Clinical Trials Register

Summary
EudraCT Number:	2004-002787-15
Sponsor's Protocol Code Number:	ML17102
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2005-05-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2004-002787-15

A.3

Full title of the trial

Phase III trial of combined immunochemotherapy with Fludarabine, Cyclophosphamide and Rituximab (FC-R) versus chemotherapy with Fludarabine and Cyclophosophamide (FC) alone in patients with previously untreated chronic lymphocytic leukemia.

Studio di fase III sull'immunochemoterapia con Fludarabina, Ciclofosfamide e Rituximab (FC-R) in confronto alla sola chemioterapia con Fludarabina e Ciclofosfamide (FC) in pazienti con leucemia linfatica cronica non trattata in precedenza.

A.3.1

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

Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia.

Fludarabina e Ciclofosfamide con o senza Rituximab in in pazienti con leucemia linfatica cronica non trattata in precedenza.

A.4.1

Sponsor's protocol code number

ML17102

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00281918

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	ROCHE
B.1.3.4	Country	Italy
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	F.Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Roche S.p.A.
B.5.2	Functional name of contact point	Head of Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Viale G.B. Stucchi, 110
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 039 247 5070
B.5.5	Fax number	+39 039 247 5084
B.5.6	E-mail	sergio.scaccabarozzi@roche.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	Yes
D.2.1.1.1	Trade name	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	RO 045-2294
D.3.9.4	EV Substance Code	SUB12570MIG
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	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	anticorpo monoclonale ricombinante umanizzato
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	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	RO 045-2294
D.3.9.4	EV Substance Code	SUB12570MIG
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	500
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	anticorpo monoclonale ricombinante umanizzato

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

chronic lymphatic leukaemia

leucemia cronica linfatica

E.1.1.1

Medical condition in easily understood language

Leukaemia

Leucemia

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10008958
E.1.2	Term	Chronic lymphocytic leukaemia
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

The objective of this study is to determine the value of immunochemotherapy with FCR in comparison with chemotherapy with FC alone in the first-line therapy of B-CLL. The study is to answer the following questions: • Is combined immunochemotherapy with FCR superior in terms of progression free survival to chemotherapy with FC alone in the first-line therapy of B-CLL? • Is combined immunochemotherapy with FCR a safe alternative to FC chemotherapy alone with regards to the adverse effects?

L'obbiettivo dello studio e' di determinare la validita' della immunochemioterapia con FCR in confronto a chemioterapia con la sola associazione FC nella terapia di prima linea della B-LLC. Lo studio dovra' fornire risposte alle seguenti domande: •L'associazione immunochemioterapica con FCR e' superiore alla chemioterapia con la sola associazione FC nella terapia di prima linea della B-LLC? •L'associazione immunochemioterapica con FCR rappresenta un' alternativa sicura alla chemioterapia con la sola associazione FC rispetto all'insorgenza di eventi avversi?

E.2.2

Secondary objectives of the trial

- Event-free survival - Overall survival - Disease-free survival - Duration of remission - Time to new CLL treatment or death - Rates of molecular, complete and partial remission - Response rates and survival times in biological subgroups - Rates of treatment-related adverse effects - Pharmacoeconomic impact - Quality of life

- Sopravvivenza libera da eventi- Sopravvivenza totale- Sopravvivenza libera da malattia- Durata della remissione- Tempo fino a nuovo trattamento di LLC o decesso- Percentuali di remissione molecolare,completa e parziale- Percentuali di risposta e tempi di sopravvivenza nei sottogruppi biologici- Percentuali degli eventi avversi correlati al trattamento- Impatto farmacoeconomico- Qualita' della Vita

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• B-CLL confirmed according to NCI Working Group criteria [1] • Binet stage C as well as Binet stage B requiring treatment All patients must fulfil the criteria of disease requiring treatment. Disease requiring treatment is defined as: • Binet stage C • Binet stage B plus at least one of the following signs or symptoms: – B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection) or constitutional symptoms (fatigue) – Continuous progression (doubling of peripheral lymphocyte count < 6 months AND absolute lymphocyte count > 50 x109/L) – evidence of progressive marrow failure as manifested by the development / worsening of anemia and/or thrombocytopenia – massive, progressive or painful splenomegaly or hypersplenism – massive lymph nodes or lymph node clusters (> 10 cm in longest diameter), danger of organ complications through large lymphomas (e.g. vascular compression, e.g. tracheal narrowing) or progressive lymphadenopathy – Occurrence of symptomatic hyperviscosity problems at leucocyte counts > 200 x109/L (symptomatic leucostasis) Attention: marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for protocol therapy. • No previous treatment of the CLL by chemotherapy, radiotherapy or immunotherapy. • Alkaline phosphatase and transaminases ≤ 2 x ULN • A negative serum pregnancy test one week prior to treatment must be available both for pre-menopausal women and for women who are < 2 years after the onset of menopause. • Willingness to use contraception for the entire duration of the treatment and 2 months thereafter • Patient`s written informed consent • Age ≥ 18 years • Life expectancy > 6 months • ECOG performance status 0-1 * Patients with stage Binet A requiring treatment could be included until July 2004 under the previous version of the protocol, but will not be included in the per protocol analysis.

•B-LLC confermata in base ai criteri del NCI Working Group; •Stadio C di Binet cosi' come stadio B di Binet che richieda trattamento Tutti i pazienti devono soddisfare i criteri per malattia che necessiti trattamento. Questa viene cosi' definita: - Stadio C di Binet - Stadio B di Binet piu' almeno uno dei seguenti segni o sintomi: Sintomi di tipo B (sudorazioni notturne, perdita di peso > 10% nei 6 mesi precedenti, febbre > 38 ° C o 100,4 ° F per > o = 2 settimane senza evidenza di infezioni) o sintomi di carattere costituzionale (affaticamento);Progressione continua (raddoppio della conta linfocitaria periferica in meno di 6 mesi E conta linfocitaria assoluta > 50 G/l); Evidenza di insufficienza midollare progressiva come mostrato dallo sviluppo / peggioramento dell’anemia e/o trombocitopenia;Splenomegalia cospicua, progressiva o dolorosa o ipersplenismo;Rigonfiamento cospicuo di linfonodi o loro raggruppamento in pacchetti (> 10 cm nel diametro piu' lungo), pericolo di complicazioni a livello di organi causato da grandi linfomi (ad es., compressione vascolare, stenosi tracheale) o linfoadenopatia progressiva; Comparsa di problemi dovuti a iperviscosita' per conte leucocitarie > 200 G/l (leucostasi sintomatica) La marcata ipogammaglobulinemia o la comparsa di proteine monoclonali in assenza di uno dei criteri sopra descritti per malattia attiva non e' sufficiente per il trattamento come da protocollo. •Nessun trattamento precedente di LLC con chemioterapia, radioterapia o immunoterapia •Fosfatasi alcalina e transaminasi < o = 2 x LSN •Il test di gravidanza sul siero deve risultare negativo ad una settimana di distanza dal trattamento sia per donne in eta' pre-menopausale che per donne che siano < 2 anni dall’inizio della menopausa •Consenso ad impiegare contraccezione per l’intera durata del trattamento e nei due mesi successivi •Consenso informato scritto del paziente •Eta' > o = 18 anni •Aspettativa di vita > 6 mesi •Stato di Validita' secondo ECOG: 0-1

E.4

Principal exclusion criteria

• Stage Binet A • Clinically significant auto-immune cytopenia, Coombs-positive haemolytic anaemia as judged by the treating physician. • Active second malignancy currently requiring treatment (except basal cell carcinoma or tumour treated curatively by surgery) • Pregnancy, and/or nursing • Concomitant disease requiring prolonged use of glucocorticoids (> 1 month) • Known hypersensitivity with anaphylactic reaction to humanised monoclonal antibodies or any of the study drugs • CIRS score > 6 • Cerebral dysfunction which makes it impossible to perform chemotherapy • Transformation to aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Richter`s syndrome, or prolymphocytic leukaemia). • Active bacterial, viral or fungal infection. Although testing for hepatitis B is not mandatory, this should be considered for all patients considered at high risk of hepatitis B infection and in endemic areas. Patients with any serological evidence of current or past hepatitis B infection are excluded unless the serological findings are clearly due to vaccination. • Total bilirubin > 2 x ULN • Creatinine clearance < 70 ml/min • Any coexisting medical or psychological condition that would preclude participation in the required study procedures. • Treatment with any other investigational agent, or participating in another clinical trial within 30 days prior to entering this study

•Stadio A di Binet •Citopenia autoimmune clinicamente significativa, anemia emolitica Coombs-positiva secondo il giudizio del medico •Malignita' secondaria attiva che richieda trattamento (ad eccezione del carcinoma basocellulare o tumore trattato in maniera radicale con chirurgia) •Gravidanza e/o allattamento al seno •Malattia concomitante che richieda uso prolungato di glicocorticoidi (> 1 mese) •Ipersensibilita' conosciuta con reazione anafilattica ad anticorpi monoclonali umanizzati o ad uno dei farmaci utilizzati in studio •Punteggio CIRS > 6 •Disfunzioni cerebrali che rendano impossibile l’effettuazione della chemioterapia •Trasformazione in malignita' aggressiva B-cellulare (ad es., linfoma diffuso a grandi cellule, sindrome di Richter, o leucemia prolinfocitica) •Infezione attiva batterica, virale o fungina •Bilirubina totale > 2 x LSN •Clearance della creatinina < 70 ml/min calcolata secondo la formula di Cockcroft e Gault •Qualsiasi coesistente condizione medica o psicologica che precluda la partecipazione alle procedure previste dallo studio.

E.5 End points

E.5.1

Primary end point(s)

- Progression-free survival (PFS)

- Sopravvivenza libera da progressione (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Median observation time at time of analysis was approximately 21 months.

E.5.2

Secondary end point(s)

- Event-free survival - Overall survival - Disease-free survival

- Sopravvivenza libera da eventi - Sopravvivenza totale - Sopravvivenza libera da malattia

E.5.2.1

Timepoint(s) of evaluation of this end point

Median observation time at time of analysis was approximately 21 months.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life

Qualita' della vita

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)

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

167

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

Australia

Israel

New Zealand

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 end of the trial is 31st October 2011 or your country approval date for this amendment after the last patient entered (unless all patients have died or withdrawn from the study before then).

La fine dello studio e' fissata al 31/10/2011 o alla data di approvazione nella nazione dell`Em. 3 al protocollo dopo l`arruolamento dell`ultimo paziente (a meno che tutti i pazienti non siano deceduti o si siano ritirati prima di tale data).

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

Number of subjects for this age range:

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:

567

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

250

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

734

F.4.2.2

In the whole clinical trial

817

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)

not applicable

non applicabile

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

2004-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2004-10-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-12-12

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IMP with orphan designation in the indication
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