Clinical Trials Register

Summary
EudraCT Number:	2015-000591-97
Sponsor's Protocol Code Number:	CLSG-CNS-001
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-05-22
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

Czechia - SUKL

A.2

EudraCT number

2015-000591-97

A.3

Full title of the trial

Study evaluating relapses in central nervous system in patients with diffuse large B-cell lymphoma treated with chemotherapy with or without CNS prophylaxis. Multicentric, prospective randomized phase III study

Studie sledující relapsy v centrálním nervovém systému u pacientů s difuzním velkobuněčným B-lymfomem léčených chemoterapií s nebo bez CNS profylaxe.
Multicentrická, prospektivní randomizovaná studie fáze III

A.3.1

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

Clinical study trying to answer the question if preventive treatment (prophylaxis) will lower the number of relapses (returns of the disease) in central nervous system in one of the aggressive form of lymph node cancer. The study is being performed in several centres, data will be collective prospectively and patients will be distributed to treatment groups by chance.

Klinická studie snažící se odpovědět na otázku, jestli preventivní léčba (profylaxe) sníží počet relapsů (návratů nemoci) v centrálním nervovém systému u jedné z agresívních forem nádoru z mízních uzlin. Studie bude prováděna v několika centrech, data budou sbírána prospektivně (tj. v průběhu studie) a rozdělení pacientů do jednotlivých léčebných skupin bude náhodné.

A.3.2

Name or abbreviated title of the trial where available

CNS relapse prophylaxis in DLBCL

Profylaxe CNS relapsů u DLBCL

A.4.1

Sponsor's protocol code number

CLSG-CNS-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02777736

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	Kooperativní lymfomová skupina, o.s.
B.1.3.4	Country	Czech Republic
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	Czech Lymphoma Study Group
B.4.2	Country	Czech Republic
B.4.1	Name of organisation providing support	Czech Ministry of Public Health
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Czech Lymphoma Study Group
B.5.2	Functional name of contact point	Všeobecná fakultní nemocnice
B.5.3	Address:
B.5.3.1	Street Address	U Nemocnice 2
B.5.3.2	Town/ city	Praha 2
B.5.3.3	Post code	128 08
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+420224962528
B.5.5	Fax number	+420224963118
B.5.6	E-mail	trnkova@lymphoma.cz

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	Methotrexate Hospira 100 mg/ml inj sol
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Methotrexate Hospira 100 mg/ml inj sol
D.3.4	Pharmaceutical form	Solution for injection/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	Methotrexate
D.3.9.1	CAS number	59-05-2
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
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	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	Methotrexate Hospira 25 mg/ml inj sol
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Methotrexate Hospira 25 mg/ml inj sol
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrathecal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methotrexate
D.3.9.1	CAS number	59-05-2
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
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	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

Diffuse large B-cell lymphoma

Difusní velkobuněčný B-lymfom

E.1.1.1

Medical condition in easily understood language

Aggressive lymph node cancer of B-cell origin

Agresívní nádorové onemocnění z mízních uzlin z B buněk

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
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

Comparison of cumulative incidence of CNS relapses in patients treated with 2 doses of intravenous methotrexate 3g/m2 (arm A) or 6 doses of intrathecal methotrexate 12mg (arm B).

Srovnání výskytu relapsu v CNS (cumulative incidence of CNS relapses) u pacientů léčených 2 dávkami intravenózního metotrexátu 3g/m2(rameno A) nebo 6 dávkami intrathekálního metotrexátu 12mg (rameno B).

E.2.2

Secondary objectives of the trial

- Evaluation and comparison of overall, survival (OS) in patients treated with 2 doses of intravenous methotrexate, 6 doses of intrathecal methotrexate and in patients without CNS prophylaxis.
- Evaluation of overall response rate (ORR),complete remission rate (CRR) in all three arms of the study (A, B, C), analysis of treatment toxicity.
- Evaluation of progression-free survival (PFS) in CNS and outside of CNS in all risk groups (low, intermediate and high risk).
- Evaluation of definition of occult meningeal involvement: cumulative incidence of CNS relapses in subgroups with occult meningeal involvement.

- Vyhodnocení a srovnání celkového přežití (overall, survival, OS) u pacientů léčených 2 dávkami intravenózního metotrexátu, 6 dávkami intrathekálního metotrexátu a u pacientů bez CNS profylaxe.
- Vyhodnocení počtu celkových odpovědí (overall response rate, ORR), kompletních remisí (complete remission rate, CRR) v jednotlivých ramenech studie (A, B, C), vyhodnocení toxicity léčby.
- Vyhodnocení přežití bez relapsu (PFS) v CNS a mimo CNS v jednotlivých rizikových skupinách (nízké, střední a vysoké riziko).
- Ověřění definice nejasného meningeálního postižení: výskyt CNS relapsů ve skupinách s nejasným postižením likvoru.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1/histologically confirmed untreated DLBCL
2/age 18-72 years
3/signed informed consent with the study
4/planned first-line treatment 6 cycles of R CHOP +2x R or 6 cycles of DA EPOCH R+ 2xR

1/histologicky potvrzený neléčený DLBCL
2/věk 18-72let
3/podepsaný informovaný souhlas se studií
4/plánovaná léčba první linie 6x R CHOP +2x R nebo 6x DA EPOCH R+ 2xR

E.4

Principal exclusion criteria

1/ patients with DLBCL and concomitant initial CNS involvement
2/ patients with PMBL
3/ DLBCL patients with planned another chemotherapy than R CHOP or DA EPOCH R
4/ HIV positive, or active hepatitis B or C
5/ other serious disease (based on the decision of the physician-investigator)
6/ non-compliance of a patient
7/ every containdication for administration of antracyclin regimen or high dose methotrexat
8/ pregnancy or breast-feeding

1/ pacienti s DLBCL a současně s iniciálním CNS postižením
2/ pacienti s PMBL
3/ pacienti s DLBCL, u nichž je plánovaná jiná chemoterapie než R CHOP nebo DA EPOCH R
4/ HIV pozitivní, nebo s aktivní hepatitidou B nebo C
5/ jiné závažné onemocnění (na základě rozhodnutí ošetřujícího lékaře)
6/ non-compliance pacienta
6/ jakákoliv kontraindikace k podání antracyklinového režimu nebo vysokodávkovaného metotrexátu
8/ těhotenství nebo kojení

E.5 End points

E.5.1

Primary end point(s)

Comparison of cumulative incidence of CNS relapses in patients treated either with methotrexate 3g/m2 i.v. or 6 doses of intrathecal methotrexate 12mg.

Srovnání kumulativního výskytu CNS relapsů u pacientů léčených 2 dávkami intravenózního metotrexátu 3g/m2 nebo 6 dávkami intrathekálního metotrexátu 12mg.

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year after end of treatment.

1 rok po ukončení léčby.

E.5.2

Secondary end point(s)

1. Complete remissions and partial remissions – will be evaluated according to PET/CT-Cheson criteria (49).
Overall survival (OS) is defined as period between the date from diagnosis until date of death due to any reason.
2. Evaluation of definition of occult meningeal involvement: cumulative incidence of CNS relapses in subgroups with occult meningeal involvement:
a/occult FCM positivity and concomitant CSF cytology negative;
b/FCM negative and concomitant occult positivity of CSF cytology;
3. Validtion of clinical predictive risk model

1. Kompletní remise (CR) a parciální remise budou vyhodnoceny pomocí PET/CT vyšetření podle Chesonových kritérií z roku 2014 (49).
Celkové přežití pacientů (overall survival, OS) je definováno jako doba od zahájení léčby do úmrtí z jakékoliv příčiny.
2. Ověřění definice nejasného meningeálního postižení: výskyt CNS relapsů ve skupinách, kde je likvor:
a/FCM nejasně pozitivní a současně cytologie negativní;
b/FCM negativní a současně cytologie nejasně pozitivní;
3. Ověření klinického prediktivního modelu

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year after end of treatment

1 rok po ukončení léčby

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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)

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

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

Různá dávka a různý způsob podání stejného produktu

Different dose and application route of the same product

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

LVLS

Poslední návštěva posledního subjektu

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

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:

160

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

200

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)

Standard follow-up and care.

Standardní sledování a péče.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-04

P. End of Trial
P.	End of Trial Status	Completed

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