6	E-mail	sonia.mammoliti@hsanmartino.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	TEPADINA
D.2.1.1.2	Name of the Marketing Authorisation holder	ADIENNE
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	Yes
D.2.5.1	Orphan drug designation number	ev/0/06/424
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for injection
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	Thiotepa
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.3	Concentration number	15
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	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	TEPADINA
D.2.1.1.2	Name of the Marketing Authorisation holder	ADIENNE
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	Yes
D.2.5.1	Orphan drug designation number	ev/0/06/424
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for injection
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	Thiotepa
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.3	Concentration number	100
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	No
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.2.1.2	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	Fludarabine
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	50
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	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	BUSILVEX
D.2.1.1.2	Name of the Marketing Authorisation holder	PIERRE FABRE PHARMA 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	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	Busulfan
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	6
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	No

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

Primary or secondary myelofibrosis after essential thrombocytemia or polycyhemia vera

Mielofibrosi primaria o secondaria dopo trombocitopenia essenziale o polichemia vera con indicazione al trapianto

E.1.1.1

Medical condition in easily understood language

myelofibrosis

mielofibrosi

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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary endpoint for this study is to compare Progression Free Survival (PFS) of two different RIC regimens for allogeneic stem cell transplantation in myelofibrosis. PFS is defined as the time from the date of randomization to the date of the first documented disease progression or relapse (according to the International Working Group Consensus Criteria, appendix B) or death due to any cause. Patients who have neither progressed nor died at the time of study completion or who are lost to follow-up are censored at the data of the last follow up for progression of disease for this study.

Progression -free survival a un anno nei due regimi di condizionamento nel trapianto di cellule staminali per la mielofibrosi

E.2.2

Secondary objectives of the trial

• Non relapse mortality (NRM) is defined as death due to any other cause than progression of malignancy after allogeneic stem cell transplantation. • Overall survival is defined as the time between randomization and the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of the data cut-off for the final analysis • Rate of clinical hematological and histological responses (according to IWG consensus criteria, appendix B) • Rate of molecular remissions in patients having a molecular marker (according to IWG consensus criteria, appendix B) • Cumulative incidence of engrafment. The day of engrafment is defined as the first 3 consecutive days on which the blood granulocyte count rises to 0.5 x 109/L • Incidence of acute graft versus host disease • Incidence of chronic graft versus host disease

• Non relapse mortality ad un anno • Sopravvivenza globale • Tasso di risposte cliniche e istologiche (in accordo all’ International Working Group consensus criteria) • Tasso di remissioni molecolari • Engraftment • Incidenza della GVHD acuta • Incidenza della GVHD cronica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 ≤ 70 years • Primary or secondary myelofibrosis after essential thrombocytemia or polycyhemia vera • One of the following unfavourable prognostic factors: - Hb < 10 g/dL - Leukocytes >25x106/L - > 1% circulating blasts in the peripheral blood - constitutional symptoms • PS (Karnofsky)≥ 60% • HCT-CI ≤ 5 • Written informed consent

• Eta' ≥ 18 ≤ 70 anni • Mielofibrosi primaria o secondaria dopo trombocitopenia essenziale o polichemia vera • Uno dei seguenti fattori prognostici sfavorevoli: - Hb < 10 g/dl - Leucociti >25x106/L - > 1% blasti nel sangue periferico - Sintomi costituzionali • PS (Karnofsky) ≥ 60% • HCT-CI ≤ 5 • Consenso informato scritto

E.4

Principal exclusion criteria

• ≥ 20% blasts in the peripheral blood and/or in bone marrow • Positive serologic markers for human immunodeficiency virus (HIV) • Acute hepatitis B virus (HBV) or acute hepatis C virus (HCV) infection • Severe irreversible renal, hepatic , pulmonary or cardiac disease , such as: - total bilirubin, SGOT or SGPT > 5 the upper normal limit - Left ventricular ejection fraction < 30% - Clearance creatinine < 30 ml/min - DLCO < 30% and/or receiving supplementary oxygen • Pregnancy or lactation • Patients not agreeing to take adequate contraceptive measures during the study • Psychiatric disease • Any active , uncontrolled infection 7.3 Donors: Inclusion criteria • Age ≥ 18 < 65 years • HLA-identical sibling donor by high resolution DNA-based HLA-A, -B, -C , -DRB1 typing. • HLA-identical unrelated donor by high resolution DNA-based HLA-A, -B, -C , -DRB1 typing . One allele mismatched (class I) can be accepted for recipients up to 60 years .

• ≥ 20% blasti nel sangue periferico o nel midollo osseo • Sierologia positiva per human immunodeficiency virus (HIV) • Infezione da virus di epatitis B virus (HBV) o C (HCV) • Disfunzioni renali, epatiche, polmonari o cardiache, cosi' descritte: - Bilirubina tot. , SGOT o SGPT > 5 il limite della norma - Frazione di eiezione ventricolare < 40% - Clearance della creatinine < 30 ml/min - DLCO < 30% e/o supporto con ossigeno • Gravidanza o allattamento • Mancato utilizzo sistemi validi di contraccezione • Disturbi psichiatrici • Qualsiasi infezione attiva e non controllata • Donatore • Eta' ≥ 18 < 65 anni • HLA-identical sibling donor by high resolution DNA-based HLA-A, -B, -C, -DRB1, typing. • HLA-identical unrelated donor by high resolution DNA-based HLA-A, -B, -C , -DRB1 typing. Un allele mismatched (class I) e' accettato per riceventi oltre i 60 anni.

E.5 End points

E.5.1

Primary end point(s)

• Progression -free survival at one year

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years of patients enrolment plus 1 year of minimum follow-up for last patient enrolled (total 4 years)

3 anni di arruolamento e 1 di follow successivo alla fine del trattamento dell'ultimo paziente arruolato

E.5.2

Secondary end point(s)

• Non relapse mortality at one year
• Overall survival
• Rate of clinical hematological and histological responses (according to International Working Group consensus criteria)
• Rate of molecular remissions in patients having a molecular marker
• Engraftment
• Incidence of acute graft versus host disease
• Incidence of chronic graft versus host disease

• Non relapse mortality ad un anno
• Sopravvivenza globale
• Tasso di risposte cliniche e istologiche (in accordo all’ International Working Group consensus criteria)
• Tasso di remissioni molecolari
• Engraftment
• Incidenza della GVHD acuta
• Incidenza della GVHD cronica

E.5.2.1

Timepoint(s) of evaluation of this end point

3 years of patients enrolment plus 1 year of minimum follow-up for last patient enrolled (total 4 years)

3 anni di arruolamento e 1 di follow successivo alla fine del trattamento dell'ultimo paziente arruolato

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

none

nessuno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-02-22

P. End of Trial
P.	End of Trial Status	Completed

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials