Clinical Trials Register

Summary
EudraCT Number:	2011-001086-41
Sponsor's Protocol Code Number:	UKM10_0014
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:	2011-09-19
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

2011-001086-41

A.3

Full title of the trial

A randomized, placebo-controlled, multi-center phase I/II trial to assess the safety and efficacy of nintedanib (BIBF 1120) added to low-dose cytarabine in elderly patients with AML unfit for an intensive induction therapy

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 nintedanib together with chemotherapy in patients with acute myeloid leukemia

A.3.2

Name or abbreviated title of the trial where available

BIBF1120 in AML

A.4.1

Sponsor's protocol code number

UKM10_0014

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01488344

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1122-6147

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 of Muenster
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.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital of Muenster
B.5.2	Functional name of contact point	Study Office/Study Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Albert-Schweitzer-Campus 1, Geb. A1
B.5.3.2	Town/ city	Muenster
B.5.3.3	Post code	48149
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492518349963
B.5.5	Fax number	+492518349964
B.5.6	E-mail	kerstin.vehring@ukmuenster.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	Vargatef ® 100 mg Weichkapseln
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
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.3.4	Pharmaceutical form	Capsule, soft
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	not yet assigned
D.3.9.1	CAS number	928326-83-4
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	Vargatef, Nintedanib
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	100
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	Vargatef ® 150 mg Weichkapseln
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim
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.3.4	Pharmaceutical form	Capsule, soft
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	not yet assigned
D.3.9.1	CAS number	928326-83-4
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	Vargatef, Nintedanib
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	150
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	Capsule, soft
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

untreated acute myeloid leukemia patients unfit for an intensive treatment

E.1.1.1

Medical condition in easily understood language

first diagnosed AML without previous treatment who cannot tolerate an intensive chemotherapy

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	19.0
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

phase I: tolerability of BIBF1120 combined with low-dose cytarabine

phase II: efficacy of BIBF1120 combined with low-dose cytarabine

E.2.2

Secondary objectives of the trial

efficacy of BIBF combined with low-dose cytarabine in predefined subgroups for predefined endpoints

identification of biomarkers correlating with the course of the disease under a therapy with BIBF combined with low-dose cytarabine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients with newly diagnosed, relapsed or refractory AML (except APL) according to the FAB or WHO classification, including AML evolving from MDS or other hematological diseases and AML after previous cytotoxic therapy or radiation (secondary AML), not eligible for a standard induction and consolidation therapy or for an intensive salvage chemotherapy or an allogeneic stem cell transplantation.
• Bone marrow aspirate or biopsy must contain > 20% blasts of all nucleated cells. In AML FAB M6 ≥ 30% of non-erythroid cells in the bone marrow must be leukemic blasts. In patients with newly diagnosed AML and either 20-30% blasts and/or adverse cytogenetics or myelodysplasia-related changes, the indication for a treatment with 5-azacytidine should be considered prior to inclusion into this trial.
• Age ≥ 60 years
• Informed consent, personally signed and dated to participate in the study
• Male patients enrolled in this trial must use adequate barrier birth control measures during the course of treatment and for at least 6 months after the last administration of study therapy (low-dose cytarabine and/or BIBF 1120).*
• Patients at risk for hollow organ perforation (i.e., ulcerative colitis, Crohn`s disease, sigma diverticulitis) should only be included if the potential benefit of the study participation outweighs the risk for perforation in the opinion of the investigator.

E.4

Principal exclusion criteria

• Patients with newly diagnosed AML with either 20-30% bone marrow blasts and/or adverse cytogenetics or myelodysplasia-related changes, which are qualifying for and consenting into a therapy with 5-azacytidine
• Known central nervous system manifestation of AML
• Inadequate liver function (ALT or AST ≥ 1.5 x ULN) if not caused by leukemic infiltration. In cases of leukemic liver involvement ALT or AST ≥ 2.5 x ULN.
• Known chronically active hepatitis C infection or acute Hepatitis
• History of acute or chronic pancreatitis
• Chronically impaired renal function (creatinine > 1.5 x ULN or GFR < 45 ml/min)
• Uncontrolled hypertension with a resting pressure systolic > 160 mmHg or diastolic > 95 mmHg despite adequate treatment
• Severe trauma or surgery within 4 weeks of study entry
• Severe, non-healing wounds, ulcer or fracture
• Uncontrolled active infection
• Concurrent malignancies other than AML or other severe diseases which in the opinion of the investigator are likely to influence the endpoint assessment
• Hypersensitivity to cytarabine (not including drug fever or exanthema)
• Hypersensitivity to nintedanib, peanut, soya, or any of the components of nintedanib capsules according to the Summary of Product Characteristics (SmPC) of nintedanib
• Phase II only: previous therapy with tyrosine kinase inhibitors or angiogenesis inhibitors
• Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. There may be exceptions at the discretion of the coordinating investigator.Any severe concomitant condition, which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol

E.5 End points

E.5.1

Primary end point(s)

phase I: safety and tolerability of BIBF 1120 combined with low-dose cytarabine

phase II: overall survival (OS) of patients treated with low-dose cytarabine plus nintedanib as compared to low-dose cytarabine plus placebo

E.5.1.1

Timepoint(s) of evaluation of this end point

phase I: after one course

Overall survival (OS) (phase II):
Time interval from day 1 of study treatment to the day of death. For a patient who is not known to have died by the end of follow-up, observation of OS will be censored on the date the patient was last known to be alive.

E.5.2

Secondary end point(s)

• response rate (ORR, consisting of: CR, CRp and CRi as defined by IWG criteria1) of the whole study population
• ORR rate of Flt3-mutated patients versus Flt3-wildtype patients and within different cytogenetic risk groups
• CR rate of the whole study population
• CR rate of the Flt3-mutated patients versus the Flt3-wildtype patients and within different cytogenetic risk groups
• overall survival (OS) of the Flt3-mutated patients versus the Flt3-wildtype patients and within different cytogenetic risk groups
• relapse-free survival (RFS) of the responding patients
• the time to response (CR, CRp or CRi) of the responding patients
• the toxicity in the whole study population
• the prognostic value of biomarkers indicating the course of disease, including genetic, epigenetic, transcriptional, protein and phosphoprotein markers in leukemic blasts, bone marrow, peripheral blood cells, serum and plasma, and bone marrow microvessel density.
• development of biomarkers indicating the course of disease

E.5.2.1

Timepoint(s) of evaluation of this end point

Complete remission rate (CR rate): at any time point during study participation.
Overall response rate (ORR): at any time point during study participation.
Overall survival (OS): Time interval from day 1 of study treatment to the day of death. For a patient who is not known to have died by the end of follow-up, observation of OS will be censored on the date the patient was last known to be alive.
Relapse-free survival (RFS): Time interval from the first day a leukemia-free state is achieved in patients who achieve a CR / CRi / CRp until relapse or death from any course, whatever occurs first. For a patient who is not known to have died or have relapsed by the end of follow-up, observation of RFS will be censored on the date the patient was last known to be alive and in CR.

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

first-in-human administration of study drug in combination with cytarabine

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 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

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.1.2.1

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:

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

113

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

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

2012-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-07-27

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