Clinical Trials Register

Summary
EudraCT Number:	2013-003250-25
Sponsor's Protocol Code Number:	B1871039
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:	2014-05-26
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

2013-003250-25

A.3

Full title of the trial

A Phase 4 Safety and Efficacy Study of Bosutinib (Bosulif®) in Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with One or More Tyrosine Kinase Inhibitors

Studio di fase 4 sull'efficacia e la sicurezza di bosutinib (Bosulif (R)) in pazienti affetti da leucemia mieloide cronica positiva per il cromosoma Philadelphia, precedentemente trattati con uno o più inibitori tirosin-chinasici

A.3.1

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

Safety and Efficacy Study of Bosutinib in Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with one or two more Tyrosine Kinase Inhibitors

Studio sulla sicurezza e l'efficacia di Bosutinib in pazienti con leucemia mieloide cronica Philadelphia positiva preccedentemente trattati con uno o più inibitori delle tirosinchinasi

A.4.1

Sponsor's protocol code number

B1871039

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

P/170/2010

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, 235 East 42nd Street, New York, NY 10017
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 Centre
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	+1800718 1021
B.5.5	Fax number	+1303739 1119
B.5.6	E-mail	ClinicalTrials.govCallCentre@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
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.3.4	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.3.9.3	Other descriptive name	BOSUTINIB MONOHYDRATE
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	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	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
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.3.4	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.3.9.3	Other descriptive name	BOSUTINIB MONOHYDRATE
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	500
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

Philadelphia Chromosome Positive Chronic Myeloid Leukaemia

E.1.1.1

Medical condition in easily understood language

Chronic Myeloid Leukaemia

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	17.0
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

Primary Objectives
•To estimate the 1-year (Week 52) probability of cumulative Major Cytogenetic Response (MCyR) in CP Ph+ CML patients with 1 or 2 prior lines of TKI therapy.
•To estimate the 1-year (Week 52) probability of cumulative MCyR in CP Ph+ CML patients with 3 or more prior lines of TKI therapy.
•To estimate the 1-year (Week 52) probability of cumulative confirmed Overall Hematological Response (OHR) in AP and BP Ph+ CML patients with any prior TKI therapy.

E.2.2

Secondary objectives of the trial

•To estimate the probability of cumulative MCyR in each disease phase (CP, AP and BP) for Ph+ CML patients.
•To estimate the probability of cumulative confirmed OHR in each disease phase (AP and BP) for Ph+ CML patients by number of lines of prior therapy.
•To characterize the distributions of best response (molecular, cytogenetic, or hematologic) in the CP, AP, and BP Ph+ CML patient populations.
•To estimate the probability of MCyR at 3, 6, 12, 18, and 24 months in the CP, AP, and BP Ph+ CML patient populations.
•To estimate the probability of confirmed OHR at 3, 6, 9, 12, 18, and 24 months in the AP and BP Ph+ CML patient populations.
•To estimate the probability of cumulative confirmed Complete Hematological Response (CHR) in the CP, AP and BP Ph+ CML patient populations.
•To estimate the probability of cumulative major molecular response (MMR) in the CP, AP and BP Ph+ CML patient populations.
•To evaluate the overall safety profile of bosutinib in the study population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Cytogenetic or PCR-based diagnosis of Ph+ CML or BCR-ABL1+ if Ph- (from initial diagnosis). NOTE: Ph- subjects will not count towards the 150 patients for primary and secondary analyses, which include Ph+ patients only.
2. Prior treatment with 1 or more TKIs for CML.
3. Any CML phase, as long as the patient is resistant to, intolerant of, or otherwise not appropriate for treatment with imatinib, dasatinib and/or nilotinib.
4. ECOG Performance Status of 0 or 1 for CP patients, or 0, 1, 2, or 3 for 4th line CP (and beyond) and AP/ BP patients.
5. Adequate bone marrow function:
For 2nd and 3rd line CP CML patients:
(1) Absolute neutrophil count >1000/mm3 (>1 x109/L).
(2) Platelets ≥75,000/mm3 (≥75 x109/L) absent any platelet transfusions during the preceding 14 days.
For 4th line CP and AP/BP CML patients:
(1) Absolute neutrophil count >500/mm3 (>0.5 x109/L).
(2) Platelets ≥50,000/mm3 (≥50 x109/L) absent any platelet transfusions during the preceding 14 days.
6. Adequate hepatic and renal function:
(a) AST/ALT ≤2.5 x ULN or ALT/AST ≤5 x ULN if attributable to liver involvement of leukaemia.
(b) Total direct bilirubin ≤1.5 x ULN.
(c) Creatinine ≤1.5 x ULN.
7. Able to take daily oral tablets.
8. Age ≥18 years.
9. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
10. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
11. Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

E.4

Principal exclusion criteria

1. Participation in other studies involving investigational drug(s) (Phase 1-4) within 14
days or 3 half-lives (whichever is longer) prior to the first dose of bosutinib.
2. Prior bosutinib exposure.
3. Prior ponatinib exposure.
4. Known T315I or V299L mutation in BCR-ABL1.
5. Clinically active leptomeningeal leukemia. Patients must be free of central nervous system (CNS) involvement for a minimum of 2 months.
6. Hypersensitivity to the active substance or to any of the following excipients:
Microcrystalline cellulose (E460), Croscarmellose sodium (E468), Poloxamer 188, Povidone (E1201), Magnesium stearate (E470b), Polyvinyl alcohol, Titanium dioxide (E171), Macrogol 3350, Talc (E553b), Iron oxide red (E172).
7. Pregnant or breastfeeding females.
8. Males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product.
9. 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 patient inappropriate for entry into this study.
10. Patients 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 patients who are Pfizer employees directly involved in the conduct of the trial.

E.5 End points

E.5.1

Primary end point(s)

(1) Cumulative MCyR by 1 year (52 weeks) in 2nd and 3rd line CP patients.
(2) Cumulative MCyR by 1 year (52 weeks) in 4th and later line CP patients.
(3) Cumulative confirmed OHR by 1 year (52 weeks) in AP and BP patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year (52 weeks)

E.5.2

Secondary end point(s)

(1) Cumulative MCyR in CP, AP and BP patients.
(2) Cumulative confirmed OHR in AP and BP patients by line of therapy.
(3) Cumulative best response in CP, AP, and BP patients.
(4) MCyR at 3, 6, 12, 18, and 24 months in CP, AP, and BP patients.
(5) Confirmed OHR at 3, 6, 9, 12, 18, and 24 months in AP and BP patients.
(6) Cumulative confirmed CHR.
(7) Cumulative MMR in CP, AP, and BP patients.

E.5.2.1

Timepoint(s) of evaluation of this end point

Various timepoints mainly 3, 6, 12, 18 and 24 months. See Table 1, schedule of activities in protocol.

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Post Marketing Study for Safety and Efficacy

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

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

Austria

Belgium

Finland

France

Germany

Italy

Netherlands

Norway

Spain

Sweden

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

Last Subject Last Visit

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

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:

132

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

120

F.4.2.2

In the whole clinical trial

165

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)

Study B1871039 is a research study. The study drug Bosutinib and the study defined medical care will only be given to the subjects during the study.

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

2014-06-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-06-10

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

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