Clinical Trials Register

Summary
EudraCT Number:	2014-002161-30
Sponsor's Protocol Code Number:	1302.5
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-05
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2014-002161-30

A.3

Full title of the trial

A multicenter, randomized, double-blind Phase III trial to evaluate efficacy and safety of BI 695502 plus chemotherapy versus Avastin® plus chemotherapy in patients with advanced nonsquamous Non-Small Cell Lung Cancer

Multicentrikus, randomizált, kettős vak, III. fázisú vizsgálat a kemoterápia mellett alkalmazott BI 695502 és a kemoterápia mellett alkalmazott Avastin® hatásosságának és biztonságosságának összehasonlító értékelésére előrehaladott, nem laphámsejtes, nem kissejtes tüdőrákban szenvedő betegek esetében

A.3.1

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

A study evaluating the efficacy and safety of BI 695502 plus chemotherapy versus Avastin® plus chemotherapy in patients with advanced nonsquamous Non-Small Cell Lung Cancer

Kemoterápia mellett alkalmazott BI 695502 és a kemoterápia mellett alkalmazott Avastin® hatásosságának és biztonságosságának összehasonlító értékelésére előrehaladott, nem laphámsejtes, nem kissejtes tüdőrákban szenvedő betegek esetében

A.4.1

Sponsor's protocol code number

1302.5

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	Boehringer Ingelheim International GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim International 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	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.com

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.3.2	Product code	BI 695502
D.3.4	Pharmaceutical form	Concentrate for 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	BI 695502
D.3.9.2	Current sponsor code	BI 695502
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Humanized Monoclonal Antibody
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Genentech
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Concentrate for 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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells.

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

Recurrent or metastatic disease (Stage IV), histologically or cytologically confirmed advanced nonsquamous Non-Small Cell Lung Cancer.

Visszatérő vagy áttétetes (IV stádium) szövettanilag vagy citológiailag
igazolt előrehaladott, nem laphamsejtes, nem kissejtes tüdőrák

E.1.1.1

Medical condition in easily understood language

Advanced nonsquamous non-small cell lung cancer.

Előrehaladott nem laphámsejtes, nem kissejtes tüdőrák

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029522
E.1.2	Term	Non-small cell lung cancer stage IV
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10059515
E.1.2	Term	Non-small cell lung cancer metastatic
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029515
E.1.2	Term	Non-small cell lung cancer recurrent
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

To establish statistical equivalence in terms of efficacy (best overall response rate [ORR] ,proportion of patients with complete response [CR] plus partial response [PR]) until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or Avastin®. As of 21 Dec2017, Sponsor recommends that patients should be switched from BI695502 to the reference product bevacizumab (IMP or commercially available Avastin®, both hereafter referred to as Avastin®) as soon as it is available at the respective clinical site.

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate further efficacy parameters, the safety and tolerability of BI 695502 versus Avastin®.
Further objectives are to evaluate the PK of BI 695502 versus Avastin® as well as the presence of antidrug antibodies (ADAs) and neutralizing antidrug antibodies (nADAs).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Aged ≥18 years (for Japan only: Age ≥20 years at Screening)
- Recurrent or metastatic disease (Stage IV) with an indication for therapy with
paclitaxel + carboplatin + Avastin®
- Negative epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation status. Patients harboring tumors with unknown or positive EGFR or ALK mutation may be included, provided chemotherapy is the site standard-of-care for those patients. Despite EGFR/ALK mutational status, patients may enter the trial if the site's best standard of care would be administer such a chemotherapy regimen for that specific patient. However, if an EGFR/ALK test result is pending, and chemotherapy treatment would be switched in case of a mutational positive result, patients may not be included in this trial.
-Patients must have at least one measurable lesion according to RECIST 1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- Life expectancy >6 months based on clinical judgment.
-Patients must have adequate hepatic, renal, and bone marrow function.

E.4

Principal exclusion criteria

- Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF
or VEGF receptors, including Avastin®.
- Prior systemic therapy for metastatic disease ( Prior systemic therapy and/or radiotherapy for locally advanced disease permitted if completed >12 months prior to Screening) .
- Known symptomatic brain metastasis.
- Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung,
NSCLC NS (not specified) or NSCLC NOS (not otherwise specified).
- Contraindication to bevacizumab

E.5 End points

E.5.1

Primary end point(s)

Best ORR based on unconfirmed response assessment as assessed by central imaging review until 18 weeks after the start of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy : Screening, Weeks 0, 6,12,18 visit

E.5.2

Secondary end point(s)

Efficacy:
• Progression-free survival (PFS) defined as the time from randomization until disease progression as per investigator assessment or death.
• Overall survival (OS) defined as the time from randomization until death of any cause.
• Duration of response defined as the time from first documented CR or PR until time of progression as per investigator assessment.

Safety:
• The proportion of patients with AEs
• The proportion of patients with AEs related to trial treatment
• The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0
• The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0 related to trial treatment
• The proportion of patients with AEs potentially related to immunogenicity.

Other endpoints:
Evaluation of PK of BI 695502 versus Avastin® and presence of antidrug antibodies (ADAs) and neutralizing antidrug antibodies (nADAs).

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy :
Screening, Weeks 0, 6,12,18,27... End of Treatment (EOT) visit

Safety:
Screening, Weeks 0,3,6,9,12,15,18,21,25,27 and onwards, End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit.

Other endpoints

Immunogenicity:
Weeks 0, 3, 6, 12, 18, 27, then every 9 weeks until End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit.

Pharmacokinetics:
Weeks 0,3,6,9,12,15,18,27 then every 9 weeks until End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit.

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

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

123

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Brazil

Bulgaria

Chile

Croatia

Egypt

Germany

Greece

Hungary

Italy

Japan

Korea, Republic of

Malaysia

Mexico

Philippines

Poland

Portugal

Romania

Russian Federation

Serbia

South Africa

Spain

Thailand

Turkey

Ukraine

United Kingdom

United States

Vietnam

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

The trial will be closed when all randomized and treated patients have either died, are lost to follow-up, or have withdrawn consent, or for a maximum of 20 months after the last patient randomized plus the EOT visit, whichever occurs earlier.

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:

410

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

261

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient's legally accepted representative)

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

146

F.4.2.2

In the whole clinical trial

671

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)

None

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

2015-09-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-16

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