Clinical Trials Register

Summary
EudraCT Number:	2012-002761-35
Sponsor's Protocol Code Number:	LAL1811
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2012-10-16
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

2012-002761-35

A.3

Full title of the trial

Trattamento di prima linea della Leucemia Linfoblastica Acuta (LLA) Philadelphia positiva (Ph+)/BCR/ABL+ con un nuovo potente inibitore delle Tirosin-chinasi (TKI), AP24534 (Ponatinib). Studio multicentrico, esplorativo, di fase II in pazienti di et� superiore ai 60 anni o non idonei al programma intensivo di chemioterapia e trapianto delle cellule staminali.

Front-line treatment of Philadelphia positive (Ph+)/BCR-ABL positive Acute Lymphoblastic Leukemia (ALL) with AP24534 (Ponatinib), a new potent tyrosine kinase inhibitor (TKI). A phase II exploratory multicentric study in patients more than 60 years old or unfit for a program of intensive chemotherapy and stem cell transplantation.

A.3.1

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

First line treatment for a kind of cancer which affects the generating cells of the white cells with a potent drug preventing the uncontrolled proliferation of the cancer cells. Study in elderly patients and in patients unfit for intensive antitumor drugs and for replacement of the cells from which result from blood cells.

Terapia di prima scelta nel trattamento di una forma di tumore che colpisce le cellule dalle quali hanno origine i globuli bianchi (cellule presenti nel sangue) con un farmaco potente che agisce contrastandone la crescita. Studio condotto in piu' centri su pazienti anziani e/o in pazienti che non possono essere trattati con farmaci forti e/o non possono sottoporsi alla sostituzione delle cellule da cui originano quelle del sangue.

A.4.1

Sponsor's protocol code number

LAL1811

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01641107

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	G.I.M.E.M.A. GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL'ADULTO
B.1.3.4	Country	Italy
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	Associazione Italiana contro le Leucemie
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	ARIAD
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	Fondazione GIMEMA
B.5.2	Functional name of contact point	Centro Dati GIMEMA
B.5.3	Address:
B.5.3.1	Street Address	via Casilina, 5
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00182
B.5.3.4	Country	Italy
B.5.4	Telephone number	0670390521
B.5.5	Fax number	0670390540
B.5.6	E-mail	gimema@gimema.it

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PONATINIB
D.3.2	Product code	AP24534
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	1114544-31-8
D.3.9.2	Current sponsor code	AP24534 (ponatinib) HCl
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	30
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	No
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	ponatinib
D.3.2	Product code	AP24534
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	1114544-31-8
D.3.9.2	Current sponsor code	AP24534 (ponatinib) HCl
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	15
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

Ph positive (Ph+)/Bcr-Abl positive Acute Lymphoblastic Leukemia (ALL)

Leucemia Acuta Linfoblastica (LAL) Ph +/BCR-ABL +

E.1.1.1

Medical condition in easily understood language

Abnormal proliferation of a kind of cells of the bone marrow (flexible tissue found in the interior of bone) which have a beginning the white cells, normal cells which are in the blood.

Malattia causata dalla crescita abnorme di alcune cellule del midollo osseo(tessuto molle presente all'interno di alcune ossa) progenitrici dei linfociti, cellule che si trovano nel sangue

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	LLT
E.1.2	Classification code	10000844
E.1.2	Term	Acute lymphoblastic leukaemia
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

The objective of the trial is to evaluate the therapeutic effects of Ponatinib in the patients with Ph+ ALL who are 60 or more than 60 years old, or are unfit for chemotherapy and stem cell transplantation. Since in these patients, the rate of CHR with other TKI is already closed to 100%, but the relapse rate at 1 year is 50% or more, the purpose of this study is to induce better and longer remissions.

L’obiettivo dello studio è valutare gli effetti terapeutici di Ponatinib nei pazienti affetti LLA Ph+ che abbiano 60 o più anni o che non siano idonei per chemioterapia e trapianto di cellule staminali. Poiché in questi pazienti, la percentuale di Remissione Ematologica Completa con altri TKI è già prossima al 100%, ma il tasso di recidiva a un anno è del 50% o più, lo scopo dello studio è indurre una migliore e più lunga remissione.

E.2.2

Secondary objectives of the trial

To evaluate: • The Complete Hematological Response (CHR) at 6, 12, 24, 36 and 48 weeks. • The Complete Cytogenetic Response (CCgR) at 6, 12, 24, 36 and 48 weeks and duration of CCgR. • The Complete molecular response (CMolR) and major molecular response (MMR) at 12, 24, 36 and 48 weeks, and the duration of CMolR. • Type and number of BCR-ABL kinase domain mutations developing during and after the study. • Relationship between the response and the biomarkers. • Event Free Survival (EFS). • Overall Survival (OS). • Failure Free Survival (FFS). • The treatment toxicity.

Valutare: • La Risposta Ematologica Completa (CHR) a 6, 12, 24, 36 e 48 settimane. • La Risposta Citogenetica Completa (CCgR) a 6, 12, 24, 36 e 48 settimane e la durata della CCgR. • La Risposta Molecolare Completa (CMolR) e la Risposta Molecolare Maggiore (MMR) a 12, 24, 36 e 48 settimane, e la durata della CMolR. • Il tipo ed il numero di mutazioni del dominio della chinasi BCR-ABL che si sviluppano durante e dopo lo studio. • La relazione tra la risposta ed i biomarkers. • Event Free Survival (EFS). • Overall Survival (OS). • Failure Free Survival (FFS). • La tossicità del trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. To be classified as having Ph+ ALL, patients must have >20% blasts in bone marrow at the time of diagnosis and no prior history of CML. 2. Patients with previously untreated Ph+ and/or BCR/ABL + ALL: - age ≥ 60 years old or - age ≥ 18 years old, but unfit for program of intensive therapy and allogeneic SCT 3. Signed written informed const according to ICH/EU/GCP and national local laws. 4. Effective contraception.

1. I pazienti, per essere classificati come affetti da LAL Ph+, devono avere, al momento della diagnosi, una concentrazione di blasti nel midollo osseo >20% e non devono presentare una precedente storia di Leucemia Mieloide Cronica (CML). 2. Pazienti con una LAL Ph+ and/or BCR/ABL + precedentemente non trattata: - di età ≥ 60 anni - di età ≥ 18 anni, ma non eleggibili per un programma di terapia intensiva o per un trapianto allogenico di cellule staminali 3. Consenso informato scritto in accordo con le ICH/EU/GCP e la normativa locale nazionale. 4. Contraccezione efficace.

E.4

Principal exclusion criteria

1. Uncontrolled congestive heart failure or/and uncontrolled hypertension. 2. History of myocardial infarction within 3 months, or uncontrolled angina pectoris. 3. Significant electric heart abnormalities, including history or presence of significant ventricular or atrial tachyarrhythmias, congenital long QT syndrome and/or QTc > 450 msec on screening ECG (using the QTcF formula) . 4. WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG). 5. Active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN. 6. Creatinine level > 2.5mg/dl or Glomerular Filtration Rate (GFR) < 20 ml/min or proteinuria > 3.5 g/day. 7. History of acute pancreatitis within 1 year of study, or history of chronic pancreatitis, history of alcohol abuse; ongoing or active infection; uncontrolled hypertriglyceridemia (triglicerides > 450 mg/dL). 8. Impairment of gastrointestinal (GI) function, or a GI disease that may significantly alter the absorption of study drugs (e.g., severe malabsorption syndrome, or extended small bowel resection). 9. Patients who are currently receiving treatment with any of the medications listed in Appendix D if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix D have the potential to prolong QT. 10. Patients who have received any investigational drug ≤ 4 weeks. 11. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy. 12. Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Ponatinib). Post menopausal women must be amenorrhoic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs. 13. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention. 14. Patients unwilling or unable to comply with the protocol.

1. Insufficienza cardiaca congestizia incontrollata e/o ipertensione incontrollata. 2. Storia di infarto miocardico entro 3 mesi, o angina pectoris incontrollata. 3. Anomalie elettrocardiografiche significative rilevate all’ECG basale (usando la formula QTcF), compresa anamnesi o presenza di tachiaritmie ventricolari o atriali, sindrome del QT lungo congenita e/o QTc > 450 msec. 4. Performance status WHO ≤ 50% (Karnofsky) o ≥ 3 (ECOG). 5. Epatite attiva da virus HBV o HCV, o AST/ALT ≥ 2.5 x ULN e bilirubina ≥ 1.5 x ULN. 6. Livelli di creatinina > 2.5mg/dl o Tasso di Filtrazione Glomerulare (GFR) < 20 ml/min o proteinuria > 3.5 g/die. 7. Anamnesi di pancreatite acuta entro un anno dall’inizio dello studio, o anamnesi di pancreatite cronica, storia di abuso di alcool; infezioni in corso o attive; ipertrigliceridemia incontrollata (trigliceridi > 450 mg/dL). 8. Deficit della funzione gastrointestinale, o presenza di una patologia gastrointestinale che possa alterare significativamente l’assorbimento dei farmaci in studio (es: grave sindrome da malassorbimento, o estesa resezione chirurgica dell’intestino tenue). 9. Pazienti che stanno attualmente ricevendo un trattamento con una qualsiasi delle terapie elencate nell’Appendix D, qualora le terapie non possono essere interrotte o cambiate con una differente terapia prima di iniziare il farmaco sperimentale. I farmaci elencati nell’Appendix D possono potenzialmente prolungare il tratto QT. 10. Pazienti che abbiano ricevuto qualsiasi farmaco sperimentale nelle precedenti 4 settimane. 11. Pazienti che siano stati sottoposti a chirurgia maggiore nelle due settimane precedenti l’inizio del farmaco sperimentale o che non siano guariti dagli effetti collaterali di un simile terapia. 12. Donne in gravidanza o che allattano al seno e adulti potenzialmente fertili che non utilizzano un efficace metodo di barriera per il controllo delle nascite (Le donne potenzialmente fertili devono eseguire un test di gravidanza che risulti negativo entro le 48 ore precedenti la somministrazione di Ponatinib). Le donne in menopausa non devono aver avuto il ciclo mestruale nei 24 mesi prima dell’inizio della terapia per essere considerate come non potenzialmente fertili. Uomini e donne devono essere d’accordo ad utilizzare una efficace metodica contraccettiva di barriera durante lo svolgimento dello studio e per 3 mesi successivi all’ultima somministrazione del farmaco sperimentale. 13. Pazienti con anamnesi di un’altra neoplasia maligna primitiva che risulti clinicamente significativa o che richieda attualmente un intervento attivo. 14. Pazienti non disposti o incapaci di attenersi al protocollo.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the proportion of patients who are in CHR (as defined in Section 11) at 6 months, calculated on the total number of patients who have been enroled and have received at least one dose of the first drug (prednisone).

L'endpoint primario è la proporzione di pazienti che sono in Remissione Ematologica Completa a 6 mesi, calcolata sul numero totale dei pazienti che sono stati arruolati e che hanno ricevuto almeno una dose del primo farmaco(prednisone).

E.5.1.1

Timepoint(s) of evaluation of this end point

During and at the end of the study.

Durante e alla fine dello studio.

E.5.2

Secondary end point(s)

To evaluate: • The rate of Complete Hematological Response (CHR) (as defined in Section 9) at 6, 12, 24, 36 and 48 weeks. • The rate of Complete Cytogenetic Response (CCgR) (as defined in Section 9) at 6, 12, 24, 36 and 48 weeks and duration of CCgR. • The rate of Complete molecular response (CMolR) and major molecular response (MMR) (as defined in Section 9) at 12, 24, 36 and 48 weeks, and the duration of CMolR. • Type and number of BCR-ABL kinase domain mutations developing during and after the study. • Relationship between the response and the biomarkers. • Event Free Survival (EFS) calculated as defined in section 9. • Overall Survival (OS) calculated as defined in section 9. • Failure Free Survival (FFS) calculated as defined in section 9. • Side effects, adverse events (AE) and serious AE (SAE).

Tasso di CHR a 6,12, 24, 36 e 48 settimane;
Tasso di remissione CCgR a 6,12, 24, 36 e 48 ela durata della CCgR;
il tasso di CMolR, la RMM 12, 24, 36 e 48 e la durata della CMolR;
tipo e numero di mutazioni del dominio della chinasi BCR-ABL che si sviluppano durante e dopo lo studio;
la relazione tyra la risposta ed il biomarker;
event free survival; overall survival;Failure Free Survival; effetti collaterali; eventi avversi ed eventi avversi gravi.

E.5.2.1

Timepoint(s) of evaluation of this end point

During and at the end of the study.

Durante e alla fine dello studio.

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)

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

E.8.1.1

Randomised