Clinical Trials Register

Summary
EudraCT Number:	2005-000657-29
Sponsor's Protocol Code Number:	CSTI571K2301
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2005-08-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2005-000657-29

A.3

Full title of the trial

A randomized open label study of 400 mg versus 800 mg of Gleevec/glivec (imatinib mesylate) in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints

Studio randomizzato in aperto, con imatinib mesilato 400 mg versus 800 mg in pazienti con leucemia mieloide cronica in fase cronica di nuova diagnosi, precedentemente non trattati, con l'utilizzo di endpoint molecolari.

A.4.1

Sponsor's protocol code number

CSTI571K2301

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	NOVARTIS FARMA
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/01/021
D.3 Description of the IMP
D.3.1	Product name	imatinib
D.3.2	Product code	STI571
D.3.4	Pharmaceutical form	Coated tablet
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	Imatinib
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/01/021
D.3 Description of the IMP
D.3.1	Product name	imatinib
D.3.2	Product code	STI571
D.3.4	Pharmaceutical form	Coated tablet
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	Imatinib
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	400
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

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

treatment of pts with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP)

Trattamento della leucemia mieloide cronica in fase cronica in pazienti di nuova diagnosi (de novo)

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10009013
E.1.2	Term	Chronic myeloid 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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the efficacy of 800 mg Gleevec/Glivec (as 400 mg bid) with that of 400 mg qd Gleevec/Glivec in newly diagnosed, previously untreated Philadelphia chromosomepositive CML-CP patients. The primary efficacy endpoint will be the rate of major molecular response defined as Bcr-Abl ratio ≤ 0.1% ≥ 3 log reduction of Bcr-Abl transcripts from a standardized baseline) as detected by RT-PCR at 12 months.

Stabilire se imatinib 800 mg e' piu' efficace di imatinib 400 mg b.i.d. nel trattamento di pazienti con Leucemia Mieloide Cronica in fase cronica (LMC-CP) di nuova diagnosi e non pre-trattati, mediante valutazione della risposta molecolare a 12 mesi (determinazione quantitativa con RT-PCR dell'entita' della riduzione del trascritto Bcr-Abl misurato su scala logaritmica).

E.2.2

Secondary objectives of the trial

• To determine the rate of complete hematologic response (CHR) in the two treatment arms • To determine the rate of complete cytogenetic response (CCyR) in the two treatment arms • To evaluate the time to (CCyR), major molecular response, and complete molecular response in the two treatment arms • To compare the percentage of patients with a major molecular response and with undetectable levels of Bcr-Abl transcripts at 12 months and yearly thereafter in the two treatment arms • To compare progression-free survival (PFS) in the two treatment arms: • To compare event-free survival (EFS) in the two treatment arms • To evaluate the safety profile of Gleevec/Glivec when given at 800 mg daily administered as 400 mg bid • To evaluate the actual dose-intensity delivered amongst the two treatment arms • To validate major molecular response (MMR) as a prognostic factor for PFS

•Det.la freq della risp ematol•Det.la freq della risp citogenetica completa(RCC).•Valut T alla RCC,risp molecolare e alla risp molecolare completa.•Confr.la % di paz con una riduz dei trascritti Bcr-Abl>=3 log e con livelli non misurabili di trascritti Bcr-Abl a 12 mesi e successivamente annualmente.•Valut laPFS a 5 aa.•Valut il profilo di sicur.di imatinib sommin alla dose di 800 mg/die rispetto a 400 mg b.i.d.•Valut la reale intensità della dose sommin nei 2 gruppi di tratt.•Valut la risp molecolare(RM)quale fatt prognostico per il tempo allaprogr•Valut la qualità della vita e l'utilizzo delle ris sanit•Det.le caratteristiche farmacocinetiche dopo la sommin di imatinib 400 mg versus imatinib 800 mg.•Esplorare le mutazioni tumorali specifiche.•Valut l'attivazione della via Bcr-Abl misurata mediante fosforilazione della tirosina delle molecole a valle del Bcr-Abl,quali Crkl e STAT-5.•Esplorare la correlazione tra il trascritto Bcr-Abl,la via di attivazione Bcr-Abl e la risp clinica.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

ALTRI SOTTOSTUDI:
markers biologici

E.3

Principal inclusion criteria

1. Ability to provide written informed consent prior to participation to the study. 2. Male or female patients ≥ 18 and ≤ 75 years of age 3. Patients with CML-CP within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow and be of satisfactory quality as outlined in Section 3.5.2.2 (Bone marrow analysis and cytogenetics). FISH analysis will not be accepted. 4. Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations and presence of Bcr- Abl 5. Documented chronic phase CML as defined by: • < 15% blasts in peripheral blood and bone marrow • < 30% blasts plus promyelocytes in peripheral blood and bone marrow • < 20% basophils in the peripheral blood • ≥ 100 x 109/L (≥ 100,000 /mm3) platelets • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly 6. Adequate end organ function as defined by: • total bilirubin < 1.5 x ULN • SGOT and SGPT < 2.5 x ULN • creatinine < 1.5 x ULN 7. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug.

· Consenso informato scritto. · Pazienti di entrambi i sessi di eta` >= 18 anni e <= 75 anni. · Pazienti con diagnosi di CML-CP non anteriore ai 6 mesi precedenti l'ingresso nello studio (la data della diagnosi corrisponde alla data della prima analisi citogenetica). Deve essere eseguita l'analisi citogenetica convenzionale su midollo osseo. L'analisi FISH non e` accettata. · Diagnosi di leucemia mieloide cronica in fase cronica, con conferma citogenetica della presenza del cromosoma Philadelphia, varianti di traslocazioni (9;22) e presenza di bcr-abl. · Fase cronica documentata di LMC definita come: o < 15% di blasti nel sangue e nel midollo osseo o < 30% di blasti piu` promielociti nel sangue periferico e nel midollo osseo o < 20% di basofili nel sangue periferico o >= 100 x 109/L ( >= 100,000/mm3) piastrine o nessuna evidenza di malattia extramidollare, con l'eccezione di epato-splenomegalia. · Funzionalita` organica adeguata definita come: o Bilirubina totale < 1,5 x ULN o SGOT e SGPT < 2,5 x ULN o Creatinina < 1,5 x ULN · Nelle donne potenzialmente fertili, deve essere eseguito un test di gravidanza sul siero, con esito negativo, nei 7 giorni precedenti l'inizio dello studio.

E.4

Principal exclusion criteria

1. Patients in late chronic phase (i.e., chronic phase diagnosed greater than 6 months ago), accelerated phase, or blastic phase are excluded 2. Patients who have received other investigational agents 3. Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed, except with any dose of Gleevec/Glivec for up to 2 weeks prior to study entry. 4. Patient received any treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide 5. Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention 6. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential). 7. Patient with a severe or uncontrolled medical condition (i.e., uncontrolled diabetes, chronic renal disease) 8. Patient previously received radiotherapy to ≥ 25% of the bone marrow 9. Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery 10. Patients with an ECOG Performance Status Score ≥ 3 11. Patients with International normalized ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants 12. Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required 13. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent 14. Patients with identified sibling donors where allogeneic bone marrow transplant is elected as first line treatment

· Pazienti in fase cronica tardiva (ad es: fase cronica diagnosticata oltre 6 mesi), fase accelerata o fase blastica. · Pazienti trattati con altri farmaci sperimentali. · Trattamento con inibitori della tirosina-chinasi prima dell'ingresso nello studio, ad eccezione di imatinib, a qualsiasi dosaggio, fino a 2 settimane prima dell'ingresso nello studio. · Trattamento per LMC prima dell'ingresso nello studio della durata superiore ad 2 settimane, ad eccezione di idrossiurea e/o anagrelide. · Anamnesi positiva per altra condizione maligna primaria clinicamente significativa oppure che richiede un intervento terapeutico al momento dell'ingresso del paziente nello studio. · Gravidanza e allattamento. Pazienti potenzialmente fertili che non presentano un test di gravidanza sul siero, con esito negativo, all'ingresso nello studio e uomini e donne che non utilizzano un metodo contraccettivo efficace (metodo di barriera). Le donne in menopausa, per essere considerate non fertili, devono essere in amenorrea da almeno 12 mesi. · Condizioni cliniche gravi o non controllate (ad es. diabete non controllato, insufficienza renale cronica). · Trattamento precedente con radioterapia >= 25% del midollo osseo. · Interventi chirurgici maggiori nelle 4 settimane precedenti l'inizio dello studio o assenza di guarigione. · ECOG Performance Status Score >= 3. · Pazienti con INR o PTT > 1,5 x IULN ad eccezione di pazienti in trattamento con anticoagulanti orali. · Diagnosi nota di infezione da HIV (il test dell'HIV non e` obbligatorio). · Scarsa collaborazione o incapacita` di partecipare allo studio. · Pazienti con fratelli donatori identificati, per i quali il trapianto allogenico di midollo osseo e` considerato il trattamento di prima scelta.

E.5 End points

E.5.1

Primary end point(s)

Hematologic and/or cytogenetic response rates (newly diagnosed chronic phase, IFN failure chronic phase,accelerated phase, blast crisis) and progression-free survival (newly diagnosed chronic phase patients).

Risposta ematologica e/o citogenetica (fase cronica di nuova diagnosi, fase cronica - fallimento della terapia con IFN, fase accelerata, crisi blastica) e sopravvivenza libera da progressione (pazienti in fase cronica di nuova diagnosi).

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

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

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-08-24.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	15
F.4.2	For a multinational trial
F.4.2.1	In the EEA	50
F.4.2.2	In the whole clinical trial	420

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

2005-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-07-26

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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