Clinical Trials Register

Summary
EudraCT Number:	2012-000770-36
Sponsor's Protocol Code Number:	TJT1315
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-10
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-000770-36

A.3

Full title of the trial

Efficacy and tolerance of nilotinib in patients with chronic graft-versus-host disease who did not respond to imatinib mesylate.

A.3.1

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

Treatment for patients whith graft-versus-host disease after bone marrow transplantation.

A.3.2

Name or abbreviated title of the trial where available

Double ITK-GVHc

A.4.1

Sponsor's protocol code number

TJT1315

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	CHU-ULg
B.1.3.4	Country	Belgium
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU-ULg
B.5.2	Functional name of contact point	Yves Beguin
B.5.3	Address:
B.5.3.1	Street Address	Av. de l'hôpital
B.5.3.2	Town/ city	Liège
B.5.3.3	Post code	4000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	32043667201
B.5.5	Fax number	32043668855
B.5.6	E-mail	yves.beguin@chu.ulg.ac.be

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	Glivec 100mg
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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 mesylate
D.3.2	Product code	L01XE01
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.3.11 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 200mg
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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
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 graft-versus-host disease .

E.1.1.1

Medical condition in easily understood language

Attack of the patient tissues by the graft after bone marrow transplantation.

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	10008907
E.1.2	Term	Chronic GVH disease
E.1.2	System Organ Class	100000004870

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Response rate at 3 months of extensive cGVH (complete or partial remission ) in nilotinib-treated patients who have not responded to imatinib mesylate.

E.2.2

Secondary objectives of the trial

* For Imatinib mesylate (IM):
- To confirm the effectiveness of IM in patients with extensive cGVH requiring treatment and resistant to at least one therapeutic line.

* For Nilotinib:
- Evaluate the effectiveness of nilotinib in patients with a resistance or intolerance to IM.
- Avoid long-term use of immunosuppresive drugs, including corticosteroids (and their long-term adverse effects).
- Reduce non-relapse mortality (NRM) of infectious or non-infectious origin.
- Improve quality-of-life parameters.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Induction phase (imatinib)
- Age: ≥ 18 and <75 years.
- Patients who underwent allogeneic hematopoietic stem cell transplantation for a hematological disease.
- Body weight ≥ 40 kg.
- Confirmed diagnosis of an extensive cGVH resistant to at least one systemic immunosuppressive therapy.
- Any source of hematopoietic stem cells is authorized.
- Myeloablative and non-myeloablative regimes are allowed.
- No contra-indication to the use of IM or nilotinib.

Salvage Phase (nilotinib):
Patients enrolled in the first phase who did not respond to IM:
- Patients who discontinued IM after 3 months du to a lack of response.
(stable disease = no response)
- Patients who experienced disease progression at any time.
- Patients who relapsed after an initial response at any time.
- Patients who discontinued treatment due to toxicity at any time.

E.4

Principal exclusion criteria

- Appearance of acute GVHD ( early form or " late onset ").
- First episode of cGVHD or cGVHD not requiring systemic treatment.
- Patient treated with IM or nilotinib , a tyrosine kinase inhibitor given after transplantation within 3 months before enrollment.
- Patients treated with ITK for GVHD.
- Contra-indication to IM or nilotinib.
- Neutropenia < 0,5.10E9 / l.
- Uncontrolled systemic infection which the investigator may associate to an increased death risk during the first month of treatment .
- Severe neurological or psychiatric disorders .
- Pregnant or breastfeeding women .
- Known uncontrolled arrhythmias or symptomatic heart disease or ventricular ejection fraction < 45% (cardiac tests according to clinical indication).
- Performance index: WHO ≥ 3 unrelated to chronic GVHD.
- Relapse of the blood disease for which transplantation was performed except presence of minimal residual disease confirmed by PCR.
- Appearance of a secondary cancer ≤ 2 years before enrollment, subject to the following exceptions :
-cutaneous basal cell carcinoma.
-squamous cell carcinoma of skin.
-carcinoma in situ of the cervix.
-carcinoma in situ of the breast.
-prostate cancer (Stage TNM [ Tumor , Node , Metastasis ] T1a or T1b) .
- Refusal to sign the consent form .
- Patients in an emergency situation or unable to consent .

E.5 End points

E.5.1

Primary end point(s)

Response rate at 3 months (complete and partial remission) after salvage therapy by nilotinib in patients with a cGVHD who did not respond to imatinib mesylate (IM).

E.5.2

Secondary end point(s)

Induction phase with imatinib mesylate :
1) Best response to IM within 12 months and duration of the response in patients who continued IM.
2) Failure rate of IM for intolerance.
3) Failure rate of IM for lack of response.
4) Tolerance profile of IM.

Nilotinib salvatage phase:
5) Best response to nilotinib in 12 months and duration of this response.
6) Failure rate of nilotinib for intolerance.
7) Failure rate of nilotinib for lack of response.
8) Tolerance profile of nilotinib.

Separately for the 2 groups : patients who have not been recruited for the 2nd phase (no treatment with nilotinib ) and patients who were recruited for the second phase.
9) Rates of dose decrease and treatment discontinuation.
10) Overall survival (OS) at one year and EFS (Event-Free Survival).
11) Cumulative incidence of relapse and cGVHD.
12) Quality-of-life parameters .
13) Decrease of transplanted-related mortality without recurrence of the haematological underlying disease.
14) Percentage of patients who no longer require immunosuppresive medications and patients who no longer need corticosteroids.

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

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)

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	65
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	5
F.4.2	For a multinational trial
F.4.2.1	In the EEA	65
F.4.2.2	In the whole clinical trial	65

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

2014-01-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-15

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

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