Clinical Trials Register

Summary
EudraCT Number:	2012-001355-38
Sponsor's Protocol Code Number:	AP-24534-12-301
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:	2012-09-21
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

2012-001355-38

A.3

Full title of the trial

A Phase 3 Randomized, Open-Label Study of Ponatinib versus Imatinib in Adult Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

Studio di Fase III, Randomizzato, in Aperto, con Ponatinib verso Imatinib in Pazienti adulti con Leucemia Mieloide Cronica in Fase Cronica di nuova diagnosi

A.3.1

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

advanced phase study, randomised, open with ponatinib versus imatinib in patients with Chronic Mieloyd Leukemia newly diagnosed

studio di fase avanzata con trattamento scelto su base casuale, aperto, con ponatinib in confronto a imatinib, in pazienti affetti da Leucemia Mieloide cronica in fase cronica di nuova diagnosi

A.3.2

Name or abbreviated title of the trial where available

EPIC

A.4.1

Sponsor's protocol code number

AP-24534-12-301

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	ARIAD PHARMACEUTICALS,INC.
B.1.3.4	Country	United States
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	Ariad Pharmaceuticals Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmanet Services GmbH Filiale Italiana
B.5.2	Functional name of contact point	Clinical Monitoring
B.5.3	Address:
B.5.3.1	Street Address	Via Maurizio Gonzaga 7
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20123
B.5.3.4	Country	Italy
B.5.4	Telephone number	02 8905 3711
B.5.5	Fax number	02 8905 3730
B.5.6	E-mail	dmarchesini@pharmanet-i3.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	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	C (2010) 789
D.3 Description of the IMP
D.3.1	Product name	Ponatinib
D.3.2	Product code	AP24534
D.3.4	Pharmaceutical form	Film-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	ponatinib
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	45
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)	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	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europhatrm Ltd
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	Film-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 MESILATE
D.3.9.1	CAS number	220127-57-1
D.3.9.4	EV Substance Code	SUB12517MIG
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	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)	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	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

Chronic Myeloid Leukemia

Leucemia Mieloide Cronica

E.1.1.1

Medical condition in easily understood language

Chronic Leukemia

Leucemia Cronica

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	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10054352
E.1.2	Term	Chronic phase chronic myeloid leukemia
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 ponatinib with imatinib as measured by major molecular response (MMR) rate at 12 months (1 month or cycle = 28 days)

Confrontare l’efficacia di ponatinib e imatinib attraverso la misurazione del grado di risposta molecolare maggiore (MMR) a 12 mesi (1 mese o ciclo = 28 giorni).

E.2.2

Secondary objectives of the trial

• To compare, according to treatment with ponatinib versus imatinib, MMR rate at 5 years
• To compare the proportion of patients achieving a ratio of <10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (<10% BCR-ABLIS), in patients administered ponatinib versus those administered imatinib
• To compare, according to treatment with ponatinib versus imatinib, the complete cytogenetic response (CCyR) rate at 12 months
• To compare, according to treatment with ponatinib versus imatinib, progression-free survival and overall survival

• Per confrontare, in base al trattamento con ponatinib rispetto a imatinib, il grado di MMR a 5 anni
• Confrontare la proporzione di soggetti che a 3 mesi raggiungono un rapporto tra i livelli di trascritto BCR-ABL e ABL < 10% secondo la scala internazionale (< 10% BCR-ABLIS) nei pazienti a cui è stato somministrato ponatinib e quelli a cui è stato somministrato imatinib.
• Confrontare, secondo il trattamento con ponatinib rispetto a imatinibGrado di risposta citogenetica completa (CCyR, Complete Cytogenetic Response) a 12 mesi.
• Confrontare, secondo il trattamento con ponatinib rispetto a imatinib, la sopravvivenza libera da progressione e la sopravvivenza globale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients ≥18 years old
2. CP CML within 6 months of diagnosis
a. CP CML will be defined by
i <15% blasts in bone marrow
ii <30% blasts plus promyelocytes in bone marrow
iii <20% basophils in peripheral blood
iv ≥100 × 109/L platelets (≥100,000/mm3)
v No evidence of extramedullary disease except hepatosplenomegaly
vi No prior diagnosis of accelerated phase (AP) or blast phase (BP) CML
3. Cytogenetic assessment must demonstrate the BCR ABL fusion by presence of the t(9;22) Philadelphia chromosome
a. Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques
b. Conventional chromosome banding must be performed
c. A minimum of 20 metaphases must be assessable at entry
4. ECOG Performance Status of 0, 1, or 2
5. Adequate hepatic function as defined by the following criteria:
a. Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome
b. Alanine aminotransferase (ALT) ≤2.5 × ULN
c. Aspartate aminotransferase (AST) ≤2.5 × ULN
6. Adequate renal function as defined by the following criterion:
a. Serum creatinine <1.5 × ULN
7. Adequate pancreatic function as defined by the following criterion:
a. Serum lipase and amylase ≤1.5 × ULN
8. For females of childbearing potential, a negative pregnancy test must be documented prior to randomization
9. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners from randomization through 30 days after the end of treatment
10. Provide written informed consent
11. Willingness and ability to comply with scheduled visits and study procedures

1. Pazienti di sesso maschile e femminile d’età ≥ 18 anni.
2. Diagnosi di CP-CML entro 6 mesi dalla diagnosi.
a. La diagnosi CP-CML sarà definita attraverso:
i < 15% blasti nel midollo osseo
ii < 30% blasti + promielociti nel midollo osseo
iii < 20% basofili nel sangue periferico
iv ≥ 100 × 109/l piastrine (≥ 100.000/mm3)
v nessuna evidenza di malattia extramidollare tranne epatosplenomegalia
vi nessuna precedente diagnosi di CML in fase accelerata (AP, accelerated phase) o in fase blastica (BP, blast phase).
3. La valutazione citogenetica deve dimostrare la fusione BCR-ABL con la presenza del cromosoma Philadelphia t(9;22).
a. Traslocazioni varianti sono ammesse solo a patto che siano valutabili per la risposta citogenetica tramite tecniche citogenetiche convenzionali.
b. È necessario effettuare un bandeggio cromosomico convenzionale.
c. Al momento dell’arruolamento deve essere verificabile un numero minimo di 20 metafasi.
4. Performance status (PS) ECOG di 0, 1 o 2.
5. Funzionalità epatica adeguata come definito dai seguenti criteri:
a. bilirubina sierica totale ≤ 1,5 x limite superiore di normalità (ULN, upper limit of normal), a meno che non sia presente la sindrome di Gilbert
b. alanina aminotransferasi (ALT) ≤ 2,5 × ULN
c. aspartato aminotransferasi (AST) ≤ 2,5 × ULN.
6. Funzionalità epatica adeguata come definito dal seguente criterio:
a. creatinina sierica < 1,5 x ULN.
7. Funzionalità pancreatica adeguata come definito dal seguente criterio:
a. amilasi e lipasi sierica ≤ 1,5 × ULN.
8. Per le pazienti di sesso femminile in età fertile, prima della randomizzazione deve essere fornito un test di gravidanza negativo.
9. I pazienti di sesso maschile e femminile in età fertile devono acconsentire all’uso di un metodo efficace di contraccezione durante i rapporti con i loro partner, dal momento della randomizzazione fino a 30 giorni dopo la fine del trattamento.
10. Rilascio di un consenso informato in forma scritta.
11. Volontà e capacità di attenersi alle visite programmate e alle procedure dello studio.

E.4

Principal exclusion criteria

1. Received prior imatinib therapy
2. Received prior dasatinib therapy
3. Received prior nilotinib therapy
4. Received, for CML, any other systemic anticancer therapy, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea
5. Major surgery within 28 days prior to initiating therapy
6. History of bleeding disorder unrelated to CML
7. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
8. History of alcohol abuse
9. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
10. Significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to:
a. Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to randomization
b. History of clinically significant (as determined by the treating physician) atrial arrhythmia; or any ventricular arrhythmia
11. Uncontrolled hypertension (diastolic blood pressure >100 mm Hg; systolic >150 mm Hg)
12. Taking medications that are known to be associated with Torsades de Pointes (Appendix A)
13. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection
14. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history
15. Pregnant or breastfeeding
16. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs
17. Diagnosed with or received anticancer therapy for another primary malignancy within 3 years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ)
18. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug

1. Precedente terapia con imatinib.
2. Precedente terapia con dasatinib.
3. Precedente terapia con nilotinib.
4. Qualsiasi altra terapia antitumorale sistemica, terapia sperimentale, o radioterapia (con l’eccezione di anagrelide o idrossiurea) per la CML.
5. Intervento di chirurgia maggiore nei 28 giorni prima dell’avvio della terapia.
6. Anamnesi di disturbi emorragici non correlati alla CML.
7. Anamnesi di pancreatite acuta nell’anno precedente lo studio o anamnesi di pancreatite cronica.
8. Anamnesi di abuso di alcol.
9. Ipertrigliceridemia non controllata (trigliceridi > 450 mg/dl) in atto.
10. Malattia cardiovascolare significativa non controllata o attiva, comprendente in particolare, ma non limitata a:
a. infarto miocardico, angina instabile e/o insufficienza cardiaca congestizia nei 3 mesi precedenti la randomizzazione
b. anamnesi di aritmia atriale clinicamente significativa (secondo la valutazione del medico curante) o di qualsiasi aritmia ventricolare.
11. Ipertensione non controllata (pressione arteriosa diastolica > 100 mm Hg, sistolica > 150 mm Hg).
12. Assunzione di farmaci di cui è nota l’associazione con la sindrome da Torsades de Pointes (Appendice A).
13. Infezioni in corso o attive. La necessità di antibiotici endovena (EV) è considerata un’infezione attiva.
14. Anamnesi accertata di infezione da virus dell’immunodeficienza umana acquisita (HIV). In assenza di tale anamnesi il test non è necessario.
15. Gravidanza o allattamento al seno.
16. Sindrome da malassorbimento o altra patologia gastrointestinale che possa interferire con l’assorbimento per via orale dei farmaci in studio.
17. Diagnosi o trattamento antitumorale ricevuto per un’altra forma maligna primaria nei 3 anni precedenti all’arruolamento (tranne che per tumore della pelle non-melanoma o cancro cervicale in situ).
18. Qualsiasi condizione o malattia che, secondo l’opinione dello sperimentatore, comprometterebbe la sicurezza del paziente o interferirebbe con la valutazione del farmaco.

E.5 End points

E.5.1

Primary end point(s)

MMR rate at 12 months (1 month or cycle = 28 days)

Grado di MMR a 12 mesi (1 mese o ciclo = 28 giorni).

E.5.1.1

Timepoint(s) of evaluation of this end point

at 12 months

a 12 mesi

E.5.2

Secondary end point(s)

• MMR rate at 5 years
• <10% BCR ABLIS rate at 3 months
• CCyR rate at 12 months
• Progression-free survival
• Overall survival

1 Grado di MMR a 5 anni.
2 Valore di BCR-ABLIS a 3 mesi < 10%.
3 Grado di CCyR a 12 mesi.
4 Sopravvivenza libera da progressione.
5 Sopravvivenza globale.

E.5.2.1

Timepoint(s) of evaluation of this end point

various

vari

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

Yes

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)

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

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

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

Hong Kong

Israel

Korea, Republic of

New Zealand

Singapore

South Africa

Switzerland

Taiwan

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

LPLV

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:

350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

175

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

390

F.4.2.2

In the whole clinical trial

528

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)

expanded access/compassionate use

accesso allargato/uso compassionevole/

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

2012-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-10-18

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