Clinical Trials Register

Summary
EudraCT Number:	2012-004092-40
Sponsor's Protocol Code Number:	CAMN107I2201
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-04-22
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2012-004092-40

A.3

Full title of the trial

A single-arm, multicenter, nilotinib treatment-free remission study in patients with BCR-ABL1 positive Chronic Myelogenous Leukemia in chronic phase who have achieved durable minimal residual disease (MRD) status on first line nilotinib treatment

Et enkeltarmet multicenter forsøg vedrørende nilotinib-behandlingsfri remission hos patienter med BCR-ABL1 positiv kronisk myeloid leukæmi i kronisk fase, der har opnået vedvarende minimal resterende sygdom (MRD) på første linje nilotinib-behandling (EnestFreedom)

A.3.1

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

A clinical research study evaluating the possibility to suspend the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients who have very small amount of leukemia cells remaining after nilotinib (Tasigna) treatment.

A.4.1

Sponsor's protocol code number

CAMN107I2201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01784068

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	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 Healthcare A/S
B.5.2	Functional name of contact point	Klinisk Forskningsafdeling
B.5.3	Address:
B.5.3.1	Street Address	Edvard Thomsens Vej 14
B.5.3.2	Town/ city	København S
B.5.3.3	Post code	2300
B.5.3.4	Country	Denmark
B.5.6	E-mail	skriv.til@dkma.dk

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.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

Adult patients treated with a planned dose of nilotinib 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of tolerance) for a minimum of 2 calendar years for newly diagnosed BCR-ABL positive Chronic Myelogenous Leukemia in chronic phase and have achieved MR 4.5 (BCR-ABL ≤ 0.0032% IS) at any time point before being enrolled in the study

E.1.1.1

Medical condition in easily understood language

Adult patients with CML who have been treated with nilotinib (Tasigna) for at least two years and who have achieved a certain level of molecular response prior to study entry.

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10054352
E.1.2	Term	Chronic phase chronic myeloid leukemia
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

To determine the percentage of patients who are in Major Molecular Response (MMR) at 48 weeks after starting the treatment-free remission (TFR) phase (patients who required re-initiation of treatment will be considered as non-responders)

E.2.2

Secondary objectives of the trial

1) To determine the percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
2) To determine the percentage of patients who are in MMR at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
3) To determine the percentage of patients who are in MR4.5 at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
4) To determine the percentage of patients in MMR at 48, 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib irrespective of whether or not patients required reinitiation of treatment
Additional objectives apply

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
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following criteria; additional inclusion criteria may apply as per protocol:
1) Male or female patients ≥18 years of age
2) Minimum of 2 calendar years of nilotinib treatment with at least the
last 12 months of nilotininb treatment prior to pre-screening at the
approved total daily dose of 600 mg or at a reduced dose of 400 mg QD if
required from the perspective of tolerance for BCR-ABL positive CML in
documented chronic phase at the time of diagnosis
3) Evidence of typical BCR-ABL transcripts [b3a2 (e14a2) and/or b2a2
(e13a2)] at the time of CML-CP diagnosis i.e. prior to first start of TKI
treatment which are amenable to standardized RT-PCR quantification"
4) Patient in MR4.5 at prescreening at Novartis designated lab
5) ECOG performance status of 0-2
6) Adequate end organ function as defined by:
• Direct bilirubin ≤ 1.5 x ULN, except for i) patients with documented
Gilbert's syndrome for whom any bilirubin value is allowed and ii) for
patients with asymptomatic hyperbilirubinemia (liver transaminases and
alkaline phosphatase within normal range)
• SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCICTCAE
v.4.03
• Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03
• Alkaline phosphatase ≤ 2.5 x ULN
• Serum creatinine < 1.5 x ULN
7) Patients must have the following electrolyte values within normal
limits or corrected to be within normal limits with supplements prior to
first dose of study medication:
• Potassium (suggested keep to prevent issues with QT and/or rhythm
abnormalities)
• Magnesium (suggested keep to prevent issues with QT and/or rhythm
abnormalities)
• Total calcium (corrected for serum albumin)
8) Patients must have normal marrow function as defined:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• Platelets ≥ 100 x 109/L
Additional inclusion criteria are defined in the protocol.

E.4

Principal exclusion criteria

criteria:
1) Previous treatment with BCR-ABL inhibitors other than nilotinib for
more than a total cumulative duration of 4 weeks
2) Previous treatment with alpha-interferon of any duration
3) Previous anticancer agents for CML other than nilotinib except for
cytoreduction after CML diagnosis until up to 4 weeks after first dose of
nilotinib
4) Known second chronic phase of CML after previous progression to
AP/BC
5) Poorly controlled diabetes mellitus (defined as HbA1c > 9%)
6) Impaired cardiac function as defined in the protocol
7) History of acute pancreatitis within 1 year of study entry or past
medical history of chronic pancreatitis
8) Known presence of significant congenital or acquired bleeding
disorder unrelated to cancer
9) History of another active malignancy within 5 years prior to study
entry with the exception of previous or concomitant basal cell skin
cancer and previous carcinoma in situ treated curatively
10) Treatment with other investigational agents (defined as not used in
accordance with the approved indication) within 4 weeks of Day 1
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11) Patients actively receiving therapy with strong CYP3A4 inhibitors
and/or inducers, and the treatment cannot be either discontinued or
switched to a different medication prior to starting study drug.
12) Patients actively receiving therapy with herbal medicines that are
strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be
either discontinued or switched to a different medication prior to
starting study drug. These herbal medicines may include Echinacea,
(including E. purpurea, E. angustifolia and E. pallida), Piperine,
Artemisinin, St. John's Wort, and Ginkgo.
13) Patients who are currently receiving treatment with any medications
that have the potential to prolong the QT interval and the treatment
cannot be either safely discontinued or switched to a different
medication prior to starting study drug. (Please see
http://crediblemeds.org/everyone/composite-list-all-qtdrugs/ for a list
of agents that prolong the QT interval)
14) 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, malabsorption syndrome, small
bowel resection, or gastric bypass surgery)
15) Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.
16) Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception during the study and for 14
days after the final dose of nilotinib. Highly effective contraception is
defined in the protocol.
Additional exclusion criteria are defined in the protocol.

E.5 End points

E.5.1

Primary end point(s)

BCR-ABL ≤ 0.1% IS (MMR or MR3) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks after starting the TFR phase

E.5.2

Secondary end point(s)

1) BCR-ABL ≤ 0.0032% IS (MR4.5) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
2) BCR-ABL ≤ 0.1% IS (MMR) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks , and in the firsts 6, 7, 8, 9, and 10 years after starting the TFR phase.
3) BCR-ABL ≤ 0.0032% IS (MR4.5) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks, and in the first 6, 7, 8, 9, and 10 years after starting the TFR phase.
4) BCR-ABL ≤ 0.1% IS (MMR) at 48, 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 48 weeks after starting the TFR phase
2) - 4) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

117

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

Argentina

Colombia

China

Japan

United Kingdom

United States

Austria

Belgium

Bulgaria

Denmark

France

Germany

Greece

Hungary

Ireland

Italy

Netherlands

Poland

Spain

Sweden

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

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

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:

171

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

180

F.4.2.2

In the whole clinical trial

215

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)

All patients still on study treatment at the time of End of Study, or if the study is stopped early, will be transitioned to prescribed nilotinib. Should nilotinib not be commercially available Novartis will have a transition plan in place to ensure that patients continue to have access to nilotinib without any interruption in treatment. Any patients who are in TFR at the End of the Study will be referred to their primary oncologist for continued monitoring of their level of BCR-ABL transcript.

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

2013-04-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-08

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
Orphan Designation Number:
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