Clinical Trials Register

Summary
EudraCT Number:	2010-024262-22
Sponsor's Protocol Code Number:	CML-V
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-09-13
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

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2010-024262-22

A.3

Full title of the trial

Treatment optimization of newly diagnosed Ph/BCR-ABL positive patients with chronic myeloid leukemia (CML) in chronic phase with nilotinib vs. nilotinib plus interferon alpha induction and nilotinib or interferon alpha maintenance therapy.

Optimalizace léčby pacientů s nově diagnostikovanou Ph/BCR-ABL pozitivní chronickou myeloidní leukémií (CML) v chronické fázi srovnávající nilotinib versus nilonitib a interferon alfa v indukční léčbě a nilotinib versus interferon alfa v udržovací terapii.

A.3.1

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

Attempt of treatment optimization of newly diagnosed Ph/BCR-ABL positive patients with chronic myeloid leukemia (CML) in chronic phase: initially with a combination of nilotinib and interferon alpha followed by a nilotinib or interferon alpha maintenance therapy

Hodnocení optimalizace léčby pacientů s nově diagnostikovanou Ph/BCR-ABL pozitivní chronickou myeloidní leukémií (CML) v chronické fázi. Je sledována úvodní léčba, kde je porovnáván nilotinib versus nilonitib a interferon alfa a udržovací léčba, kde je porovnán nilotinib versus interferon alfa.

A.3.2

Name or abbreviated title of the trial where available

Tasigna and Interferon alpha evaluation initiated by the German CML Study Group – the TIGER study

A.4.1

Sponsor's protocol code number

CML-V

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	Friedrich-Schiller-Universität Jena
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	MSD SHARP & DOHME 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	Universitätsklinikum Jena
B.5.2	Functional name of contact point	CML V Information
B.5.3	Address:
B.5.3.1	Street Address	Erlanger Allee 101
B.5.3.2	Town/ city	Jena
B.5.3.3	Post code	07747
B.5.3.4	Country	Germany
B.5.6	E-mail	Andreas.Hochhaus@med.uni-jena.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	PegIntron
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited, Hoddesdon
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Peginterferon alpha-2b
D.3.2	Product code	L03AB10
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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 Ltd., Horsham, West Sussex
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 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	Yes
D.2.1.1.1	Trade name	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd., Horsham, West Sussex
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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 phase CML

chronická fáze chronické myeloidní leukémie

E.1.1.1

Medical condition in easily understood language

patients with CML in chronic phase

pacienti v chronické fázi chronické myeloidní leukémie

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10009700
E.1.2	Term	CML
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Co-primary objectives are:
1. To evaluate the rate of MMR at 18 months of nilotinib 300 mg BID monotherapy vs. nilotinib 300 mg BID + pegylated interferon alpha (Peginterferon alpha-2b)
2. To evaluate the rate of continuous MMR after discontinuation of nilotinib vs. interferon alpha.

Ko-primární cíle jsou:
1. Zhodnocení podílu velkých molekulárních odpovědí (major molecular response, MMR) v 18 měsících (nilotinib versus nilotinib + pegylovaný interferon-α (INF)
2. Zhodnocení podílu přetrvávajících MMR po vysazení udržovací terapie nilotinibem versus pegylovaným interferonem-α2b

E.2.2

Secondary objectives of the trial

To evaluate
1. Rate of CCyR and MMR by 12, 18 and 24 months
2. Time to CCyR, MMR, MR4 and MR4.5
3. Rate of MR4 and MR4.5 during maintenance therapy and after discontinuation
4. Progression-Free Survival and Overall Survival at 12, 24, and 60 months of treatment
5. Rate of patients off treatment for at least 6 months at 60 months after start of treatment: all patients and comparison of treatment arms
6. Safety and tolerability profile of nilotinib in comparison with
nilotinib + IFN and IFN
7. Patients compliance to nilotinib based therapies
8. Quality of life during induction therapy with nilotinib vs. nilotinib + IFN and during maintenance therapy with nilotinib vs. IFN.
9. Pharmacoeconomics of the treatment strategies.

1. Zhodnocení podílu pacientů v CCgR a MMR ve 12, 18 a 24 měsících od zahájení léčby
2. Zhodnocení doby do dosažení CCgR, MMR, MR4 a MR4,5
3. Zhodnocení podílu pacientů s MR4 a MR4,5 během udržovací terapie a po jejím vysazení
4. Zhodnocení PFS a OS ve 12, 24 a 60 měsících od zahájení terapie
5. Zhodnocení podílu pacientů s vysazenou léčbou v délce alespoň 6 měsíců v 60 měsících od startu léčby
6. Zhodnocení bezpečnosti a tolerance terapie nilotinibem vs. nilotinibem + INF a INF
7. Zhodnocení compliance pacientů k terapii nilotinibem
8. Zhodnocení kvality života v jednotlivých léčebných ramenech
9. Zhodnocení farmakoekonomiky jednotlivých typů léčby

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome [t(9;22)(q34;q11)].
• Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR(Cross, et al 1994)are eligible as well.
• ECOG performance status of <2.
• Pretreatment with hydroxyurea for 6 months and imatinib or nilotinib for a duration of up to 6 weeks is permitted.
• Age ≥ 18 years old (no upper age limit given)
• Normal serum levels ≥LLN (lower limit of normal) of potassium, magnesium, total calcium, or corrected to within normal limits with supplements.
• ASAT and ALAT ≤ 2.5 x ULN (upper limit of normal) or ≤ 5.0 x ULN if considered due to leukemia
• Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia
• Total bilirubin ≤ 1.5 x ULN, except known Mb. Gilbert
• Serum lipase and amylase ≤ 1.5 x ULN
• Serum creatinine ≤ 2 x ULN
• Written informed consent prior to any study procedures being performed.

- Pacienti s Ph a/nebo BCR-ABL pozitivní CML v CP, do 6 měsíců od stanovení dg. a do 6 týdnů od zahájení terapie imatinibem či nilotinibem
- Věk ≥ 18 let
- ECOG <2
- Bilirubin < 1,5 x ULN; AST a ALT < 2,5 x ULN; kreatinin < 2 x ULN; sérová amyláza a lipáza ≤ 1,5 x ULN; ALP ≤ 2,5 x ULN
- Normální hodnoty sérového kalia, magnézia, celkového vápníku, či po korekci suplementy na normální hodnoty
- Podepsaný informovaný souhlas
- Žádné známky extramedulárního leukemického postižení (s výjimkou hepatosplenomegalie)

E.4

Principal exclusion criteria

• Known impaired cardiac function, including any of the following:
- Left ventricular ejection fraction (LVEF)< 45%
- Congenital long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia (< 50 beats per minute)
• QTc>450 msec on screening ECG. If QTc > 450 ms and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTc criterion.
• Myocardial infarction within 12 months prior to starting therapy.
• Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
• History of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
• Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled.
• Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
• Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
• Concomitant medications with potential QT prolongation
• Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for up to 3 months following discontinuation of study drug
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
• Active autoimmune disorder, including autoimmune hepatitis
• Known serious hypersensitivity reactions to peginterferon alfa-2b or interferon alfa-2b or drug excipients
• Known serious hypersensitivity reactions to nilotinib
• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
• Patients unwilling or unable to comply with the protocol.

- Předchozí specifická terapie pro CML vyjma hydroxyurey a déle než 6-ti týdenního podávání imatinibu či nilotinibu
- Srdeční onemocnění či porucha charakteru:
– implantovaný ventrikulární pacemaker
– vrozený syndrom dlouhého QT či pozitivní RA na sy dlouhého QT
– anamnéza či přítomnost významných síňových či komorových tachyarytmií
– významná klidová bradykardie (< 50/min)
– QTcF > 450ms
– infarkt myokardu ≤ 12 měsíců před vstupním hodnocením
– další klinicky významná srdečně-cévní onemocnění (nestabilní AP, městnavé srdeční selhání, nekontrolovaná hypertenze, LVEF < 45%)
- Léčba inhibitory CYP3A4 či medikací prodlužující QT interval je kontraindikována
- Akutní pankreatitida do 1 roku do startu studie či anamnéza chronické pankreatitidy
- Nádorové onemocnění vyjma klinicky nevýznamné či intervenci nevyžadující choroby
- Těžké či nekontrolované onemocnění (diabetes mellitus, jaterní postižení, závažné onem. ledvin, aktivní či nekontrolovaná infekce, onemocnění GIT ohrožující absorbci)
- Anamnéza závažné krvácivé diatézy
- Ženy těhotné, kojící či ve fertilním věku s pozit. těhotenským testem vstupně; muži i ženy bez účinné antikoncepce
- Velký chirurgický výkon ≤ 2 týdny před startem studiové terapie
- Známá infekce virem HIV
- Aktivní AI onemocnění
- Známá hypersenzitivita na PEG-INF či nilotinib
- Pacienti neschopní či neochotní se podrobit protokolu studie

E.5 End points

E.5.1

Primary end point(s)

1. Rate of MMR at 18 months (nilotinib vs. nilotinib+IFN)
2. Rate of continuous MMR 12 and 24 months after discontinuation of nilotinib and IFN ("Cure").

1. Zhodnocení podílu velkých molekulárních odpovědí (major molecular response, MMR) v 18 měsících (nilotinib versus nilotinib + pegylovaný interferon-α (INF)
2. Zhodnocení podílu přetrvávajících MMR po vysazení udržovací terapie nilotinibem versus pegylovaným interferonem-α2b

E.5.1.1

Timepoint(s) of evaluation of this end point

at 18 months and continuously after dicontinuation of trial drugs;

v 18 měsících (nilotinib versus nilotinib + pegylovaný interferon-α (INF)

E.5.2

Secondary end point(s)

1. Rate of CCyR and MMR by 12, 18 and 24 months
2. Time to CCyR, MMR, MR4 and MR4.5
3. Rate of MR4 and MR4.5 during maintenance therapy and after discontinuation

E.5.2.1

Timepoint(s) of evaluation of this end point

12, 18 and 24 months

ve 12, 18 a 24 měsících od zahájení léčby

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

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)

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

Yes

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)

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

Yes

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

150

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

150

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

last patient out

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

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:

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

628

F.4.2.2

In the whole clinical trial

628

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)

none

není

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-03-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-25

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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