Clinical Trials Register

Summary
EudraCT Number:	2013-000077-68
Sponsor's Protocol Code Number:	CAMN107ADE18T
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
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

Germany - BfArM

A.2

EudraCT number

2013-000077-68

A.3

Full title of the trial

Imatinib continuation versus Nilotinib 300 mg twice daily in patients with chronic myeloid leukemia (CML) in chronic phase and major molecular response (MMR) without molecular response ≥ 4.5 log (MR4.5) receiving Imatinib at a dose of 400 to 800 mg daily. An open-label, randomised multicenter phase 3b study to determine the confirmed rate of molecular response ≥ 4 log (MR4) at two years

A.3.1

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

Imatinib continuation versus Nilotinib 300 mg twice daily in patients with chronic myeloid leukemia (CML) in chronic phase and major molecular re-sponse (MMR) without molecular response ≥ 4.5 log (MR4.5) receiving Imatinib at a dose of 400 to 800 mg daily. An open-label, randomised multicenter phase 3b study to determine the confirmed rate of molecular response ≥ 4 log (MR4) at two years

A.3.2

Name or abbreviated title of the trial where available

DECLINE

A.4.1

Sponsor's protocol code number

CAMN107ADE18T

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02174445

A.5.4

Other Identifiers

Name:

DRKS

Number:

DRKS00006285

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	Medical Center - University of Freiburg
B.1.3.4	Country	Germany
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	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Freiburg
B.5.2	Functional name of contact point	Clinical Trials Unit
B.5.3	Address:
B.5.3.1	Street Address	Elsässer Str. 2
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79106
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049761270-72110
B.5.5	Fax number	0049761270-74250
B.5.6	E-mail	nadine.roethling@uniklinik-freiburg.de

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 Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nilotinib
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.3.9.4	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	Comparator
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	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Imatinib
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.3.9.1	CAS number	152459-95-5
D.3.9.3	Other descriptive name	IMATINIB
D.3.9.4	EV Substance Code	SUB25387
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	400
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) in 1st chronic phase and confirmed major molecular response (MMR)

E.1.1.1

Medical condition in easily understood language

chronic myeloid leukemia (CML) in 1st chronic phase and confirmed major molecular response (MMR)

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10009700
E.1.2	Term	CML
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10066506
E.1.2	Term	CML progression
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Goal of the study is to investigate whether in patients with CML in chronic phase and confirmed MMR without MR4.5 receiving Imatinib at 400 to 800 mg daily a switch to Nilotinib at 300 mg twice daily results in a higher proportion of patients with con-firmed MR4 after two years of study treatment when compared with patients who continue receiving Imatinib (400 to 800 mg daily).

E.2.2

Secondary objectives of the trial

To determine
-the cumulative incidence of MR4 and MR4.5 after one and two years of study treatment
-and the proportion of patients with MR4 and MR4.5 lasting for at least two years
-and the kinetics of BCR-ABL transcript levels over time
-and the proportion of patients with confirmed MR4 two years after cross-over from Imatinib to Nilotinib in patients failing the primary endpoint in the Imatinib arm
-and whether baseline clinical data are informative with respect to achievement of confirmed MR4
-and changes in the health-related Quality of Life

-To investigate the predictive value of a previously developed mathematical model of CML treatment with respect to the patient-specific probability of reaching confirmed MR4 under continuous Imatinib
-To collect data to establish a mathematical model regarding the prediction accuracy of the molecular relapse probability after treatment discontinuation (to be validated in DECLINEplus)
-Study drug compliance

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed written informed consent
2. Male or female patients aged ≥18 years (without upper limit of age)
3. ECOG performance status of 0 to 2
4. CML in chronic phase, with chronic phase defined as blasts < 15% in blood and/or bone marrow and peripheral blood basophils < 20% and platelets ≥ 100 G/L
5. Pretreatment with Imatinib with a treatment duration of at least 18 months at a dosage of 400 to 800 mg daily
6. Major molecular response (MMR) without molecular response ≥ 4.5 log (MR4.5), i.e. BCR-ABL>0.0032% and ≤0.1% IS confirmed by central laboratory at screen-ing will be required for randomisation
7. Patients must have a serum Creatinine of ≤ 1.5 x ULN, SGOT ≤ 1.5 x ULN, total bilirubin ≤ 1.5 x ULN (except known M. Gilbert), and Lipase ≤ 1.5 x ULN
8. Women of child-bearing potential defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months, must have a negative serum pregnancy test during screening period. Male and female patients of reproductive potential must agree to employ highly effective methods of birth control throughout the study and for up to 3 months following discontinuation of study drug. Appropriate methods are e.g. a highly effective method of first choice, i.e. a method with a low failure rate (less than 1% per year) like sexual abstinence, combined oral contraceptives, implants, injectable, some Intra Uterine Devices (IUDs), vasectomized partner, in combination with a method of second choice like condom, diaphragm, or cup pessary with spermicidal foam/gel/film/cream/suppository.

E.4

Principal exclusion criteria

1. Any previous treatment for CML other than Hydroxyurea, Imatinib or Interferon alpha
2. Evidence of features of accelerated or blast phase at any time (by European Leu-kemia Net; at least one crit.)
• Accelerated phase:
o Blasts in blood or marrow 15-29%, or blasts plus promyelocytes in blood or marrow >30% with blasts <30%
o Basophils in blood ≥20%
o Persistent thrombocytopenia (<100 × 109/L) unrelated to therapy
o Clonal chromosome abnormalities in Ph+ cells (CCA/Ph+), major route, on treatment
• Blast phase
o Blasts in blood or marrow ≥30%
o Extramedullary blast proliferation, apart from spleen
3. Previous loss of hematologic or cytogenetic response
4. Concomitant medications known to be strong inducers or inhibitors of P450 Iso-enzyme CYP3A4 (see Cytochrome P450 Drug Interaction Table under www.drug-interactions.com)
5. Finding of a secondary BCR-ABL resistance mutation at any time
6. History of intolerance to Imatinib that required treatment interruption longer than 4 weeks (cumulative) or dose reductions to less than 400 mg daily for longer than 4 weeks (cumulative) during the last 12 months before informed consent
7. Patients who had prior allogeneic, syngeneic or autologous bone marrow trans-plant or stem cell transplant
8. Patients unwilling to or unable to comply with the planned therapeutic intervention or to comply with the study treatment visits including blood sample collection with-in the protocol
9. History of pancreatitis, chronic inflammatory diseases or autoimmune diseases
10.Patients who underwent solid organ transplantation
11.Impaired cardiac function, including any of the following:
• History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemi block, bifascicular block in screening ECG
• Use of a cardiac pacemaker
• ST depression of > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG
• Congenital long QT syndrome
• QTc> 450 msec in the screening ECG
• QT prolonging concomitant medication
• History of or presence of significant ventricular or atrial tachyarrhythmia in screening ECG
• History of or presence of clinically significant resting bradycardia (< 50 beats per minute)
• Myocardial infarction within 12 months prior to informed consent
• Unstable angina diagnosed or treated during the past 12 months before in-formed consent
• Other clinically significant heart disease (e.g., congestive heart failure, uncon-trolled hypertension, history of labile hypertension)
12.Known HIV and/or hepatitis B or C infection (testing is not mandatory)
13.Other malignancies within the past 3 years before informed consent except for adequately treated carcinoma of the cervix and basal or squamous cell carcinoma of the skin
14.Women who are pregnant or breast feeding
15.Male/female patients of reproductive potential unwilling to practice a highly effec-tive method of birth control
16.History of noncompliance to medical regimens
17.Treatment with another investigational product during this study or during the last 30 days prior to informed consent

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with confirmed MR4 at two years of study treatment in both treatment arms. Confirmed MR4 at two years is defined as either BCR-ABL ≤ 0.01% IS at 21 and 24 months or BCR-ABL ≤ 0.01% IS at 24 months and confirmation with-in six weeks.

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 21 and 24

E.5.2

Secondary end point(s)

• Cumulative incidence of confirmed MR4 after two years of study treatment. Confirmed MR4 is defined as BCR-ABL ≤ 0.01% IS at two consecutive time points
• Cumulative incidence of MR4and MR4.5 after one and two years of study treat-ment
• Proportion of patients with MR4 lasting for at least one year, defined as BCR-ABL ≤ 0.01% IS in at least three out of four consecutive 3-monthly measure-ments with first and last measurement showing MR4
• Proportion of patients with MR4 lasting for at least two years, defined as BCR-ABL ≤ 0.01% IS in at least six out of eight consecutive 3-monthly measure-ments with first and last measurement showing MR4
• Proportion of patients with MR4.5 lasting for at least one year, defined as BCR-ABL ≤ 0.0032% IS in at least three out of four consecutive 3-monthly meas-urements with first and last measurement showing MR4,5
• Proportion of patients with MR4.5 lasting for at least two years, defined as BCR-ABL ≤ 0.0032% IS in at least six out of eight consecutive 3-monthly measure-ments with first and last measurement showing MR4,5
• Kinetics of BCR-ABL transcript levels over time
• Proportion of patients with confirmed MR4 two years after cross-over from Imatinib to Nilotinib in patients failing the primary endpoint in the Imatinib arm (patients failing to achieve confirmed MR4 two years after randomisation and continued treatment with Imatinib)
• Analysis of baseline clinical data which are informative with respect to achievement of confirmed MR4
• Application of a previously developed mathematical model to predict the pa-tient-specific probability of reaching confirmed MR4 under continuous Imatinib
Study Code: DECLINE CAMN107ADE18T
Version 3.0, 11.09..2015 Page 28 of 67
• To establish a mathematical model to predict molecular relapse probability af-ter treatment discontinuation (to be validated in DECLINEplus)
• Analysis of changes in the health-related Quality of Life (EORTC-QLQ-C30, EORTC-QLQ-CML24)
• Study drug compliance (patient diary)

E.5.2.1

Timepoint(s) of evaluation of this end point

see above, point E.5.2

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

E.6.5

Efficacy

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

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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.8.6 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

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

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:

100

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

132

F.4.2

For a multinational trial

F.4.2.1

In the EEA

132

F.4.2.2

In the whole clinical trial

132

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)

Further treatment is at the discretion of the investigator (local practice).

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

2013-08-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-09-18

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