Clinical Trials Register

Summary
EudraCT Number:	2009-014980-38
Sponsor's Protocol Code Number:	TJB0909P1
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:	2010-01-26
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2009-014980-38

A.3

Full title of the trial

Co-transplantation of mesenchymal stem cells and HLA-mismatched allogeneic hematopoietic cells after reduced-intensity conditioning: a phase II randomized double-blind study.

A.3.1

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

Bone marrow transplantation from a donor to a patient who have incompatible blood cells. Before transplantation, patients will receive a less intensive treatment with a low-dose chemiotherapy. The day of transplantation, patients will be injected with a population of blood cells from the donor as well as a specific cell population, named mesenchymal stem cells.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

TJB0909P1

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 de Liège
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 de Liège
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

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	No
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	mesenchymal stem cells
D.3.2	Product code	MSC
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	MSC
D.3.10	Strength
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5 x 10E6MSC/kg to -3.0 x 10E6MSC/kg
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hematological malignancies confirmed histologically and not rapidly progressing:
- AML in Complete Remission;
- ALL in Complete Remission;
- CML unresponsive/intolerant to Imatinib but not in blast crisis;
- Other myeloproliferative disorders not in blast crisis and not with extensive myelofibrosis;
- MDS with < 5% blasts;
- Multiple myeloma not rapidly progressing;
- CLL;
- Non-Hodgkin’s lymphoma (aggressive NHL should have chemosensitive disease);
- Hodgkin’s disease

E.1.1.1

Medical condition in easily understood language

Types of cancer that affect blood, bone marrow and lymph nodes.

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	PT
E.1.2	Classification code	10027703
E.1.2	Term	Mismatched donor bone marrow transplantation therapy
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The present project aims at evaluating the capacity of mesenchymal stem cells to improve one-year overall survival of patients transplanted with HLA-mismatched peripheral blood stem cells from related or unrelated donors after non-myeloablative conditioning.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patient
1. Hematological malignancies confirmed histologically and not rapidly progressing (see E1.1).
2. Theoretical indication for a standard allo-transplant, but not feasible because: Age > 55 yrs. Unacceptable end organ performance. Patient’s refusal.
3. Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
4. Male or female; fertile female patients must use a reliable contraception method;
5. Age < ou = 75 yrs.
6. Informed consent given by patient or his/her guardian if of minor age.
7. One or two HLA mismatches as described in the protocol.

PBSC donors
1. Related to the recipient (sibling, parent or child) or unrelated who hve 1-2 HLA mismatches as either:
- One antigenic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1
- Two allelic mismatches at HLA-A or -B or -C or -DRB1 or -DQB1
- One antigenic mismatch  1 allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1.
- One antigenic mismatch at -DQB1 and one other antigenic mismatch at HLA-A or -B or -C or -DRB1
- Patients with one single allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1 can also be included in the protocol.
2. Male or female;
3. Weight > 15 Kg (because of leukapheresis);
4. Fulfills generally accepted criteria for allogeneic PBSC donation;
5. Informed consent given by donor or his/her guardian if of minor age, as per donor center standard procedures.

MSC donors
1. Related to the recipient (sibling, parent or child) or unrelated;
2. Male or female;
3. Age > 16 yrs (no age limit if same as HSC donor);
4. No HLA matching required;
5. Fulfills generally accepted criteria for allogeneic HSC donation;
6. Informed consent given by donor or his/her guardian if of minor age.

E.4

Principal exclusion criteria

Patient
1. Any condition not fulfilling inclusion criteria;
2. HIV positive;
3. Terminal organ failure, except for renal failure (dialysis acceptable)
- Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction <35%; uncontrolled arrhythmia, uncontrolled hypertension;
- Pulmonary: DLCO < 35% and/or receiving supplementary continuous oxygen;
- Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dL, and symptomatic biliary disease;
4- Uncontrolled infection, arrhythmia or hypertension;
5- Previous radiation therapy precluding the use of 2 Gy TBI;
6- 10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC.

PBSC donor
1. Any condition not fulfilling inclusion criteria;
2. HIV positive;
3. Unable to undergo leukapheresis because of poor vein access or other reasons.

MSC donor
1. Any condition not fulfilling inclusion criteria;
2. HIV positive;
3. Known allergy to lidocaine;
4. If donor other than HSC donor: any risk factor for transmissible infectious diseases.

E.5 End points

E.5.1

Primary end point(s)

To compare one-year overall survival between patients treated with MSC or placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

One year

E.5.2

Secondary end point(s)

To evaluate in each arm: 1.the incidences of grade II-IV and grade III-IV acute GVDH disease. 2.the cumulative incidence of nonrelapse mortality at days 100, 365 and 730. 3.the incidence of extensive chronic GVHD (at day 365). 4.the incidence of graft rejection.5.the cumulative incidence of relapse at days 365 and 730. 6.the incidence of progression-free survival (at days 365 and 730). 7.the incidence of infections (at day 100). 8.To investigate the quality and timing of immunologic reconstitution in each arm. 9.To detect MSC of MSC donor origin in recipient marrow after hematopoietic cell transplantation (HCT) in patients given MSC (ULg-CHU patients only). 10.To assess the proportion of patients with measurable disease at HCT who achieve a complete response in each arm. 11.To compare the number of absolute donor T cells on day 28 after in each arm. 12.To compare these endpoints in patients conditioned with either fludarabine and 2 Gy TBI or fludarabine-busulfan-ATG.

E.5.2.1

Timepoint(s) of evaluation of this end point

1.grade II-IV and grade III-IV acute GVDH disease the first three months.
2.nonrelapse mortality at days 100, 365 and 730.
3.chronic GVHD at day 365.
4.the incidence of graft rejection at days 28, 40, 60, 80, 100, 120, 180, 365 and 730 .
5.relapse at days 365 and 730.
6.PFS at days 365 and 730.
7.infections at day 100.
8.immunologic reconstitution at days 28, 40, 60, 80, 100, 120, 180, 365 and 730.
9.to detect MSC of MSC donor origin at days 40 and 100.
10.complete response in each arm at day 730.
11.To compare the number of absolute donor T cells on day 28 after in each arm.
12.To compare these endpoints in patients conditioned with either fludarabine and 2 Gy TBI or fludarabine-busulfan-ATG.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Information not present in EudraCT

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

The stopping rule for mortality willbe triggered if 4 of 5, 6 of 10, 8 of 15, 10 of 20, 12 of 25, 14 of 30, 16 of 35, 18 of 40, 19 of 45, or 21 of 50 patients experience nonrelapse mortality by day +180. Comparison of overall survival and nonrelapse mortality in the 2 arms will be analyzed after 20, 30, and 40 patients are included in each arm. The protocol will be stopped if a significant difference between the 2 arms is observed.

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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)

Yes

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In case of a minor age patient the consent will be given by his/her guardian.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

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

2010-03-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-07-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-08-23

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