Clinical Trials Register

Summary
EudraCT Number:	2013-000691-15
Sponsor's Protocol Code Number:	B1871040
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:	2013-05-28
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

2013-000691-15

A.3

Full title of the trial

AN OPEN-LABEL BOSUTINIB TREATMENT EXTENSION STUDY FOR SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008

Studio di estensione del trattamento in aperto su bosutinib per soggetti con leucemia mieloide cronica (LMC) che hanno precedentemente partecipato agli studi B1871006 o B1871008 su bosutinib

A.3.1

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

EXTENSION STUDY FOR SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008

Studio di estensione per soggetti con leucemia mieloide cronica (LMC) che hanno precedentemente partecipato agli studi B1871006 o B1871008 su bosutinib

A.4.1

Sponsor's protocol code number

B1871040

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	Pfizer Inc, 235 East 42nd Street, New York, NY 10017
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 E 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800 7181021
B.5.5	Fax number	+1303 7391119
B.5.6	E-mail	ClinicalTrials.gov.CallCenter@pfizer.com

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	Bosulif 100 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Bosutinib
D.3.2	Product code	PF-05208763; SKI-606
D.3.4	Pharmaceutical form	Film-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	Bosutinib
D.3.9.1	CAS number	380843-75-4
D.3.9.2	Current sponsor code	PF-05208763; SKI-606
D.3.9.3	Other descriptive name	SKI-606 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 (CML)

Leucemia mieloide cronica (LMC)

E.1.1.1

Medical condition in easily understood language

CML is a type of Philadelphia Chromosome positive leukaemia resulting due to changes in chromosomes. It is characterized by the uncontrolled growth of white blood cells.

LMC è una forma di leucemia in fase cronica positiva per il cromosoma Philadephia dovuto ad un’anomalia dei cromosomi. E’ caratterizzata dalla crescita incontrollata dei globuli bianchi

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10009012
E.1.2	Term	Chronic myelogenous leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To allow long term bosutinib treatment in subjects with chronic or advanced phases Ph+ CML who received bosutinib in a previous Pfizer sponsored CML study (ie, studies B1871006 and B1871008) and who have the potential, as judged by the investigator, to derive clinical benefit from continued treatment with bosutinib;
• To collect long term safety and efficacy data for bosutinib;
• To assess the duration of clinical benefit for Ph+ CML subjects treated with bosutinib;
• To fulfill the European Medicines Agency (EMA) post approval requirement for the collection and analysis of safety data about diarrhea incidence after switch from clinical study to commercial bosutinib formulation.

•Consentire il trattamento a lungo termine a base di bosutinib nei soggetti affetti da LMC Ph+ in fase cronica o avanzata che avevano ricevuto bosutinib nell’ambito di un precedente studio sulla LMC sponsorizzato da Pfizer (ovvero, gli studi B1871006 e B1871008) e che, a giudizio dello sperimentatore, sono in possesso del potenziale di trarre benefici clinici dal trattamento continuato a base di bosutinib;
•Raccogliere dati sulla sicurezza e sull’efficacia a lungo termine di bosutinib;
•Valutare la durata dei benefici clinici per i soggetti affetti da LMC Ph+ trattati con bosutinib;
•Soddisfare i requisiti dell’Agenzia Europea per i medicinali (European Medicines Agency, EMA) dopo l’approvazione, per la raccolta e l’analisi dei dati sulla sicurezza relativi all’incidenza di diarrea dopo il passaggio dalla formulazione dello studio clinico a quella commerciale di bosutinib.

E.2.2

Secondary objectives of the trial

Not applicable

Non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Previous enrollment in the bosutinib arm of one of the two Pfizer parent studies: B1871006 or B1871008. This includes:
a. Subjects still receiving bosutinib in either study B1871006 or B1871008;
b. Subjects who have discontinued bosutinib but are still in the long term follow up phase of the study B1871006 or B1871008;
c. Subjects from study B1871006 who have discontinued bosutinib and have already completed the long term follow up period.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

I soggetti devono soddisfare tutti i seguenti criteri di inclusione per risultare idonei all’arruolamento nello studio:
1. Possesso di documento di consenso informato firmato e datato personalmente, indicante che il soggetto (o un rappresentante legale) è stato informato su tutti gli aspetti pertinenti dello studio.
2. Precedente arruolamento nel braccio assegnato a bosutinib di uno dei due studi originari sponsorizzati da Pfizer: B1871006 o B1871008. Ciò comprende:
a. Soggetti che ancora ricevono bosutinib nello studio B1871006 o nello studio B1871008;
b. Soggetti che hanno sospeso l’assunzione di bosutinib ma sono ancora in fase di follow-up a lungo termine dello studio B1871006 o dello studio B1871008;
c. Soggetti provenienti dallo studio B1871006 che hanno sospeso l’assunzione di bosutinib e già completato il periodo di follow-up a lungo termine.
3. Soggetti disposti e in grado di attenersi al programma delle visite, al piano di trattamento, alle analisi di laboratorio e ad altre procedure dello studio.
4. I soggetti di sesso maschile e femminile in età fertile devono acconsentire all’adozione di un metodo contraccettivo altamente efficace per l’intera durata dello studio e per almeno 30 giorni dopo l’assunzione dell’ultima dose del trattamento loro assegnato. Un soggetto è in età fertile se, a giudizio dello sperimentatore, è biologicamente in grado di generare figli ed è sessualmente attivo.

E.4

Principal exclusion criteria

Subjects presenting with any of the following will not be included in the study:
1. Participation in other studies involving investigational drug(s) (Phases 1 to 4) while subject in the active treatment phase of the current study.
2. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
3. Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
4. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 30 days after last dose of investigational product.

I soggetti che evidenziano una qualsiasi delle seguenti condizioni saranno esclusi dallo studio:
1. Partecipazione ad altri studi condotti su farmaco/i sperimentale/i (fasi 1-4) mentre il soggetto è in fase di trattamento attivo nell’attuale studio.
2. Soggetti membri del personale del centro di sperimentazione direttamente coinvolti nella conduzione della sperimentazione e membri delle rispettive famiglie, membri del personale del centro altrimenti supervisionati dallo sperimentatore o soggetti dipendenti di Pfizer direttamente coinvolti nella conduzione della sperimentazione.
3. Presenza di altra grave condizione medica o psichiatrica, acuta o cronica, compresi ideazione suicidaria o comportamento suicidario recenti (nel corso dell’ultimo anno) o attivi, o anomalie di laboratorio in grado di incrementare il rischio associato alla partecipazione allo studio o alla somministrazione del prodotto sperimentale, o in grado di interferire con l’interpretazione dei risultati dello studio e che, a giudizio dello sperimentatore, rendano il soggetto non idoneo a partecipare al presente studio.
4. Donne in stato di gravidanza; donne in fase di allattamento al seno; uomini e donne in età fertile che non adottano un metodo contraccettivo altamente efficace o che non accettano di continuare ad adottare un metodo contraccettivo altamente efficace per almeno 30 giorni dopo l’assunzione dell’ultima dose del prodotto sperimentale.

E.5 End points

E.5.1

Primary end point(s)

The objective of the study is to provide long term access to bosutinib treatment and assess long term safety, tolerability and duration of clinical benefit, without any formal hypothesis testing; therefore, there is no formal primary endpoint.
In addition, study endpoints to be reported and data to be collected, specifically efficacy data, are planned to be different in the first line CP subjects relative to the later line and advanced subjects.

For all subjects regardless of the line of treatment:
• Long term safety of bosutinib, including type, incidence, severity, timing, seriousness and relatedness of AEs and laboratory abnormalities as well as reason of treatment discontinuation. A special focus will be made on diarrhea in order to satisfy the EMA post commitment request;
• BCR ABL mutations present at the time subjects discontinue bosutinib;
• Overall survival (OS),

For 2nd or later line subjects coming from study B1871006:
as long as subjects are on treatment with bosutinib, the following efficacy endpoints will be assessed:
• Duration of hematologic and cytogenetic responses;
• Progression free survival;
• Time to transformation to accelerated or blast phase.

L’obiettivo dello studio è quello di fornire accesso a lungo termine al trattamento a base di bosutinib e di valutarne la sicurezza e la tollerabilità a lungo termine nonché la durata dei benefici clinici, senza alcuna verifica dell’ipotesi formale; non è pertanto previsto alcun endpoint primario formale.
Si prevede inoltre che gli endpoint dello studio da riportare e i dati da raccogliere, in particolare i dati sull’efficacia, saranno differenti nei soggetti in fase cronica in trattamento di prima linea rispetto a quelli in fase avanzata in trattamento di linea successiva.

Per tutti i soggetti, a prescindere dalla linea di trattamento:
• La sicurezza a lungo termine di bosutinib, compresi tipologia, incidenza, gravità, tempistica, serietà e correlazione di EA e anomalie di laboratorio, oltre che il motivo della sospensione del trattamento. Sarà dedicata particolare attenzione alla diarrea, al fine di soddisfare la richiesta di impegno post-marketing EMA;
• Le mutazioni BCR-ABL presenti nel momento in cui i soggetti sospendono l’assunzione di bosutinib;
• La sopravvivenza complessiva (SC).

Per i soggetti assegnati al trattamento di 2° linea o di linea successiva provenienti dallo studio B1871006:
fino a che i soggetti saranno in trattamento con bosutinib, saranno valutati i seguenti endpoint di efficacia:

• Durata delle risposte ematologica e citogenetica;
• Sopravvivenza senza progressione;
• Tempo di trasformazione alla fase accelerata o blastica.

E.5.1.1

Timepoint(s) of evaluation of this end point

For CML 1st line subjects coming from B1871008:
• AEs collected at ≤ 28 days from last dose on parent study, at site visit at month 3, every 12 months, at phone calls every 3 months, and at ≤ 28 days after last dose of bosutinib.
For CML 2nd and later line subjects coming from B1871006:
• AEs collected at ≤ 28 days from last dose on parent study, at site visit at month 3, at every 6 months, at phone calls every 3 months, and at ≤ 28 days after last dose of bosutinib.
For all subjects:
• Diarrhea information collected at ≤ 28 days from last dose on parent study and at month 3 site visit.
• BCR ABL mutation analysis at ≤ 28 days after last dose of bosutinib.
• Survival follow-up at every 3 months from last dose of bosutinib for up to 10 years from first dose (including parent study).

Per i soggetti affetti da LMC in trattamento di 1° linea provenienti dallo studio B1871008:
• AEs raccolti ≤ 28 giorni dall’assunzione dell’ultima dose nello studio originario, visita presso il centro al 3° mese, ogni 12 mesi, visite telefiche ogni 3 mesi e ≤ 28 giorni dall’assunzione dell’ultima dose di bosutinib.
Per i soggetti affetti da LMC in trattamento di 2° linea e linea successiva provenienti dallo studio B1871006:
• AEs raccolti ≤ 28 giorni dall’assunzione dell’ultima dose nello studio originario, visita presso il centro al 3° mese, ogni 6 mesi, visite telefoniche ogni 3 mesi e ≤ 28 giorni dall’assunzione dell’ultima dose di bosutinib.
Per tutti i soggetti:
si prega di fare riferimento alla Sinossi.

E.5.2

Secondary end point(s)

Not applicable

Non applicabile

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

Non applicabile

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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

Yes

E.8.1.7.1

Other trial design description

studio di estensione - la fase non è applicabile

extension study - phase is N/A

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Brazil

Canada

Chile

China

Colombia

Finland

France

Germany

Hong Kong

Hungary

India

Italy

Japan

Korea, Republic of

Latvia

Lithuania

Mexico

Netherlands

Peru

Poland

Russian Federation

Singapore

South Africa

Spain

Thailand

Turkey

Ukraine

United Kingdom

United States

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 (please refer to protocol)

LVLS (fare riferimento al protocollo)

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:

450

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

136

F.4.2.2

In the whole clinical trial

500

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

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

2013-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-20

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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