Clinical Trials Register

Summary
EudraCT Number:	2012-005414-18
Sponsor's Protocol Code Number:	ZKS000783
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-14
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

2012-005414-18

A.3

Full title of the trial

Thiotepa- Fludarabine- Treosulfan (TFT) conditioning for 2nd allogeneic PBSCT from a different unrelated donor in patients with AML relapsing from prior allogeneic HCT

Konditionierung mit Thiotepa-Fludarabin-Treosulfan (TFT) bei zweiter allogener Stammzelltranplantation von einem anderen nicht verwandten Spender für Patienten mit Rezidiv einer AML nach 1. allogener Stammzelltransplantation

A.3.1

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

Thiotepa- Fludarabine- Treosulfan conditioning for allogeneic PBSCT in patients with AML relapsing from prior allogeneic HSCT

Konditionierung mit Thiotepa-Fludarabin-Treosulfan bei zweiter allogener Stammzelltranplantation von einem anderen nicht verwandten Spender für Patienten mit Rezidiv einer AML nach 1. allogener Stammzelltransplantation

A.3.2

Name or abbreviated title of the trial where available

TFT-2Tx

A.4.1

Sponsor's protocol code number

ZKS000783

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	University Medical Center 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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Trials Unit University Medical Center Freiburg
B.5.2	Functional name of contact point	Clinical Trial Information
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	79110
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49761270-74410
B.5.5	Fax number	+49761270-73770
B.5.6	E-mail	olga.grichina@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	Tepadina
D.2.1.1.2	Name of the Marketing Authorisation holder	ADIENNE S.r.l.
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Thiotepa
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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	Fludarabinmedac
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie B.V.
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	Fludarabine
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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	Ovastat
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac 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	Treosulfan
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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: 4
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	Ovastat
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac 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	Treosulfan
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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

Patients with relapse of AML after the 1st allogeneic PBSCT.

AML Rezidiv nach allogener hämatopoetischer Stammzelltransplantation

E.1.1.1

Medical condition in easily understood language

Patients with relapse of AML after the 1st allogeneic PBSCT.

Patienten mit AML Rezidiv nach allogener hämatopoetischer Stammzelltransplantation

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001941
E.1.2	Term	AML
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

To assess the probability of disease-free survival, defined as being alive and free of relapse at 1 year after 2nd allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT, 2nd Tx) from unrelated donors after a uniform "intensive-RIC" conditioning with the TFT regimen and defined Graft-versus-Host-Disease (GvHD) prophylaxis

Bestimmung der Wahrscheinlichkeit des krankheitsfreien Überlebens (DFS), definiert als Überleben frei von einem Rezidiv ein Jahr nach der zweiten allogenen (PBSCT, 2nd Tx) von einem nicht verwandten Spender nach einheitlicher „intensiver intensitätsreduzierter Konditionierung“ mit dem TFT Protokoll und definierter Transplant-gegen-Wirt-Reaktion (GvHD) Prophylaxe.

E.2.2

Secondary objectives of the trial

• To assess the probability of disease-free survival (DFS) over time
• To assess the probability of relapse and non-relapse mortality over time
• To assess the probability of overall survival (OS) over time
• To assess the probability and severity of acute and chronic GvHD over time
• To assess the safety of the regimen

• Bestimmung der Wahrscheinlichkeit des krankheitsfreien Überlebens über die Zeit
• Bestimmung der Wahrscheinlichkeit für ein Rezidiv und der Nicht-Rezidiv (=Transplant)-Mortalität über die Zeit
• Bestimmung der Wahrscheinlichkeit des Gesamtüberlebens über die Zeit
• Bestimmung der Wahrscheinlichkeit des Auftretens und des Schweregrades der akuten und chronischen GvHD über die Zeit
• Bestimmung der Sicherheit des Therapieprotokolls

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent obtained according to international guidelines and local laws;
2.Male or female patients aged 18-65 years;
3.Patients with AML including secondary and therapy-related AML;
4.Patients with hematological relapse > 6 months after prior allogeneic HCT;
5.Patients designated to undergo second PBSCT from unrelated donor different from the previous donor;
6.Patients with a HLA-A, -B, -C and HLA-DRB1 matched (at least 6 out of 8 alleles; high DNA-based resolution) unrelated donor;
7.Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2;
8.Ability to understand the nature of the trial and the trial related procedures and to comply with them.

1.Vorliegen einer schriftlichen Patienten-Einwilligungserklärung entsprechend den internationalen Richtlinien und den entsprechenden deutschen Rechtsvorschriften;
2.Männer und Frauen zwischen 18 und 65 Jahren;
3.AML (Akute myeloische Leukämie) einschließlich sekundärer und therapiebedingter AML;
4.Hämatologisches Rezidiv > 6 Monate nach der ersten allogenen Stammzelltransplantation;
5.Zweite PBSCT von einem anderen Spender als bei der ersten Stammzelltransplantation, der nicht mit dem Patienten verwandt ist;
6.Patienten mit einem Humanen Leukozyten Antigen (HLA)-A, -B, -C und HLA-DRB1 passenden (mindestens 6 von 8 Allelen, hohe DNA-basierte Auflösung) nicht verwandten Spender;
7.ECOG (Eastern cooperative oncology group)-Performance-Status ≤ 2;
8.Fähigkeit, die Inhalte der Studie sowie die studienspezifischen Abläufe zu verstehen und einzuhalten;

E.4

Principal exclusion criteria

1.Patients with known congestive heart failure New York Heart Association (NYHA) Class III and IV, cardiac arrhythmias (except atrioventricular block type I and II, atrial fibrillation/flutter, bundle brunch block) or other signs and symptoms of relevant cardiovascular disease;
2.Known Human immunodeficiency virus (HIV) infection, infectious hepatitis (type A, B or C) or another uncontrolled infection;
3.Known hypersensitivity to the active substances or any of the excipients;
4.Renally impaired patients with creatinine clearance < 30 ml/min (Cockcroft-Gault Equation);
5.Decompensated haemolytic anaemia;
6.Any condition, including laboratory abnormalities, which places the subject at unacceptable risk in the study;
7.Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed;
8.Participation in a clinical trial within the last 30 days before the start of this trial (except for registry and diagnostic trials);
9.Known or persistent abuse of medication, drugs or alcohol;
10.Female patients who are pregnant or breast feeding;
11.Fertile patients refusing to use safe contraceptive methods during the study (for details see clinical trial protocol section 4.3).

1.Bekannte Herzinsuffizienz NYHA Grad III und IV, Arrhythmien (außer atrioventrikuläre Blockade Typ I und II, Vorhofflimmern, Schenkelblockade) oder andere Anzeichen und Symptome einer relevanten kardiovaskulären Erkrankung;
2.Bekannte HIV Infektion, bekannte aktive Hepatitis (Typ A, B oder C) oder eine andere nicht kontrollierte Infektion;
3.Bekannte Überempfindlichkeit gegen eines der Studienmedikamente oder deren Bestandteile;
4.Niereninsuffizienz mit einer Kreatinin Clearance von < 30 ml/min (Cockcroft-Gault Formel);
5.Dekompensierte hämolytische Anämie;
6.Jede Gegebenheit, einschließlich Abweichungen von Laborwerten, die den Prüfungsteilnehmer nicht akzeptablen Risiken aussetzt;
7.Gleichzeitige Teilnahme an anderen interventionellen Studien, die die Ergebnisse dieser Studie beeinflussen können; die gleichzeitige Teilnahme an Registern und diagnostischen Studien ist erlaubt;
8.Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage vor Einschluss in diese Studie (Ausnahme: Register und diagnostische Studien);
9.Bekannter oder ständiger Missbrauch von Arzneimitteln, Drogen oder Alkohol;
10.Schwangere und Stillende;
11.Bei zeugungsfähigen Männern und gebärfähigen Frauen die Weigerung sichere Mittel zur Empfängnisverhütung während der Studie anzuwenden (Details siehe Abschnitt 4.3. im Prüfplan).

E.5 End points

E.5.1

Primary end point(s)

Disease-free survival (DFS) defined as being alive and free of relapse at 1 year post 2nd Tx.

Krankheitsfreies Überleben (DFS) definiert als Überleben frei von Rezidiv ein Jahr nach der 2nd Tx.

E.5.1.1

Timepoint(s) of evaluation of this end point

One year after the second Tx.

ein Jahr nach der 2. Tx.

E.5.2

Secondary end point(s)

• DFS time post 2nd Tx
• Time to relapse post 2nd Tx.
• Time to non-relapse mortality (NRM) post 2nd Tx
• OS time post 2nd Tx.
• Time to and severity of acute and chronic GvHD post 2nd Tx.

• Zeit bis zum Rezidiv oder bis zum Tod nach der 2nd Tx
• Zeit bis zum Rezidiv nach der 2nd Tx.
• Zeit bis zum Tod ohne vorheriges Rezidiv nach der 2nd Tx.
• Zeit bis zum Tod nach der 2nd Tx.
• Zeit bis zum Auftreten und der Schweregrad von akuter und chronischer GvHD nach der 2nd Tx.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Evaluation day +30, +100 (after 2ndTx)
- Evaluation at Month 6, 9, 12, 18, 24, 30, 36 (after 2ndTx)
- Extensive follow-up evaluations will be performed after patient’s Visit month 36 up to 36 months after the registration date of the last patient enrolled in the study

- Evaluierung Tag +30, +100 (nach 2ndTx)
- Evaluierung Monat 6, 9, 12, 18, 30, 36 (nach 2ndTx)
- Durchführung intensiver follow-up Evaluierungen nach Visite im Monat 36 bis zu 36 Monate nach Registrierungsdatum des letzten in die Studie eingeschlossenen Patienten

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

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

Yes

E.8.1.7.1

Other trial design description

einarmig

single-arm study

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

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

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

After end of the trial patient’s treatment will be performed according to standards of care.

Nach Beendigung der Studie werden die Patienten nach klinischen Standards weiter behandelt.

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

2014-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-04-17

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