Clinical Trials Register

Summary
EudraCT Number:	2011-000921-61
Sponsor's Protocol Code Number:	NONK-3/NOA-12
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:	2011-11-17
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

2011-000921-61

A.3

Full title of the trial

A phase I/II, randomized, open-label, multi-centre study of BIBF1120 +
reirradiation (R-RT) versus reirradiation in the treatment of patients with
first or second progression of glioblastoma

A.3.1

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

Randomisierte, unverblindete, multizentrische klinische Prüfung der Phase I/II zum Vergleich einer Re-Bestrahlung plus einer Gabe von BIBF1120 gegenüber einer alleinigen Re-Bestrahlung zur Behandlung von Patienten mit erster oder zweiter Progression eines Glioblastoms

A.3.2

Name or abbreviated title of the trial where available

NOA-12: BIBF1120 and R-RT in glioblastoma

A.4.1

Sponsor's protocol code number

NONK-3/NOA-12

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	Ruprecht-Karls-University Heidelberg, Medical Faculty
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
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	No
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	BIBF 1120
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	Nintedanib
D.3.9.2	Current sponsor code	BIBF 1120
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	No
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	BIBF 1120
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	Nintedanib
D.3.9.2	Current sponsor code	BIBF 1120
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

glioblastoma

Patienten mit dem ersten oder zweiten Progress eines
Glioblastoms nach dem Versagen der Standardtherapie, die eine
Radiochemotherapie mit Temozolomid beinhaltet hat und
welche außerdem Kandidaten für Re-Bestrahlung sind.

E.1.1.1

Medical condition in easily understood language

Patients with glioblastoma at first or second progression who have failed standard treatment that must have included radiochemotherapy with temozolomide and who are a candidate for a reirradiation

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10018337
E.1.2	Term	Glioblastoma multiforme
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I
- Maximal tolerated dose of BIBF1120 in combination reirradiation
- Safety and tolerability of BIBF1120 in conjunction with
radiotherapy
- Pharmacokinetic studies in plasma and cerebrospinal fluid

Phase II
Primary objective:
- 6 months rate of progression-free survival (PFS6)

E.2.2

Secondary objectives of the trial

Secondary objectives:
- Safety and tolerability of BIBF1120
Phase II
Secondary objectives:
- Safety and tolerability of BIBF1120
- Progression-free survival
- Objective response rates (OR)
- Duration of response (DR) in responders
- Overall survival
- Quality of life as determined by EORTC QLQ-C15-PAL and the
EORTC brain module QLQ-BN 20
- Cognitive function determined by MMSE/NeuroCoq Fx

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and female patients with a recurrence / progression of
glioblastoma either not being eligible for tumour resection or
having macroscopic residual tumor after resection of the
recurrence
- Diagnosis of glioblastoma must be proven histologically and
progress must be documented by MRI. MRI images must not be
older than 2 weeks before first dosing/start of RT
- Not more than two prior therapy regimens including one or two
resections, one or two chemotherapies (one temozolomidecontaining concomitant to radiotherapy) and one radiotherapy (RT) for the brain tumor
- Previous irradiation therapy of the primary tumor with a maximal dose of 60 Gy; at least 8 months since the end of preirradiation
- Candidate for reirradiation with recurrent tumor visible on MRIT1 (Gd) and with the largest diameter measuring 1 cm to 5 cm
- Informed consent
- Age ≥ 18 years, smoking or non-smoking, of any ethnic origin
- Karnofsky performance index (KPI) ≥ 60%
- Neutrophile counts > 1500/μl / Platelet counts > 80.000/μl /
Haemoglobin > 10 g/dl / Serum creatinine < 1.5-fold upper normal range / Bilirubin, AST or ALT < 2,5-fold upper normal range unless attributed to anticonvulsants / Alkaline phosphatase < 2,5-fold upper normal range
- Adequate contraception
- If on steroids, stable or decreasing treatment with steroids within 5 days before treatment start

E.4

Principal exclusion criteria

- More than one RT of brain, prior first radiotherapy with more than 60 Gy
- Cumulative total dose on the optical chiasm >54 Gy for 2
Gy/fraction, α/β=2
- Prior treatment with bevacizumab, iodine seeds and/or
brachytherapy
- Unable to undergo contrast-enhanced MRI
- Past medical history of diseases with poor prognosis according to the judgement of the Investigator, e.g. severe coronary heart
disease, severe diabetes, immune deficiency, residual deficits after
stroke, severe mental retardation
- HIV or hepatitis infection
- Pregnancy or breast feeding
- Treatment within any other clinical trial parallel to the treatment
phase of the current study or within 30 days before inclusion
- Known coronary artery disease, significant cardiac arrhythmias or severe congestive heart failure (NYHA class III – IV)

E.5 End points

E.5.1

Primary end point(s)

Phase I: Maximal tolerated dose of BIBF1120 in combination with reirradiation

Phase II: Progression free survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I: Daily evaluation of dose limiting toxicities
Phase II: every 6 weeks

E.5.2

Secondary end point(s)

Phase I: safety and tolerability
Phase II: response rates, overall survival, quality of life

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I: weekly evaluation
Phase II: every 6 weeks / 6 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Pharmacokinetic parameters of BIBF 1120 in plasma and cerebrospinal fluid

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

radiotherapy against radiotherapy with chemotherapy

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

Disease progression, unacceptable toxicity, need to reduce dose of BIBF1120 below 150 mg twice daily, need for another anticancer therapy, non-compliance of the patient, withdrawal of patient’s consent

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

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.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)

A 28-day and a 90-day follow-up visit should be carried out for all patients with the following assessments:
Physical / neurological examination, Vital signs, ,Karnofsky Performance Index, Changes in concomitant medication, adverse events. At the 90-day visit in addition: clinical chemistry, haematology, coagulation and urinalysis.
After this 8-weekly Follow-up-phone calls are carried out to collect survival information.

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

2012-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-09-30

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