Clinical Trials Register

Summary
EudraCT Number:	2014-002702-21
Sponsor's Protocol Code Number:	UKH062014
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2015-03-04
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

Germany - BfArM

A.2

EudraCT number

2014-002702-21

A.3

Full title of the trial

A double- blind, placebo controlled, randomized, multicenter, Phase II study to assess the efficacy of BL-8040 addition to consolidation therapy in AML patients

A.3.1

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

A trial to test the effect of BL-8040 or placebo given to AML patients in addition to standard treatment in masked manner.

A.3.2

Name or abbreviated title of the trial where available

BLAST

A.4.1

Sponsor's protocol code number

UKH062014

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	Martin-Luther-Universität Halle- Wittenberg
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	BioLineRX
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Halle
B.5.2	Functional name of contact point	Principial Investigator
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496221 56 8001
B.5.5	Fax number	0049622156 5813
B.5.6	E-mail	Carsten.Mueller-Tidow@med.uni-heidelberg.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	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	BL-8040
D.3.2	Product code	BL-8040
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BL-8040
D.3.9.1	CAS number	664334-36-5
D.3.9.2	Current sponsor code	BL-8040
D.3.9.3	Other descriptive name	N-(4-Fluoro-benzoyl)-L-arginyl-L-arginyl-[L-3-(naphthyl)alanyl]-L-cysteinyl-L-tyrosyl-L-citrullinyl-L-lysyl-Dlysyl-L-prolyl-L-trosyl-L-arginyl-L-citrullinyl-L-cysteinyl-L-aginine amide, cyclic (4-13)-disulfide acetate salt
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	73
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

consolidation therapy in acute myeloid leukemia in first complete remission

E.1.1.1

Medical condition in easily understood language

patients with acute myeloid leukemia in first complete remission after induction therapy who are fit for intensive therapy and no allogeneic transplantation is provided.

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	21.0
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

to compare Relapse Free Survival (RFS) of subjects receiving BL-8040 compared to placebo, on top of standard consolidation therapy in subjects with AML

E.2.2

Secondary objectives of the trial

• to compare overall survival (OS)
• time to relapse in the treatment groups
• to report RFS in the treatment groups at 6, 9, 12 and 18 months after randomization
• to report relapse rates of the groups at 6, 9, 12 and 18 months after randomization
• to compare RFS and OS of AML subjects between treatment groups in the two subgroups according to different cytogenetic and molecular risk
• to report the Minimal residual disease (MRD; LSC rate) (by FACS at baseline, end of study treatment (EOT), 6, 9, 12 and study termination/early study termination visit (ST/EST) (month 18/EST)
• to report RFS and OS in the two subgroups groups with/with no CXCR4 overexpression
• to assess the toxicity, safety and tolerability of BL-8040 in combination with high-dose cytarabine
• to report the incidence of Early Treatment termination
• to report the incidence of Early Study termination (18 months)
• to report the incidence of Early Treatment termination due to adverse events

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects must be at least 18 years old at the time of registration
2. Histologically or morphologically confirmed diagnosis of AML except for AML M3 (acute promyelocytic leukemia).
3. Subjects with AML who achieved complete remission (CR), including CRi and CRp after a maximum number of two cycles of induction chemotherapy (must contain at the minimum cytarabine as well as an anthracycline or mitoxantrone). CR (or CRi or CRp) needs to be confirmed by bone marrow aspirate up to 7 days prior to randomization.
4. AML subjects younger than 60 yearswith intermediate or high-risk cytogenetics at the time of diagnosis
5. 60 years old AML subjects and older at the time of diagnosis can be enrolled into the trial independent of cytogenetics or molecular genetic risk group.
6. Subjects must provide written informed consent at screening, prior to performance any study-specific procedures or assessments which are not routinely performed for diagnosis or monitoring of AML, and the subjects must be willing to comply with treatment and to follow up assessments and procedures
7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 at screening
8. The clinical laboratory values should be as follows (at screening):
- WBC < 30.000/µl and > 1000/µl;
- Platelets count > 70.000/µl
- Creatinine < 1.0 mg/dl. If creatinine is between 1.0mg/dl and 1.3mg/dl, the creatinine clearance should be > 30ml/min as calculated using the Cockroft-Gault formula (See appendix 17.4)
9. Women of child-bearing potential must practice an acceptable method of birth control until 6 month after the last dose of treatment was administered [acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive or double-barriermethod (condom or diaphragm with spermicide)].
Female subjects who are lactating must discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide) or abstinence during the study.
10. Subject is able and willing to comply with the requirements of the protocol

E.4

Principal exclusion criteria

1. Relapsed or refractory AML
2. Start of induction cycle > 90 days before randomization.
3. Subjects who have received >2 cycles of induction chemotherapy for AML therapy.
4. Subjects younger than 60 years with favorable cytogenetics (t(8;21) or inv(16) or t(16;16) or t(15;17)) or the confirmed presence of the resulting fusion protein AML1-ETO, CBFB-MYH11 or PML-RARA at the time of diagnosis .
5. Subjects for which allogeneic HSCT is planned in CR1. If subject refuses HSCT, participation is allowed.
6. Subjects planned for a further maintenance therapy after the end of the protocol defined consolidation therapy.
7. Known allergic or hypersensitivity to BL-8040- or Cytarabine or to any of the test compounds, materials
8. Use of investigational device or agents within 2 weeks or less than 5 half lifes for each investigational product /device at the time of enrollment. Subjects be treated with an experimental drug for two weeks before randomization. Subjects cannot take part in other clinical trials starting from screening. Registry studies / observational studies are permissible.
9. Abnormal liver function tests:
- Serum AST/ GOT or ALT/ GPT > 3x upper limit of normal (ULN)
- Serum bilirubin: Total bilirubin > 2.0mg/dl or conjugated bilirubin > 0.8mg/dl
10. O2 saturation < 92% (on room air)
11. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk, including, but not limited to:
• Subject has been diagnosed or treated for another malignancy within 3 years of enrollment, except in situ malignancy, or low-risk prostate, skin or cervical cancer after curative therapy. History of other cancer that according to the Investigator might confound the assessment of the endpoints of the study.
• A co-morbid condition which, in the view of the Investigators, renders the subject at high risk from treatment complications.
• History of any or more of the following cardiovascular conditions: cardiac angioplasty (within 6 months) or stenting (within 6 months) and/or myocardial infarction (MI) (within 6 months) or cerebro-vascular event within the past 6 months, unstable angina, vascular disease, class III or IV, congestive heart failure (as defined by the New York Heart Association (NYHA))• Known central nervous system disease that may jeopardize the subject’s study participation according to the investigator judgement
• Active, uncontrolled infection.
• The participation of subject´s receiving long acting insulin (with high protein binding) and oral antidiabetic agents should be weighed by the investigator due to increased susceptibility of hypoglycaemia. If such patients are enrolled, an increased frequency of blood glucose monitoring is required.
12. Prior clinically significant grade 3-4 non-hematological toxicity to high-dose cytarabine or grade ≥ 2 of neurological toxicity
13. Positive serology for HIV, active Hepatitis C and Hepatitis B (HBsAG pos.).Serology must be performed within 2 months before Randomization..
14. Left ventricular ejection fraction (LVEF) of <40% by echocardiogram (ECHO) at screening.
15. Subjects with psychological, psychiatric, neurological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

E.5 End points

E.5.1

Primary end point(s)

Relapse Free Survival (RFS) time

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months after randomization

E.5.2

Secondary end point(s)

- overall survival (OS)
- time to relapse
- RFS at 6, 9, 12 and 18 months after randomization
- relapse at 6, 9, 12 and 18 months after randomization
- Minimal residual disease (MRD) (by FACS at baseline, end of study treatment (EOT), 6, 9, 12 and study termination/early study termination visit (ST/EST) (month 18/EST)
- toxicity, safety and tolerability of BL-8040 in combination with high-dose cytarabine
- Early Treatment termination,
- Early Study termination (18 months)
- Early Treatment termination due to Adverse events

E.5.2.1

Timepoint(s) of evaluation of this end point

month 6, 9, 12 and 18 months after randomization

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

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.8.2.4

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

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

end of the trial is defined as the time point the data bank is locked, Justification for this definition: study- specific documentation has to be completed until this time-point

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:

100

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

194

F.4.2

For a multinational trial

F.4.2.1

In the EEA

194

F.4.2.2

In the whole clinical trial

194

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)

not different from the expected normal treatment of that condition: bone marrow analysis every 3 months after end of consolidation therapy. In case of relapse further treatment depends on ivestigator´s choice.

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

2015-07-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-08

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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