Clinical Trials Register

Summary
EudraCT Number:	2010-022945-52
Sponsor's Protocol Code Number:	ADVL0516
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2012-01-26
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2010-022945-52

A.3

Full title of the trial

A Phase 1 Study of BMS-354825 (Dasatinib) in Children with Recurrent/Refractory Solid Tumors or Imatinib Resistant Ph+ Leukemia.

A.3.1

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

Study of Dasatinib in Children with Solid Tumors or Imatinib Resistant Ph+ Leukemia

A.4.1

Sponsor's protocol code number

ADVL0516

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00316953

A.5.4

Other Identifiers

Name:

Bristol Myers Squibb

Number:

CA180-038

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/200/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Children’s Oncology Group
B.1.3.4	Country	United States
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	Children’s Oncology Group
B.4.2	Country	United States
B.4.1	Name of organisation providing support	National Cancer Institute
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	The Children's Hospital of Philadelphia
B.5.2	Functional name of contact point	Richard Aplenc, Study Chair
B.5.3	Address:
B.5.3.1	Street Address	3501 Civic Center Blvd, CTRB 10060
B.5.3.2	Town/ city	Philadelphia
B.5.3.3	Post code	PA 19104
B.5.3.4	Country	United States
B.5.4	Telephone number	1267426 7252
B.5.5	Fax number	1215590 7544
B.5.6	E-mail	raplenc@mail.med.upenn.edu

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.2.5	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/3/05/338-339
D.3 Description of the IMP
D.3.1	Product name	Dasatinib
D.3.2	Product code	BMS-354825
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	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	BMS-354825
D.3.9.4	EV Substance Code	SUB23322
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	5
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	No
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/3/05/338-339
D.3 Description of the IMP
D.3.1	Product name	Dasatinib
D.3.2	Product code	BMS-354825
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	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	BMS-354825
D.3.9.4	EV Substance Code	SUB23322
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	20
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	No
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/3/05/338-339
D.3 Description of the IMP
D.3.1	Product name	Dasatinib
D.3.2	Product code	BMS-354825
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	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	BMS-354825
D.3.9.4	EV Substance Code	SUB23322
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	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.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

Refractory solid tumors
Ph+ leukemia

E.1.1.1

Medical condition in easily understood language

Solid Tumor and Leukemia

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10034877
E.1.2	Term	Philadelphia chromosome positive
E.1.2	System Organ Class	10022891 - Investigations

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

• Describe and define the toxicities, estimate the MTD, and recommend a Phase 2 dose of dasatinib administered as an oral agent given twice daily in children with refractory solid tumors.
• Describe and define the toxicities of dasatinib administered as an oral agent given twice daily in children with imatinib resistant Ph+ leukemia.
• Characterize the PK of dasatinib in children with refractory solid tumors and imatinib resistant Ph+ leukemia.

E.2.2

Secondary objectives of the trial

• Preliminarily define the antitumor activity of dasatinib in children with refractory solid tumors within the confines of a Phase 1 study.
• Obtain pilot data on the activity of dasatinib administered in children with Ph+ leukemia.
• Determine the phosphotyrosine state of SRC and ABL substrates and correlate this with dasatinib dosage and antitumor activity (pharmacodynamics study).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Greater than 12 months and less than or equal to 21 years of age at the time of study entry
2. Histologic verification of solid tumor malignancy at original diagnosis or relapse, or had imatinib resistant Ph+ ALL, or CML. Subjects with tumors of the central nervous system were not eligible.
Imatinib resistance in Ph+ CML was defined as any of the following:
a. Increasing white blood cell (WBC) or platelet count while on imatinib therapy
b. Lack of any cytogenetic response after an adequate duration of imatinib therapy, as defined by failure to achieve a complete hematological response after 3 months of imatinib therapy OR failure to achieve a partial or complete cytogenetic response (ie, ≤ 35% Ph+) after 6 months of imatinib therapy
c. Appearance of accelerated or blastic features while on imatinib therapy
d. Reappearance of Ph+ clones after an initial complete cytogenetic response to imatinib
e. An increase in Ph+ cells of > 30% in peripheral blood or bone marrow cytogenetics while on imatinib therapy
f. Imatinib intolerance as defined by development of an AE requiring discontinuation of imatinib therapy
3. Solid tumors with measurable or evaluable disease. Leukemia with measurable disease: for subjects with CML, hematologic, cytogenetic, and molecular studies determined measurable disease. For subjects with ALL, bone marrow blast percentage determined measurable disease.
4. Current disease state for which there is no known curative therapy or one proven to prolong survival with an acceptable quality of life
5. Karnofsky score ≥ 50% for subjects > 10 years of age or Lansky score ≥ 50 for subjects ≤ 10 years of age
6. Organ function requirements
a. Adequate bone marrow function
b. Adequate renal function
c. Adequate liver function
d. Adequate cardiac function
e. Adequate pulmonary function
7. Signed subject informed consent

E.4

Principal exclusion criteria

Subjects who met any of the following criteria were excluded from the study.
1. Pregnant or breast-feeding.
2. Use of the following concomitant medications during the study:
a. Growth factors that support the number or function of platelets or white cells within 7 days of study entry
b. Another investigational drug
c. Other anticancer agents
d. Enzyme-inducing anticonvulsants
e. Antithrombotic and antiplatelet agents
f. Specific CYP3A4 inhibitors
3. Uncontrolled infection
4. Unable to swallow oral or liquid medication
5. Human immunodeficiency virus-positive subjects whose highly active antiretroviral therapy regimen could interact with dasatinib
6. Unable, in the opinion of the investigator, to comply with the safety monitoring requirements of the study

E.5 End points

E.5.1

Primary end point(s)

Safety:
Safety/toxicity is assessed by adverse events (AEs), which are graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0.

Pharmacokinetics:
Pharmacokinetics of dasatinib and BMS-582691 are derived from plasma concentration versus time. The single dose PK parameters to be assessed included:
- Cmax Maximum observed plasma concentration
- Tmax Time of maximum observed plasma concentration
- AUC(0-T) Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration
- AUC(INF) Area under the plasma concentration-time curve from time zero extrapolated to infinite time
- T1/2 Plasma half-life

E.5.1.1

Timepoint(s) of evaluation of this end point

On an ongoing basis during each course. One course of therapy is equal to 28 days. A course could be repeated every 28 days and repeated 24 times, for a total of 24 courses.

E.5.2

Secondary end point(s)

Efficacy:
Efficacy evaluations include response rate for solid tumors using Response Evaluation Criteria in Solid Tumors (RECIST) from the NCI for assessment of radiographic response. Overall response assessment is classified using computed tomography (CT) or magnetic resonance imaging (MRI).
For subjects with leukemia Ph+ CML, efficacy is determined by hematologic response (based on white blood cell [WBC] count), cytogenetic response (based on percentage of Ph+ chromosome positive metaphase cells in bone marrow), and molecular response (based on resolution of bone marrow and blood morphologic abnormalities, absence of Ph chromosome by standard cytogenetic
analysis, and absence of BCR-ABL rearrangement by reverse transcription-polymerase chain reaction [RT-PCR] analysis). For subjects with Ph+ ALL, efficacy was evaluated based on percentage of blast cells and marrow cellularity.

Pharmacodynamics:
Peripheral blood mononuclear cells were to be evaluated for phosphorylation of SRC family kinases, ABL, and their substrates and for gene expression changes. These evaluations were also to be performed on blast cells for leukemia samples collected.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of each course. One course of therapy is equal to
28 days. A course could be repeated every 28 days and repeated 24 times, for a total of 24 courses.

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

Yes

E.6.7

Pharmacodynamic

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

PK study

E.7.2

Therapeutic exploratory (Phase II)

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

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

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

The end of trial if the last patient last visit 30 days observation for toxicities.

E.8.9 Initial estimate of the duration of the trial

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

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children from 12 months to 21 years old

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

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)

Subjects proceeded to normal care or standard of care for their condition as determined by their health care provider after conclusion of trial participation.

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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