Clinical Trials Register

Summary
EudraCT Number:	2016-002216-40
Sponsor's Protocol Code Number:	CML1516
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:	2021-06-08
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002216-40

A.3

Full title of the trial

BOSUTINIB EFFICACY SAFETY TOLERABILITY (BEST) STUDY IN ELDERLY CHRONIC MYELOID LEUKEMIA PATIENTS FAILING FRONT-LINE TREATMENT WITH OTHER TYROSINE KINASE INHIBITORS

STUDIO DI EFFICACIA, SICUREZZA E TOLLERABILIT¿ DI BOSUTINIB (BEST) IN PAZIENTI ANZIANI AFFETTI DA LEUCEMIA MIELOIDE CRONICA RESISTENTI AL TRATTAMENTO DI PRIMA LINEA CON ALTRI FARMACI INIBITORI DELLA TIROSIN-CHINASI

A.3.1

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

Efficacy, safety and tolerability of a drug called Bosutinib, in eldery patients affected by Chronic Myeloid Leukemia failing front-line treatment with other drugs with similar features.

Studio sull'efficacia, sicurezza e tollerabilit¿ di un farmaco denominato Bosutinib in pazienti anziani affetti da Leucemia Mieloide Cronica non responsivi a trattamenti di elezione con altri farmaci con caratteristiche simili.

A.3.2

Name or abbreviated title of the trial where available

CML1516

A.4.1

Sponsor's protocol code number

CML1516

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02810990

A.5.4

Other Identifiers

Name:

BEST

Number:

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 GIMEMA (GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL' ADULTO) FRANCO MANDELLI 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	Pfizer
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	A.I.L Associazione Italiana contro le Leucemie
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	Fondazione GIMEMA Onlus Franco Mandelli
B.5.2	Functional name of contact point	Centro dati GIMEMA
B.5.3	Address:
B.5.3.1	Street Address	Via Casilina 5
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00182
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0670390526
B.5.5	Fax number	+39 0670390540
B.5.6	E-mail	gimema@gimema.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	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.3.4	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	NA
D.3.9.4	EV Substance Code	SUB120769
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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) in Chronic Phase

Leucemia Mieloide Cronica (LMC) in Fase Cronica

E.1.1.1

Medical condition in easily understood language

Chronic Myeloid Leukemia (CML) is a type of cancer starts in certain blood-forming cells of the bone marrow. In CML a genetic change takes place in a early (immature) version of myeloid cells- the cel

La leucemia mieloide cronica (LMC) ¿ una forma di cancro che ha origine dalle cellule del midollo osseo che rappresentano i precursori delle cellule del sangue (piastrine, globuli rossi e globuli bian

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10009013
E.1.2	Term	Chronic myeloid leukaemia
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to assess the activity of second- line Bosutinib treatment with a dose adjustments in case of unsatisfactory response or toxicity in elderly patients with Ph+/BCR-ABL1+ CP CML, who have failed (resistance or intolerance) first-line treatment with another TKI.

L¿obiettivo primario ¿ quello di valutare l¿attivit¿ del trattamento di seconda linea con Bosutinib con un aggiustamento della dose in caso di risposta insoddisfacente o tossicit¿ in pazienti anziani affetti da CML in fase cronica (CP) Ph+/BCR-ABL1+, per i quali sia fallito (per resistenza o intolleranza) il trattamento di prima linea con un altro TKI.

E.2.2

Secondary objectives of the trial

1.To assess the response at 6 and at 12 months
2.To describe the dynamics of cytogenetic and molecular response
3.To evaluate the proportion of patients discontinuing the treatment, describing the reasons of treatment discontinuation
4.To assess the safety and tolerability
5.To assess overall survival
6.To assess progression-free survival
7.To evaluate the dose intensity and the impact of dose adjustments on efficacy, toxicity and survival outcomes
8.To analyze BCR-ABL1 mutations that develop on study
9.To assess the quality of life

1.Valutare la risposta a 6 e 12 mesi
2.Descrivere le dinamiche della risposta citogenetica e molecolare
3.Valutare la proporzione di pazienti che interrompono il trattamento, descrivendo le motivazioni dell¿interruzione.
4.Valutare sicurezza e tollerabilit¿
5.Valutare l¿Overall Survival
6.Valutare la Progression Free Survival
7.Valutare l¿intensit¿ della dose e l¿impatto di un aggiustamento della dose sull¿efficacia, la tossicit¿ e gli outcome di sopravvivenza
8.Analizzare le mutazioni BCR-ABL1 che si sviluppano in corso di studio
9.Valutare la qualit¿ della vita

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

Life quality
Version: 1.0
Date: 15/06/2016
null
Objectives: The main objective is to describe QoL patterns over time of patients undergoing second line treatment with Bosutinib, by using standard and validated QoL questionnaires.
¿ To outline the baseline patients¿ QoL and symptom profile in relation to comorbidity, socio-demographic, clinical and laboratory values (cross-sectional analyses only).
¿ To investigate the prognostic value of baseline and early changes of QoL and symptoms for treatment discontinuation and major molecular response (MMR) at 1 year.

Qualita' della vita
Versione: 1.0
Data: 15/06/2016
Titolo: Qualit¿ della vita
Obiettivi: L'obiettivo principale ¿ quello di descrivere i modelli di qualit¿ della vita nel tempo dei pazienti sottoposti a trattamento di seconda linea con Bosutinib, utilizzando questionari QoL standard e convalidati.
Descrivere la qualit¿ della vita e il profilo dei sintomi dei pazienti al basale in relazione alle comorbidit¿, valori socio-demografici, clinici e di laboratorio (solo analisi trasversale).
Studiare il valore prognostico di base e i primi cambiamenti di QoL e dei sintomi per l'interruzione del trattamento e risposta molecolare maggiore (MMR) a 1 anno.

E.3

Principal inclusion criteria

1.Molecular confirmed diagnosis of BCR-ABL1+ CML
2.Chronic phase CML (ELN 2013 criteria)
3.Age greater than or equal to 60 years
4.Prior first-line treatment with any other TKIs
5.Intolerance to prior treatment, based on investigator and patient assessment or failure of prior treatment according to any one of the ELN 2013 criteria, as listed below
• Non complete hematologic response (CHR) at 3 months
• No cytogenetic response (Ph+ > 95%) at 3 months
• Less than Partial Cytogenetic Response (PCyR) (Ph+ >35%) at 6 months
• BCR-ABL1 > 10% at 6 months
• Non complete CyR (CCyR) (Ph+ > 0) at 12 months
• BCR-ABL1 > 1% at 12 months
• Loss of CHR at any time
• Loss of CCyR at any time
• Confirmed loss of major molecular response (MMR) (BCR-ABL1 > 0.1%) in two consecutive tests, of which one > 1%, at any time
• New BCR-ABL1 Mutations at any time
• New Clonal Chromosomal Abnormalities in Ph+ cells (clonal evolution) at any time
6.An effective form of contraception from enrolment through 30 days after the end of treatment
7.Signed written informed consent according to ICH/EU/GCP and national and local laws prior to any study procedures
8.Willingness and ability to comply with scheduled visits and study procedures.

1.Diagnosi molecolare di CML BCR-ABL1+ confermata
2.CML in fase cronica (criteri ELN 2013)
3.Età maggiore o uguale a 60 anni
4.Precedente trattamento di prima linea con qualsiasi altro TKI
5.Intolleranza al trattamento precedente basato sulla valutazione dello sperimentatore e del paziente o fallimento del trattamento precedente in accordo con uno qualunque tra i criteri dell’ELN 2013 come elencato in seguito:
• Risposta ematologica (CHR) incompleta a 3 mesi
• Nessuna risposta citogenetica (Ph+ > 95%) a 3 mesi
• Risposta inferiore a quella Citogenetica Parziale (PCyR) (Ph+ >35%) a 6
mesi
• BCR-ABL1 > 10% a 6 mesi
• CyR incompleta (CCyR) (Ph+ > 0) a 12 mesi
• BCR-ABL1 > 1% a 12 mesi
• Perdita di CHR in ogni momento
• Perdita di CCyR in ogni momento
• Perdita di risposta molecolare maggiore (MMR) (BCR-ABL1 > 0.1%) confermata in due test consecutivi, uno dei quali > 1%, in ogni momento
• Nuove mutazioni di BCR-ABL1 in ogni momento
• Nuove anomalie cromosomiche nelle cellule Ph+ (evoluzione clonale) in ogni momento
6.Un metodo di contraccezione efficace dal momento dell’arruolamento fino a 30 giorni dopo la fine del trattamento.
7.Consenso informato scritto e firmato in accordo con ICH/EU/GCP e legislazioni nazionali e locali prima dell’inizio di ogni procedura di studio
8.Volontà e capacità di aderire alle visite programmate ed alle procedure dello studio.

E.4

Principal exclusion criteria

1.Accelerated or blastic phase CML (according to ELN 2013 criteria)
2.Patients with the T315I or the V299L mutation
3.Patients previously treated with 2 or more TKIs
4.Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation
5.Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
6.HBV markers positivity
7.Lack of informed consent

1.CML in fase accelerata o blastica (in accordo ai criteri dell’ELN 2013)
2.Pazienti con mutazione T315I o V299L
3.Pazienti precedentemente trattati con 2 o più TKI
4.Pazienti obbligati a ricevere cure associate alla Torsione di Punta e/o ad un prolungamento significativo del QT.
5.Qualsiasi condizione o patologia che, secondo lo sperimentatore, potrebbe compromettere la sicurezza del paziente o interferire con la valutazione del farmaco
6.Positività dei marcatori di HBV
7.Mancanza di consenso informato

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the rate of MMR (BCR-ABL1 less than or equal to 0.1% by the International Scale) at 52 weeks (1year), in elderly (= 60 years old) patients with Ph+/BCR-ABL1+ CP CML, who have failed (resistance or intolerance) first-line treatment with another TKI, with a dose adjustments in case of unsatisfactory response or toxicity.

L'endpoint primario è il tasso di MMR (BCR-ABL1 minore o uguale a 0,1% dalla scala Internationale) a 52 settimane (1 anno), in pazienti anziani (= 60 anni) con LLA Ph + / BCR-ABL1 + CP LMC, non responsivi (resistenza o intolleranza) al trattamento di prima linea con un altro TKI, con un aggiustamento della dose in caso di risposta insoddisfacente o di tossicità.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 52 weeks

A 52 settimane

E.5.2

Secondary end point(s)

1. The response rates at 6 and at 12 months
2. The dynamics of cytogenetic and molecular response by12 months3. The proportion of patients discontinuing the treatment for failure, adverse events or other reasons at 12 and 36 months
4. The type and the grade of AEs
5. Overall survival at 36 months
6. Progression-free survival at 36 months
7. The median daily dose and the proportion of patients on treatment at 200, 300, 400 mg or more daily at 6, 12 and 36 months
8. The number and type of BCR-ABL1 mutations;
9. The patient-reported quality of life and adherence to therapy at 3, 6, 12 months.

1. I tassi di risposta a 6 e a 12 mesi
2. La dinamica della risposta citogenetica e molecolare by12 months3. La percentuale di pazienti che hanno interrotto il trattamento per l'insufficienza, gli eventi avversi o per altri motivi a 12 e 36 mesi
4. Il tipo e il grado di eventi avversi
5. La sopravvivenza globale a 36 mesi
6. la sopravvivenza libera da progressione a 36 mesi
7. La dose media giornaliera e la proporzione di pazienti in trattamento a 200, 300, 400 mg o pi¿ al giorno a 6, 12 e 36 mesi
8. Il numero e il tipo di mutazioni BCR-ABL 1;
9. La qualit¿ riferito dal paziente della vita e aderenza alla terapia a 3, 6, 12 mesi.

E.5.2.1

Timepoint(s) of evaluation of this end point

At 6, 12 weeks and at the end of the study

1. Valutare la risposta a 6 e 12 mesi
2. Descrivere le dinamiche della risposta citogenetica e molecolare
3. Valutare la proporzione di pazienti che interrompono il trattamento, descrivendo le motivazioni dell¿interruzione.
4. Valutare sicurezza e tollerabilit¿
5. Valutare l¿Overall Survival
6. Valutare la Progression Free Survival
7. Valutare l¿intensit¿ della dose e l¿impatto di un aggiustamento della dose sull¿efficacia, la tossicit¿ e gli outcome di sopravvivenza
8. Analizzare le mutazioni BCR-ABL1 che si sviluppano in corso di studio
9. Valutare la qualit¿ della vita

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

Yes

E.6.10

Pharmacogenetic

Yes

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

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

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.8.2.4

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.8.5.1

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

Information not present in EudraCT

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.1.1.1

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

The patients will continue to be followed according current clinical practice

I pazienti continueranno ad essere seguiti secondo normale pratica clinica

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	G.I.M.EM.A Gruppo Italiano Malattie EMatologiche dell'Adulto
G.4.3.4	Network Country	Italy

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-13

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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