Clinical Trials Register

Summary
EudraCT Number:	2013-000200-41
Sponsor's Protocol Code Number:	CAMN107A2203
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-21
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2013-000200-41

A.3

Full title of the trial

A multi-center, open label, non-controlled phase II study to evaluate efficacy and safety of oral nilotinib in pediatric patients with newly diagnosed Ph+ chronic myelogenous leukemia (CML) in chronic phase (CP) or with Ph+ CML in
CP or accelerated phase (AP) resistant or intolerant to either imatinib or dasatinib

A.3.1

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

Open label, phase II study to evaluate efficacy and safety of oral nilotinib in Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) pediatric patients.

A.4.1

Sponsor's protocol code number

CAMN107A2203

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/297/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Hungary Kft.
B.5.2	Functional name of contact point	Public Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Bartók Béla út 43-47
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1114
B.5.3.4	Country	Hungary
B.5.4	Telephone number	00 36 1 457-6500
B.5.5	Fax number	00 36 1 457-6600
B.5.6	E-mail	infoph.hungary@novartis.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	Tasigna
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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/3/06/375
D.3 Description of the IMP
D.3.1	Product name	nilotinib
D.3.2	Product code	AMN107
D.3.4	Pharmaceutical form	Capsule, hard
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	NILOTINIB
D.3.9.1	CAS number	641571-10-0
D.3.9.2	Current sponsor code	AMN107
D.3.9.4	EV Substance Code	SUB25225
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	150
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	Tasigna
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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/3/06/375
D.3 Description of the IMP
D.3.1	Product name	nilotinib
D.3.2	Product code	AMN107
D.3.4	Pharmaceutical form	Capsule, hard
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	NILOTINIB
D.3.9.1	CAS number	641571-10-0
D.3.9.2	Current sponsor code	AMN107
D.3.9.4	EV Substance Code	SUB25225
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	200
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/3/06/375
D.3 Description of the IMP
D.3.1	Product name	nilotinib
D.3.2	Product code	AMN107
D.3.4	Pharmaceutical form	Capsule, hard
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	NILOTINIB
D.3.9.1	CAS number	641571-10-0
D.3.9.2	Current sponsor code	AMN107
D.3.9.4	EV Substance Code	SUB25225
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

- leukemia
- leukemia,pediatric
- leukemia, myleiod
- leukemia, mylegenous, chronic
- leukemia, mylegenous, accelerated
- BCR-ABL positive
- myeloproliferative disorder
- bone marrow disease
- hematologic diseases
- neoplastic processes

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	19.1
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

1. To assess efficacy of nilotinib in pediatric patients with Ph+ CML-CP resistant or intolerant to either imatinib or dasatinib
2. To assess efficacy of nilotinib in pediatric patients with Ph+ CML-AP resistant or intolerant to either imatinib or dasatinib
3. To assess efficacy of nilotinib in pediatric patients with newly diagnosed Ph+ CML-CP

E.2.2

Secondary objectives of the trial

1. To further characterize efficacy and PK profile of nilotinib in pediatric patients with Ph+ CML
2. To further characterize safety and tolerability of nilotinib in pediatric patients with Ph+ CML
3. To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML
4. To identify emerging signs of resistance to nilotinib
5. To describe acceptability of the study drug formulation

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients from 1 year of age to less than 18 years of age at study entry
2. Newly diagnosed Ph+ CML-CP or Ph+ CML-CP or AP resistant or intolerant to either imatinib or dasatinib (as defined in the protocol)
3. Performance status: Karnofsky ≥50% for patients >10 years of age, and Lansky ≥50 for patients ≤10 years of age.
4. Adequate renal, hepatic and pancreatic function as defined in the protocol
5. Patients must have potassium, magnesium, phosphorus and total calcium values ≥LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication
6. Written informed consent prior to any screening procedures. However, if requested tests were performed as part of clinical practice within the window required per protocol, this data can be used provided all parameters required per protocol were verified.

E.4

Principal exclusion criteria

Patients eligible for this study must not meet any of the following criteria:
1. Female patients who are : (a) pregnant, (b) of childbearing potential without a negative hCG pregnancy test prior to baseline and (c) female of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of highly effective contraception
2. Patients actively receiving therapy with strong CYP3A4 inhibitors or inducers and the treatment cannot be either discontinued or switched to a different medication at least 14 days prior to starting study drug
3. Patients who are currently receiving treatment with any medications that have a known risk or possible risk to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
4. Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML
5. History of pancreatitis within 12 months of starting study drug or past medical history of chronic pancreatitis
6. Active or systemic bacterial, fungal, or viral infection as documented by positive cultures, radiological imaging techniques, or septic shock syndrome. Such infections should have been resolved for ≥2 weeks before including the patient in the study
7. Impaired cardiac function as defined in the protocol
8. Patients with documented T315I mutation in BCR-ABL
9. Previous treatment with more than one TKI for imatinib or dasatinib resistant/intolerant Ph+ CML patients. Previous treatment with any TKI for newly diagnosed Ph+ CML patients is not permitted unless the patient has received imatinib for less than 2 weeks prior to the first dose of study drug and discontinued at least 5 days prior to the first dose of nilotinib.
10. Patients who have received myelosuppressive chemotherapy within 3 weeks, imatinib within 5 days, or dasatinib within 3 days prior to the first dose of study drug
11. Patients who have not recovered from all acute toxicities from all prior myelosuppressive chemotherapy prior to starting study drug
12. Patients receiving hydroxyurea greater than 21 days for the treatment of Ph+ CML either prior to initiation of nilotinib or with maximum duration planned to exceed one week post initiation of nilotinib
13. Patients who have received hematopoietic growth factors within 7 days prior to starting study drug
14. Patients who have received Pegfilgrastim (Neulasta®) within 14 days prior to starting study drug
15. In case of Stem Cell Transplant (SCT) or Rescue without total body irradiation (TBI):
Evidence of either active graft vs. host disease or less than 3 months since SCT.
16. In case of radiation therapy: less than 2 weeks if local palliative, less than 3 months after total body irradiation (TBI), or craniospinal radiation therapy or if at least 50% radiation of pelvis; less than 6 weeks after other substantial BM radiation
17. Patients with known Hepatitis B, Hepatitis C, or HIV infection
18. Patients who, in the opinion of the investigator, are unlikely to comply with the protocol or safety monitoring requirements
19. Patients who are breast feeding
20. Patients who have a known hypersensitivity to the active ingredient or any of the excipients including lactose
21. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, mal-absorption, small bowel resection, or gastric bypass surgery)
22. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g., diabetes, infection, febrile neutropenia etc.).

E.5 End points

E.5.1

Primary end point(s)

1. Rate of Major Molecular Response (MMR)
2. Rate of Complete Hematological Response (CHR)
3. Rate of Major Molecular Response (MMR)
4. Rate of Complete Cytogenetic Response (CCyR)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. At 6 cycles
2. By 3 cycles
3. By 12 cycles
4. At 12 cycles

E.5.2

Secondary end point(s)

1. Rate of MCyR and CCyR
2. Rate of each cytogenetic response category
3. Rate of MMR and CHR
4. Time to response, duration of response, time to disease progression, overall survival, event free survival
5. Population pharmacokinetic parameters of nilotinib
6. Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood)
7. Safety and tolerability: incidence and severity of adverse events, as assessed by patient symptoms, physical exam assessments, abnormal laboratory tests, echocardiograms and electrocardiograms
8. Assessment of development (growth and sexual maturation), and
thyroid function
9. Mutational assessment of BCR-ABL
10.Questionnaire on acceptability (including palatability) of dose forms used after first dose, cycle 1 and cycle 12

E.5.2.1

Timepoint(s) of evaluation of this end point

1. By 6, 12, 18, 24, 36, 48, and 66 cycles
2. By 6, 12, 18, 24, 36, 48, and 66 cycles
3. By 3, 6, 9, 12, 18, 24, 36, 48, and 66 cycles
4. Up to 66 cycles
5. Up to 66 cycles
6. Continuous
7. Up to 66 cycles
8. Up to 66 cycles
9. Up to 66 cycles
10. After 1st dose, cycle 1, and cycle 12

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

acceptability of study drug formulation (including palatability)

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

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

Canada

France

Germany

Hungary

Italy

Japan

Korea, Republic of

Malaysia

Netherlands

Russian Federation

Spain

Thailand

Turkey

United Kingdom

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

End of study is defined as the timepoint when all patients have completed the Study Evaluation Completion (SEC) visit. The SEC will either be a minimum of 30 days post Cycle 66 or a minimum of 30 days post early discontinuation.

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

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)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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 eligible to continue to a roll-over or alternative study protocol in order to collect further safety data and allow patients to receive treatment with nilotinib for as long as they continue to demonstrate benefit, do not experience unacceptable toxicities, or until nilotinib is commercially available in pediatric patients.

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

2013-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-08-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-08-28

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