Clinical Trials Register

Summary
EudraCT Number:	2012-005834-12
Sponsor's Protocol Code Number:	NVALT19
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-05-17
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

Netherlands - Competent Authority

A.2

EudraCT number

2012-005834-12

A.3

Full title of the trial

Switch maintenance treatment with gemcitabine for patients with malignant mesothelioma who do not progress after 1st line therapy with a pemetrexed-platinum combination. A randomised open label phase II study.
NVALT 19

Onderhoudsbehandeling met gemcitabine bij patiënten met longvlieskanker bij wie de tumor niet groeit na de eerste lijn chemotherapie met een pemetrexed –platinum combinatie. Een gerandomiseerde fase II studie.

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

Maintenance treatment with gemcitabine for patients with malignant mesothelioma

NVALT19

A.4.1

Sponsor's protocol code number

NVALT19

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	Stichting NVALT studies
B.1.3.4	Country	Netherlands
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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	KWF Kankerbestrijding
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	NVALT mesothelioma working party
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NVALT
B.5.2	Functional name of contact point	NVALT Datacenter
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066 CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310205122672
B.5.5	Fax number	+310205122679
B.5.6	E-mail	wa.multicenter@nki.nl

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	Gemcitabine
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Powder 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 1000
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 histologically or cytologically proven malignant mesothelioma

Patiënten met histologisch of cytologisch bewezen borstvlieskanker

E.1.1.1

Medical condition in easily understood language

malignant mesothelioma

longvlieskanker

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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	10035605
E.1.2	Term	Pleural mesothelioma malignant advanced
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

Determine the potential improvement of the duration of progression-free survival by maintenance treatment with gemcitabine

Bepalen van de mogelijke verlenging van de duur van progressie-vrije overleving door onderhoudsbehandeling met gemcitabine

E.2.2

Secondary objectives of the trial

1. To compare the objective radiological response (ORR) rate
2. To compare overall survival (OS)
3. To assess and compare the lung function
4. To describe the toxicity
5. To identify potential biomarkers

1. Het vergelijken van de objectieve radiologische response (ORR)
2. Het vergelijken van de algemene overleving (OS)
3. Het beoordelen en vergelijken van de longfunctie
4. Het beschrijven van de toxiciteit
5. Het identificeren van mogelijke biomarkers

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients with histologically or cytologically proven malignant mesothelioma
• Age >18 years.
• At the date of randomisation, the patients must have completed 4 cycles of first-line chemotherapy with a platinum (cisplatin or carboplatin) and pemetrexed combination at least 21 days but no more than 42 days prior to study entry, and have no evidence of progressive disease following first-line treatment.
• Measurable or evaluable disease, according to modified RECIST criteria for pleural mesothelioma
• Ability to understand the study and give signed informed consent prior to beginning of protocol specific procedures.
• WHO performance status ≤ 2
• Adequate organ function as evidenced by the following peripheral blood counts or serum chemistries at study entry:
- Hematology: Neutrophil count ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l, Hemoglobin ≥ 6.2 mmol/l.
- Hepatic function as defined by serum bilirubin ≤ 1.25 times the upper limit of normal (ULN), ALT and AST ≤ 2.5 times the ULN, except if liver metastases then ALAT and ASAT < 5 times the ULN.
- Renal function as defined by serum creatinine ≤ 1.25 times ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula).

• Patiënten met histologisch of cytologisch bewezen borstvlieskanker
• Leeftijd ≥ 18 jaar
• Op de dag van randomisatie moeten de patiënten 4 cycli eerstelijns chemotherapie met een platinum (cisplatin of carboplatin)-pemetrexed combinatie hebben voltooid, minstens 21 dagen en niet meer dan 42 dagen voor start van de studie en geen evidente progressieve ziekte vertonen na eerstelijns behandeling.
• Meetbare of evalueerbare ziekte, volgens gemodificeerde RECIST criteria voor pleuraal mesothelioom
• Patient moet in staat zijn om de studie te begrijpen en informed consent te geven, voordat er studie specifieke procedures worden gestart.
• ECOG performance status < 2
• Adequaat orgaan functie zoals blijkt uit de volgende perifere bloedwaarden of serum chemie voor start van de studie:
- Hematologie: Neutrofielen ≥ 1.5 x 109/l, Thrombocyten ≥ 100 x 109/l, Hemoglobine ≥ 6.2 mmol/l.
- Lever functie gedefinieerd als serum bilirubin ≤ 1.25 x ULN, ALT en AST ≤ 2.5 x ULN, behalve als er sprake is van levermetastasen, dan mag het ALAT en ASAT < 5 x ULN zijn.
- Nierfunctie gedefinieerd als serum creatinine ≤ 1.25 x ULN of creatinine klaring ≥ 50 ml/min (berekend met de Cockcroft-Gault formule).

E.4

Principal exclusion criteria

• Active uncontrolled infection, severe cardiac dysfunction or uncorrectable bleeding tendency.
• Presence of symptomatic CNS metastases.
• Radiotherapy within 2 weeks prior to study entry.
• Unstable peptic ulcer, unstable diabetes mellitus or other serious disabling condition.
• Concomitant administration of any other experimental drugs under investigation.

• Actieve ongecontroleerde infectie, ernstig hartfalen of niet corrigeerbare bloedingsneiging.
• Aanwezigheid van symptomatische uitzaaiingen in de hersenen.
• Radiotherapie binnen 2 weken voor start van de studie.
• Actieve maagzweer, slecht ingestelde suikerziekte of andere ernstige actieve aandoeningen.
• Gelijktijdige behandeling met enig ander experimenteel geneesmiddel.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is progression free survival, defined as time from randomisation to disease progression or death (in case no progression has been documented)

Het primaire eindpunt is progressie vrije overleving, gedefinieerd als de tijd tussen randomiseren en ziekte progressie of dood (in het geval er geen progressie gedocumenteerd is)

E.5.1.1

Timepoint(s) of evaluation of this end point

every 6 weeks

Elke 6 weken

E.5.2

Secondary end point(s)

- Adverse events
- Objective radiological response rate in patients with measurable disease
- Overall survival
- Changes in vital capacity and FEV1.

- Adverse events
- Objectieve radiologische respons bij patiënten met meetbare ziekte
- Algemene overleving
- Veranderingen in vitale capaciteit en FEV1.

E.5.2.1

Timepoint(s) of evaluation of this end point

every 6 weeks until off-study, thereafter every 12 weeks until dead

elke 6 weken t/m offstudy, daarna elke 12 weken tot aan overlijden

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

Yes

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

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

beste ondersteunende verzorging

best supportive care

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

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 final analysis will be performed 1 year after the last patient has been randomized. It will take 3 years to register all patients (124) in the trial.

De eindanalyse zal plaatsvinden 1 jaar nadat de laatste patient gerandomiseerd is. Het zal 3 jaar duren voordat alle patienten (124) in de studie geregistreerd zijn.

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

124

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)

Patients who progress in the treatment arm are treated according to the best options as suggested by their treating physicians.
Patients in the control arm are similary treated. The protocol suggests to consider second line therapy with gemcitabine.

Patiënten die progressie vertonen in de behandelingsarm worden behandeld volgens de beste opties zoals voorgesteld door hun behandelende artsen.
Patiënten in de controle-arm worden op dezelfde wijze behandeld. Het protocol stelt voor om tweedelijns therapie met gemcitabine te overwegen.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	NVALT mesothelioma working party
G.4.3.4	Network Country	Netherlands

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-09

P. End of Trial
P.	End of Trial Status	Ongoing

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