Clinical Trials Register

Summary
EudraCT Number:	2010-018539-16
Sponsor's Protocol Code Number:	KKS-134
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-07-25
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

Austria - BASG

A.2

EudraCT number

2010-018539-16

A.3

Full title of the trial

A double-blind, placebo-controlled, randomized, multi-center
phase II trial to assess the efficacy of Sorafenib-maintenance therapy in Flt3-ITD positive AML in complete hematological remission after allogenic stem cell transplantation

Eine doppelt-blinde, Placebo-kontrollierte, randomisierte, multizentrische, Phase 2-Studie um die Wirksamkeit von Sorafenib bei Flt3-ITD-positiver AML nach allogener Stammzelltransplantation und kompletter hämatologischer Remission zu zeigen.

A.3.1

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

The Study tests the efficacy of Sorafenib against a relapse of Acute Myeloic Leukemia (AML) with FLT3-ITD mutation after allogenic stemcelltransplantation and without any clinical signs of continuity of AML. It will be compared with a placebo. The selection will be randomised, so that physician and patient don´t know which substance they will get (double-blind). The study is performed in several clinics.

Es soll die Wirksamkeit von Sorafenib gegen ein Wiederauftreten der Akuten Myeloischen Leukämie (AML) mit Flt3-ITD-Mutation nach einer Stammzelltransplantation (Fremdspender) ohne klinische Anzeichen des Weiterbestehens der AML gezeigt werden. Es wird mit einem Placebo verglichen. Die Auswahl erfolgt zufällig (randomisiert) und weder Arzt noch Patient wissen welche Substanz gegeben wird (doppelt-blind). Die Studie wird in mehreren Kliniken durchgeführt.

A.3.2

Name or abbreviated title of the trial where available

Sormain

A.4.1

Sponsor's protocol code number

KKS-134

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	Philipps-Universität Marburg
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	Bayer Vital GmbH, Bayer Schering Pharma, 51368 Leverkusen; Germany
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
B.5.2	Functional name of contact point

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	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Schering Pharma AG 13342 Berlin Deutschland
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	Sorafenib
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SORAFENIB
D.3.9.1	CAS number	284461-73-0
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
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	Yes
D.3.11.13.1	Other medicinal product type	multi kinase inhibitor

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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Flt3-ITD positive AML in complete hematological remission (CHR) after allogenic stem cell transplantation (allo-SCT)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
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

Primary objective:
Relapse free survival (RFS) of Flt3-ITD+ AML patients in complete hematological remission after allo-SCT receiving Sorafenib maintenance therapy versus placebo

E.2.2

Secondary objectives of the trial

Secondary objective:
1. To compare the median overall survival (OS) of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo
2. To compare the median RFS and OS of Flt3-ITD+ AML patients with and without NPM mutations receiving Sorafenib versus placebo
3. To compare the median RFS and OS of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo depending on the baseline expression level of Flt3-ITD at diagnosis
4. To compare the toxicity of Sorafenib maintenance versus placebo
5. To longitudinally evaluate biomarkers associated with Sorafenib treatment response and Sorafenib resistance
and correlation with RFS and OS
6. To assess safety with type, severity graded by NCI CTC criteria version 4.02.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written informed consent
• Age 18 y.
• ECOG performance ≤ 1
• FLT3-ITD-positive AML
• Complete hematological remission (CHR) after allo-SCT
CHR must be confirmed by bone marrow analysis within 14 days before randomization (CHR criteria are: ≤ 5% marrow blasts, no peripheral blasts, blood platelet count > 100/nl, WBC count > 3 G/L, ANC > 1000 G/l).
• Allo-SCT with a HLA-identical allo-family donor (FAM) or a matched unrelated donor (MUD) with up to 1 antigen mismatch acceptable (9/10)
• Time point of study treatment start of patients in CHR: between d+60 up to d+100 after allo-SCT
• Adequate organ function:
Serum creatinine  1.5 x upper normal value
ALT, AST, AP  2.5 x upper normal value
Total bilirubin  1.5 x upper limit of normal
PT-INR/PTT  1.5 x upper limit of normal
• Patients who are being therapeutically anticoagulated with an agent such as Coumadin or Heparin will be allowed to participate in the trial provided that the medical need for anticoagulation is evidence-based (level I evidence) and PT-INR and PTT values are closely monitored to maintain the therapeutic window.
• Negative serum pregnancy test within seven days prior to first dose in women of child-bearing potential (WOCBP)
• WOCBP must use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months).
• Male subjects whose sexual partners are WOCBP must use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.

E.4

Principal exclusion criteria

• Any severe concomitant conditions which make it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol (such as substance abuse, uncontrolled infection, known HIV, HBV, HCV infection
• Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up.
• Cardiac disease: heart failure NYHA III/IV, unstable coronary artery disease (MI more than 6 months prior to study entry is permitted), serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted)
• Resting blood pressure consistently higher than systolic 150 mmHg and/or diastolic 90 mmHg despite antihypertensive therapy
• Patients undergoing renal dialysis
• Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
• Patients with uncontrolled seizure disorder despite medication
• History of organ allograft (except for allogenic SCTX)
• Patients with major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to start of first dose of study drug
• Serious non-healing wound, ulcer or bone fracture
• Known Flt3-kinase inhibitor resistance
• Previous Sorafenib therapy
• Active (uncontrolled) graft versus host disease GvHD (> grade I) at time of randomization despite the use of adequate therapeutic measures
• Investigational drug therapy outside of this trial during or within 4 weeks of study entry
• Pregnancy or breast feeding
• Allergy to study medication or compositions of excipients in study medication
• Secondary allo-SCT
• Previous or concurrent cancer curatively treated ≤ 3 years prior to study entry

E.5 End points

E.5.1

Primary end point(s)

Relapse free survival (RFS), 50 events (relapse)
RFS is defined as time interval from randomization until relapse of AML or death from any cause, which ever occurs first. Relapse is defined as any blast appearance in the peripheral blood, in the bone marrow (> 5%) or extramedullary blasts (chloroma). For a patient with no relapse before the end of study follow-up, observation of RFS will be censored at the date of his or her last follow-up examination.

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

Yes

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

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)

E.8.2.2

Placebo

Yes

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

Yes

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

study ends with last vist of the last patient

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

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.1.3

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-07-25.

Yes

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

200

F.4.2.2

In the whole clinical trial

200

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 the treatment phase(24 months) and post treatment follow up of 6 months, further follow up is planned until month 42 for evaluation of RFS and OS only.

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

2012-09-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-10-31

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