Clinical Trials Register

Summary
EudraCT Number:	2014-000477-39
Sponsor's Protocol Code Number:	AMLSG20-13
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-11-17
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

2014-000477-39

A.3

Full title of the trial

Dose Finding safety run in Phase followed by a randomized Phase II Trial of Intensive Chemotherapy With or Without Volasertib (BI 6727) Administered Prior or After Chemotherapy in Patients With Newly Diagnosed High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

AMLSG 20-13

A.4.1

Sponsor's protocol code number

AMLSG20-13

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02198482

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 Hospital Ulm
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	Boehringer Ingelheim
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	University Hospital Ulm
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	WiSP GmbH
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	University Hospital Ulm
B.5.2	Functional name of contact point	Hartmut Döhner
B.5.3	Address:
B.5.3.1	Street Address	Albert-Einstein-Allee 23
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89081
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4973150045521
B.5.5	Fax number	+4973150045525
B.5.6	E-mail	hartmut.doehner@uniklinik-ulm.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/01/084
D.3 Description of the IMP
D.3.1	Product name	Volasertib
D.3.2	Product code	BI 6727
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VOLASERTIB
D.3.9.1	CAS number	755038-65-4
D.3.9.3	Other descriptive name	BI6727
D.3.9.4	EV Substance Code	SUB168429
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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 newly diagnosed high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

E.1.1.1

Medical condition in easily understood language

patients with newly diagnosed high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10068361
E.1.2	Term	MDS
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
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 evaluate efficacy (CR/CRi rate) of the combination of intensive chemotherapy with volasertib administered prior or after chemotherapy

E.2.2

Secondary objectives of the trial

To evaluate cumulative incidence of relapse (CIR) and death (CID), relapse-free survival (RFS), event-free survival (EFS), overall survival (OS) of the combination of intensive chemotherapy with volasertib administered prior or after chemotherapy

Safety objectives
To evaluate incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v4.03 of the combination of intensive chemotherapy with Volasertib administered prior or after chemotherapy

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with confirmed diagnosis of acute myeloid leukemia (AML) or related precursor neoplasm, or acute leukemia of ambiguous lineage according to the current World Health Organization (WHO) classification,
or
patients with myelodysplastic syndrome (MDS) classified as refractory anemia with excess blasts-2 (RAEB-2)
2. Consent for a genetic assessment in AMLSG central laboratory
3. Patients considered eligible for intensive chemotherapy
4. ECOG performance status of ≤ 2
5. Age ≥ 18; there is no upper age limit.
6. No prior chemotherapy for acute leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase; patients may have received prior therapy for myelodysplastic syndrome.
7. Non-pregnant and non-nursing. Due to the teratogenic potential of volasertib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner’s vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) for 6 months after therapy is stopped. “Women of childbearing potential” is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
8. Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while receiving therapy and for 6 months after therapy is stopped, even if they have undergone a successful vasectomy.
9. Signed written informed consent.

E.4

Principal exclusion criteria

1. Patients with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); PML-RARA, or with variant translocations
2. Prior treatment with volasertib or any other PLK1 inhibitor
3. Performance status WHO >2 (see Appendix I)
4. Patients with ejection fraction <50% by echocardiography within 14 days of day 1
5. QTcF prolongation >470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome). The QTcF will be calculated as the mean of 3 ECGs taken at screening.
6. Any clinically significant, advanced or unstable disease or history of that may interfere with primary or secondary variable evaluations or put the patient at special risk, such as:
• creatinine >1.5x upper normal serum level;
• total bilirubin, AST or AP >2.5x upper normal serum level;
• heart failure NYHA III/IV,
• uncontrolled hypertension,
• unstable angina,
• serious cardiac arrhythmia;
• severe obstructive or restrictive ventilation disorder
• uncontrolled infection
7. Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
8. Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
9. Known or suspected active alcohol or drug abuse
10. Known positive for HIV, active HBV, HCV, or hepatitis A infection
11. Hematologic disorder independent of leukemia
12. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
13. No consent for biobanking.
14. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study
15. Breast feeding women or women with a positive pregnancy test at Screening visit

E.5 End points

E.5.1

Primary end point(s)

Rate of complete remission (CR) and CR with incomplete blood count recovery (CRi)

E.5.1.1

Timepoint(s) of evaluation of this end point

First Safety Analysis will be performes after 38 treated patients and after Follow up period of all patients

E.5.2

Secondary end point(s)

Cumulative incidence of relapse (CIR) and death (CID), relapse-free survival (RFS), event-free survival (EFS), overall survival (OS)

Safety endpoints
Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v4.03.

E.5.2.1

Timepoint(s) of evaluation of this end point

First Safety Analysis will be performes after 38 treated patients and after Follow up period of all patients.

Continuous assessment for safety is performed for i) rates of ED/HD with a maximally tolerated rate (MTR) of 20%; ii) gastrointestinal toxicity grade 4 with an MTR of 10%; iii) neutropenia grade 4 after each cycle of induction therapy of longer than day 35 after start of treatment cycle with an MTR of 10% (not attributable to persistent leukemia); and iv) thrombocytopenia grade 4 after each induction therapy of longer than day 35 after start of treatment cycle with an MTR of 10% (not attributable to persistent leukemia).

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety Run in Phase -dose escalation

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

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:

230

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

245

F.4.2

For a multinational trial

F.4.2.1

In the EEA

288

F.4.2.2

In the whole clinical trial

288

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 finishing all study relevant procedures, therapy and follow-up period, the patient will be followed in terms of routine aftercare and treated if necessary by the primary responsible investigative center.

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

2016-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-28

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-11-28

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