Clinical Trials Register

Summary
EudraCT Number:	2014-003126-40
Sponsor's Protocol Code Number:	alloCML
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:	2015-05-13
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

2014-003126-40

A.3

Full title of the trial

Allogeneic haematopoietic stem cell transplantation from a matched donor in patients with chronic myeloid leukemia failing to gain normal hemopoiesis under TKIs therapy

A.3.1

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

Stem cells transplant from matched donor in patients with chronic myeloid leukemia who do not improve with TKI therapy

Trapianto di cellule staminali da donatore compatibile in pazienti affetti da Leucemia Mieloide Cronica che non ottengono miglioramento grazie alla terapia convenzionale con TKI

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

alloCML

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	UNIVERSITà DEGLI STUDI MILANO BICOCCA
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	Azienda Farmaceutica: Pfizer
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	Università degli Studi di Milano Bicocca
B.5.2	Functional name of contact point	Prof. Carlo Gambacorti-Passerini -
B.5.3	Address:
B.5.3.1	Street Address	via Cadore 48
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	039 233 9553
B.5.5	Fax number	039 233 3539
B.5.6	E-mail	carlo.gambacorti@unimib.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	No
D.2.1.1.1	Trade name	BOSULIF - 100 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (PVC/ACLAR/PVC) - 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER LIMITED
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/762
D.3 Description of the IMP
D.3.1	Product name	BOSULIF
D.3.2	Product code	PF-05208763
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	BOSUTINIB
D.3.9.1	CAS number	380843-75-4
D.3.9.2	Current sponsor code	PF - 05208763
D.3.9.3	Other descriptive name	bosutinib monohydrate
D.3.9.4	EV Substance Code	SUB29176
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	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.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

Chronic Myeloid Leukemia

Leucemia Mieloide Cronica

E.1.1.1

Medical condition in easily understood language

CML is a disease ought to abnormal proliferation of immature blood cells with chromosomes alterations which develops into the bone marrow and has systemic symptoms

La LMC è una malattia dovuta alla proliferazione di cellule immature del sangue con alterazione dei cromosomi, che si sviluppa nel midollo osseo ed ha sintomi di tipo sistemico.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10054352
E.1.2	Term	Chronic phase chronic myeloid leukemia
E.1.2	System Organ Class	100000004864

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 complete cytogenetic responses (CCyR) at 12 months post transplant, based on at least 20 metaphases

Valutazione della risposta citogenetica completa a 12 mesi

E.2.2

Secondary objectives of the trial

Efficacia
- Valutazione di attecchimento
- Valutazione della sopravvivenza complessiva (OS)
- Valutazione delle risposte molecolari
- Valutazione di incidenza di recidiva (RI)
- Documentazione del chimerismo del donatore il giorno 28, 56 e 100

Sicurezza
- Valutazione di incidenza di mortalità senza ricadute (NRM) al giorno 28 e 360
- Valutazione di incidenza cumulativa e della gravità di malattia acuta e cronica vs host disease (GvHD).

Qualità di Vita
- Valutazione della Qualità di Vita con EQ-5D-5L (Italiano - Versione 2) and FACT-Leu (Italiano - Versione 4) allo screening, al giorno -6, +100, al mese 6, 12 e a fine trattamento.

Fine del totale follow-up per OS, PFS, RI, NRM, cGVHD =
2 anni dopo il trapianto del paziente dell'ultimo paziente arruolato

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- 1. Chronic Myeloid Leukaemia -CML- in chronic phase (CP)
2. Failure to achieve at least a Major Cytogenetic Response (MCyR) after a minimum of 18 months of TKIs treatment
3. Inability to tolerate 3 months of uninterrupted full dose TKIs therapy due to hematological toxicity
4. A minimum of three treatment interruptions due to hematological toxicity Availability of a HLA-identical related donor (Matched Related Donor, MRD)
5. Availability of unrelated donor (Matched Unrelated Donor, MUD) satisfying the criteria of a 10/10 antigen match at HLA-A, -B, -C and - DRB1, -DQB1 at high resolution typing, or 9/10 with a permissive – DP disparity according to Fleischhauer model (Crocchiolo et al, Blood 2009)
6. Target graft size (bone marrow):
7. bone marrow: > 3 x 106 CD34+ cells/kg BW recipient
or > 3 x 108 nucleated cells/kg BW

8. Karnofsky Index ≥ 80 %
9. Age ≥18 and ≤70 years
10. Adequate contraception in female patients of child-bearing
potential
11. Written informed consent

1. Leucemia mieloide cronica in fase cronica

2. Il mancato raggiungimento di almeno una risposta citogenetica maggiore (MCR) dopo un minimo di 18 mesi di trattamento TKIs

3. Incapacità di tollerare tre mesi di terapia con TKIs a dose piena senza interruzioni dovute a tossicità ematologica

4. Un minimo di tre interruzioni di terapia dovute a tossicità ematologica

5. Disponibilità di donatore di midollo familiare compatibile (Matched Related Donor, MRD)

6. Disponibilità di donatore compatibile non consanguineo (Matched Unrelated Donor, MUD) con 10/10 antigen match per HLA-A, -B, -C e -DRB1, -DQB1 ad alta risoluzione, o 9/10 –DP in accordo con il modello Fleischhauer (Crocchiolo et al, Blood 2009)

7. Target graft size (preferibilmente da midollo)
a. Da midollo: 3 - 10 x 106 CD34+ cellule/kg BW
o > 3 x 108 cellule nucleate/kg BW

o

b. Da sangue periferico: 4 - 10 x 106 CD34+ cellule/kg BW

8. Karnofsky ≥ 80 %
9. età ≥ 18 e ≤ 70 anni
10. adeguata contraccezione in donne in età fertile
11. consenso informato scritto

E.4

Principal exclusion criteria

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

1. Tumori secondari
2. Indice di comorbidità per trapianto di cellule emopoietiche > 4 (Sorror et al)
3. Interessamento del SNC
4. Presenza di patologia infettiva in fase di attività
5. HIV e HBV attive o infezione da HCV
6. Alterazione della funzionalità epatica (Bilirubina > limite superiore di norma; Transaminasi > 3.0 x limite superiore di norma)
7. Alterazione della funzionalità renale (Creatinina-clearance < 60 ml/min; Creatinine sierica> 1.5 x limite superiore di norma).
8. versamento pleurico o ascitico > 1.0 L
9. gravidanza o allattamento
10. nota ipersensibilità al Busilvex e/o fludarabina e/o MTX
11. Comportamento del paziente non cooperative e scarsa compliance
12. patologie psichiatriche o condizioni che potrebbero ostacolare la comprensione del consenso informato

E.5 End points

E.5.1

Primary end point(s)

Complete Cytogenetic Response

Risposta citogenetica completa

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

Overall Survival
Relapse Incidence
Donor chimerism
Non Relapse Mortality
Incidence of Acute and Chronic Graft vs Host Disease
Quality of Life

Sopravvivenza complessiva
Incidenze di recidiva
Chimerismo del donatore
Incidenza Mortalità senza Ricadute
Incidenza di malattia acuta e cronica vs host disease
Qualità di Vita

E.5.2.1

Timepoint(s) of evaluation of this end point

2 years after transplantation of the last patient included
day 28, 56 and 100
screening, day 6, day 100, month 6, month 12 and End of Study

2 anni post-trapianto ultimo paziente arruolato
giorno 28, 56 e 100
screening, giorno 6, giorno 100, mese 6, mese 12 e fine studio

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

E.8.2.2

Placebo

E.8.2.3

Other

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.8.5.1

Number of sites anticipated in the EEA

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

Yes

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.1.1.1

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)

At the end of the study patients will be treated with the raccomended standard of care

Al termine dello studio i pazienti saranno trattati secondo la pratica clinica

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

2015-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-05

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

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