Clinical Trials Register

Summary
EudraCT Number:	2016-000521-38
Sponsor's Protocol Code Number:	EORTC-08112
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-30
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-000521-38

A.3

Full title of the trial

Nintedanib as maintenance treatment of malignant pleural mesothelioma (NEMO): a double-blind randomized phase II study of the EORTC Lung Cancer Group

A.3.1

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

Nintedanib as maintenance treatment of malignant cancer of the pleura

A.3.2

Name or abbreviated title of the trial where available

NEMO

A.4.1

Sponsor's protocol code number

EORTC-08112

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02863055

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	European Organisation for Research and Treatment of Cancer
B.1.3.4	Country	Belgium
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	European Organisation for the Research and Treatment of Cancer
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Boehringer Ingelheim Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	European Organisation for the Research and Treatment of Cancer
B.5.2	Functional name of contact point	Regulatory Affairs Department
B.5.3	Address:
B.5.3.1	Street Address	83/11 Avenue E. Mounier
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	003227741511
B.5.5	Fax number	003227727063
B.5.6	E-mail	regulatory@eortc.org

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH & Co. KG
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.3.1	Product name	Nintedanib 100 mg
D.3.2	Product code	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.3.9.1	CAS number	656247-17-5
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	NINTEDANIB
D.3.9.4	EV Substance Code	SUB120728
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
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH & Co. KG
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.3.1	Product name	Nintedanib 150 mg
D.3.2	Product code	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.3.9.1	CAS number	656247-17-5
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	NINTEDANIB
D.3.9.4	EV Substance Code	SUB120728
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
D.8 Placebo: 2
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

Malignant pleural mesothelioma

E.1.1.1

Medical condition in easily understood language

Patient with malignant cancer of the pleura

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10035606
E.1.2	Term	Pleural mesothelioma malignant localised
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

the primary objective is to evaluate activity in terms of progression-free survival of nintedanib versus placebo as switch maintenance after first line chemotherapy treatment for patients with unresectable Malignant Pleural Mesothelioma

E.2.2

Secondary objectives of the trial

- To evaluate the activity of nintedanib relative to placebo in terms of Overall Survival
- To evaluate the activity of nintedanib relative to placebo in terms of Time to Treatment Failure
- To evaluate the activity of nintedanib relative to placebo in terms of Overall Response Rate according to modified RECIST
- To assess the treatment safety according to CTCAE version 4.0.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

♦Histological diagnosis of unresectable Malignant Pleural Mesothelioma (MPM);
♦ Response or Stable disease according to modified RECIST criteria (Ref. 48) after first line platinum-pemetrexed chemotherapy for 4-6 cycles;
♦ Last platinum chemotherapy dose administered within 60 days (i.e. randomization must occur within 60 days from the last dose of the last cycle of platinum-pemetrexed chemotherapy);
♦ Age ≥ 18 years;
♦ ECOG performance status 0-2;
♦ Life expectancy of at least 12 weeks in the opinion of the investigator;
♦ Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of first dose:
♦ hemoglobin ≥9.0 g/dL;
♦ neutrophil count ≥ 1.5 x109/L;
♦ platelet count ≥ 100 x109/L;
♦ adequate renal function:
♦ Serum creatinine ≤ 1.5 mg/dL or ≤ 130 μmol/l; or GFR >45mL/min (If serum creatinine is greater than 1.5 mg/dL, then CrCl must be ≥ 50 mL/min (either according to Cockroft-Gault (Appendix D) or determined by 24 -hour urine collection));
♦ No proteinuria CTCAE grade 2 or greater;
♦ total bilirubin ≤1.5 x upper limit of normal;
♦ ALT and AST ≤1.5 x upper limit of normal for patients without any liver metastasis or ≤2.5 x upper limit of normal for patients with liver metastasis;
♦ alkaline phosphatase ≤ 4 x upper limit of normal;
♦ PT-INR (international normalized ratio of PT) / PTT ≤ 1.5 x upper limit of normal;
♦ Ability to understand and the willingness to sign a written informed consent;
♦ Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
♦ Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
♦ Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
♦ A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
♦ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
♦ Intrauterine device (IUD)
♦ Intrauterine hormone-releasing system (IUS)
♦ Bilateral tubal occlusion
♦ Vasectomised partner
♦ Sexual abstinence
♦ Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy. Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 3 months after the last study treatment.

E.4

Principal exclusion criteria

♦ Prior systemic anticancer therapy including cytotoxic or immune-checkpoint inhibitor therapy, for MPM, other than first line platinum-based doublet chemotherapy;
♦ Previous extra-pleural pneumonectomy (other forms of previous surgery eg pleurectomy are acceptable);
♦ Previous Vascular Endothelial Growth Factor (VEGF) inhibitors (eg bevacizumab, sorafenib, etc);
♦ Patients that, in the opinion of the investigator, have reduced performance status by 2 ECOG levels (e.g. PS 0 to 2 or PS 1 to 3) from beginning to completion of 1st line chemotherapy;
♦ Radiotherapy (with the exception of palliative radiotherapy) during study or within 3 weeks of start of study drug;
♦ Active brain metastases (e.g. stable for < 4 weeks; no adequate previous treatment with radiotherapy; symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization); patients with suspicious neurological symptoms should undergo a CT scan/MRI of the brain to assess brain metastasis;
♦ Leptomeningeal metastases;
♦ Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the present trial;
♦ Pre-existing clinically significant ascites and/or clinically significant pleural effusion;
♦ Active or chronic hepatitis C and/or B infection;
♦ Active or history of bleeding complications that would prevent anti-angiogenic therapy e.g.:
♦ Major injuries and/or surgery within the past ten days prior to randomization with incomplete wound healing; no surgery planned during the on-treatment study period;
♦ Evidence or history of bleeding diathesis or coagulopathy;
♦ History of clinically significant hemoptysis within the past 3 months (more than one tea-spoon of fresh blood per day);
♦ History of major thrombotic or clinically relevant major bleeding event in the past 6 months;
♦ Known inherited predisposition to bleeding or thrombosis;
♦ Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels; typical mediastinal pleural involvement with mesothelioma remains eligible;
♦ Clinically active cancer other than mesothelioma within 5 years prior to start of study treatment;
♦ Radiographic evidence of cavitatory or necrotic tumors;
♦ Treatment with other investigational drugs or treatment in another clinical interventional trial within the past 4 weeks before start of therapy or concomitantly with the trial;
♦ Unstoppable use of therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid ≤ 325mg per day);
♦ Clinically significant cardiovascular diseases (i.e. hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, congestive New York Heart Association (NYHA) II, serious cardiac arrhythmia, clinically significant pericardial effusion);
♦ Any clinical, psychological, familial, sociological or geographical condition that is unstable or could jeopardize the safety of the patient and their compliance in the study protocol and follow-up schedule (those conditions should be discussed with the patient before registration in the trial), e.g.:
♦ Clinically active ulcers (gastro-intestinal tract, skin);
♦ Known or suspected allergy to the investigational agent or any agent given in association with this trial;
♦ Clinically serious infections requiring systemic antibiotic (e.g antiviral, antimicrobial, antifungal) therapy;
♦ Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results;
♦ Allergy to soy or peanuts;
♦ Patients unable to swallow oral medications or any malabsorption condition.

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival according to modified RECIST criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 8 weeks (+/-1 week), until disease progression irrespective of treatment delays, interruptions or early treatment discontinuation (for any other reason than disease progression)

E.5.2

Secondary end point(s)

- Overall Survival
- Time to Treatment Failure
- Overall Response Rate (according to modified RECIST)
- Safety/toxicity

E.5.2.1

Timepoint(s) of evaluation of this end point

- Overall Survival: every 4 weeks
- Time to Treatment Failure: every 4 weeks
- Overall Response Rate (according to modified RECIST): every 8 weeks
- Safety/toxicity: every 4 weeks

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

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

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

Egypt

Belgium

Italy

United Kingdom

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 study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis

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:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

114

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)

according to the discretion of the treating clinician

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

2017-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-06-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-10-12

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