Clinical Trials Register

Summary
EudraCT Number:	2012-005062-34
Sponsor's Protocol Code Number:	PhilosoPhi34
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-12-21
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

2012-005062-34

A.3

Full title of the trial

An open label, single arm, phase II study of nilotinib 300 mg BID in newly diagnosed
CP-CML patients, in order to verify disappearance of CD34+/lin-Ph+ cells from bone marrow
during treatment.

Studio non randomizzato di fase II con Nilotinib 300 mg BID in pazienti con nuova diagnosi di leucemia mieloide cronica (LMC) in fase cronica, al fine di verificare la scomparsa delle cellule CD34+/lin-Ph+ midollari durante il trattamento

A.3.1

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

An open label, single arm, phase II study of nilotinib 300 mg BID in newly diagnosed
CP-CML patients, in order to verify disappearance of CD34+/lin-Ph+ cells from bone marrow
during treatment.

Studio non randomizzato di fase II con Nilotinib 300 mg BID in pazienti con nuova diagnosi
di leucemia mieloide cronica (LMC) in fase cronica, al fine di verificare la scomparsa delle
cellule CD34+/lin-Ph+ midollari durante il trattamento

A.3.2

Name or abbreviated title of the trial where available

PhilosoPhi34

A.4.1

Sponsor's protocol code number

PhilosoPhi34

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	AZIENDA OSPEDALIERA OSPEDALE NIGUARDA CA' GRANDA (A.O. DI RILIEVO NAZIONALE)
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	REL Niguarda Novartis
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SC EMATOLOGIA
B.5.2	Functional name of contact point	ester.pungolino@ospedaleniguarda.it
B.5.3	Address:
B.5.3.1	Street Address	P.zza Ospedale Maggiore 3
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20162
B.5.3.4	Country	Italy
B.5.4	Telephone number	0264442367 0264442668
B.5.5	Fax number	0264443019 0264442033
B.5.6	E-mail	ester.pungolino@ospedaleniguarda.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	Yes
D.2.1.1.1	Trade name	TASIGNA*112CPS 150MG
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Capsule, hard
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	NILOTINIB
D.3.9.1	CAS number	641571-10-0
D.3.9.4	EV Substance Code	SUB25225
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	150
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

newly diagnosed CP-CML patients

pazienti con nuova diagnosi di leucemia mieloide cronica (LMC) in fase cronica

E.1.1.1

Medical condition in easily understood language

newly diagnosed CP-CML patients

pazienti con nuova diagnosi di leucemia mieloide cronica (LMC) in fase cronica

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	10052065
E.1.2	Term	Chronic phase chronic myeloid leukaemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To verify the disappearance of BM CD34+/lin- Ph+ cells at the end of 6 months of treatment using cell selection system and FISH in patients showing a CCyR.

Verificare, mediante selezione cellulare e FISH, la scomparsa delle cellule midollari CD34+/lin- Ph+ nei pazienti in risposta citogenetica completa, dopo 6 mesi di trattamento con Nilotinib.

E.2.2

Secondary objectives of the trial

To estimate CCyR at 3, 6 and 12 months; to estimate the percentage of patients with MR ≤ 10% IS at 3 months in the peripheral blood (PB); to estimate the percentage of patients with MR ≤ 1% IS at 6 months in the PB; to estimate MMR IS by 3, 6 and 12 month periods in the PB; to estimate MR4,5 IS by 3, 6 and 12 month periods in the PB; to estimate the disappearance of CD34+/lin- Ph+ cells in the BM at the end of 3 and 12 months of treatment using cell selection system and FISH.

valutare la CCyR a 3, 6 e 12 mesi; Stimare la percentuale di pazienti con risposta molecolare (MR) ≤ 10% IS, dopo 3 mesi di trattamento, da sangue periferico (SP); Stimare la percentuale di pazienti con MR ≤ 1% IS, dopo 6 mesi di trattamento, da SP; Stimare la MMR in IS a 3, 6, e 12 mesi, da SP; Stimare la MR4,5 in IS a 3, 6 e 12 mesi, da SP; Valutare la scomparsa delle cellule CD34+/lin-Ph+ nel midollo osseo dopo 3 e 12 mesi di trattamento, mediante l’impiego di selezione cellulare e FISH

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome [(9;22) translocation] within 3 months of diagnosis; 2. Patients Ph negative or with variant translocations by standard cytogenetic analysis but Ph positive by FISH, are eligible as well; 3. Age ≥ 18 years old (no upper age limit given); 4. WHO performance status ≤2; 5. Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication; 6. AST and ALT ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to leukaemia; 7. Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukaemia; 8. Total bilirubin ≤ 1.5 x ULN, except know Mb Gilbert; 9. Serum lipase and amylase ≤ 1.5 x ULN; 10. Serum creatinine ≤ 1.5 x ULN; 11.Written informed consent signed prior to any study procedures being performed.

1. Pazienti (maschi e femmine) affetti da LMC in fase cronica, con conferma citogenetica della presenza della t(9;22), entro 3 mesi dalla diagnosi; 2. Pazienti con citogenetica normale, o con traslocazioni varianti, ma con Ph positività confermata in FISH; 3. Età ≥ 18 anni (non è dato un limite massimo di età); 4. Performance status ≤ 2 secondo classificazione WHO; 5. Concentrazioni sieriche di potassio, magnesio, calcio e fosforo nella norma o correggibili mediante supplementazione prima dell’inizio del trattamento con Nilotinib (1° dose); 6. Concentrazioni di AST e ALT ≤ 2.5 x ULN (o ≤ 5.0 x ULN se alterazione correlata allo stato di malattia); 7. Valori di fosfatasi alcalina ≤ 2.5 x ULN (se alterazione non correlata allo stato di malattia); 8. Bilirubina totale ≤ 1.5 x ULN (salvo nei casi di noto morbo di Gilbert); 9. Valori di lipasi e amilasi sieriche ≤ 1.5 x ULN; 10. Creatinina sierica ≤ 1.5 x ULN; 11. Presenza di consenso informato scritto firmato prima di qualsiasi procedura relativa allo studio

E.4

Principal exclusion criteria

1. Pre-treatment with hydroxyurea for > 3 months and with imatinib is not permitted; 2. Prior accelerated phase including clonal evolution or blast crisis; 3. Contraindication to excipients in study medication; 4. Known impaired cardiac function including any of the following: a. LVEF < 45% b. Complete left bundle branch block c. Right bundle branch block plus left anterior hemiblock, bifascicular block d. Use of a ventricular-paced pacemaker e. Congenital long QT syndrome f. History or presence of clinically significant ventricular or atrial tachyarrhythmias g. Clinically significant resting bradycardia (< 50 beats per minute) h. QTcF > 450 msec on screening ECG. If QTcF > 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion i. Myocardial infarction within 12 months prior to starting nilotinib j. Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension); 5. History of acute (i.e. within 1 year of starting study medication) or chronic pancreatitis; 6. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol; 7. Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery); 8. Concomitant medications with potential QT prolongation (see link for complete list: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm); 9. Concomitant medications known to be strong inducers or inhibitors of the CYP450 Isoenzyme CYP3A4:see link for complete list (http://medicine.iupui.edu/flockhart/table.htm); 10. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy; 11. Patients who are pregnant or breast feeding or women of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib. Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. 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 drug; 12. Treatment with any haematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF) ≤ 1 week prior to starting study drug; 13. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory); 14. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention; 15. Patients unwilling or unable to comply with the protocol.

1. Non sono consentiti il pretrattamento con idrossiurea per più di 3 mesi e la terapia con Imatinib; 2. Fase accelerata di malattia, evoluzione clonale o crisi blastica; 3. Controindicazione agli eccipienti contenuto nel farmaco in studio; 4. Cardiopatia nota, con una qualsiasi delle seguenti alterazioni: a. FE < 45% b. blocco di branca sinistro completo c. blocco di branca destro più emiblocco anteriore sinistro, blocco bifascicolare d. impiego di un pace-maker ventricolare e. sindrome congenita del QT lungo f. storia o presenza di tachiaritmie ventricolari o atriali clinicamente significative g. bradicardia a riposo clinicamente significativa (< 50 battiti al minuto) h. QTcF > 450 msec all’ECG di screening. Se QTcF > 450 msec ed elettroliti al di fuori del range di normalità prima dell’inizio di nilotinib, gli elettroliti andrebbero corretti e il paziente rivalutato per rideterminazione del QTcF i. infarto miocardico nei 12 mesi precedenti l’inizio del nilotinib j. altre patologie cardiache clinicamente significative (es: angina instabile, insufficienza cardiaca congestizia, ipertensione non controllata); 5. Storia di pancreatite acuta (entro un anno dall’inizio del farmaco in studio) o cronica; 6. Altre condizioni patologiche concomitanti non controllate (es. diabete non controllato, infezioni attive o non controllate, epatopatia e nefropatia acute o croniche) che potrebbero causare rischi inaccettabili per la sicurezza del paziente o compromettere l’aderenza al protocollo; 7. Compromissione della funzionalità gastrointestinale o patologie che possano alterare l’assorbimento del farmaco in studio (es. malattia ulcerativa, nausea incontrollata, vomito e diarrea, sindrome da malassorbimento, resezioni del piccolo intestino o by-pass gastrico); 8. Terapie concomitanti, che determinino potenziale rischio di prolungamento del QT (confrontare il seguente link per la lista completa: http://www.torsades.org/medical-pros/drug-lists/printabledrug- list.cfm); 9. Terapia concomitanti note per essere induttori o inibitori dell’isoenzima CYP3A4 del CYP450: per una lista completa vede il seguente link (http://medicine.iupui.edu/flockhart/table.htm); 10. Pazienti sottoposti a interventi di chirurgia maggiore nelle 2 settimane precedenti l’inizio della terapia con nilotinib, che presentino ancora effetti avversi di tali interventi; 11.Donne in gravidanza o allattamento o donne in età fertile, che non impieghino metodi contraccettivi efficaci. Le donne in età fertile devono aver effettuato un test di gravidanza, risultato negativo, nei 14 giorni prima dell’inizio della somministrazione di nilotinib. Le donne in menopausa devono presentare amenorrea da almeno 12 mesi al fine di essere considerate non potenzialmente fertili. Le pazienti di sesso femminile devono accettare di impiegare metodi contraccettivi di barriera per l’intera durata dello studio e fino a 3 mesi dopo l’uscita dallo studio; 12.Trattamento con qualunque fattore di crescita emopoietico (es. G-CSF, GM-CSF) nella settimana prima dell’inizio del trattamento; 13.Diagnosi nota di infezione da HIV (il test per l’HIV non è obbligatorio); 14.Pazienti con storia di altre neoplasie primitive, che siano correntemente clinicamente significative o che richiedano interventi attivi; 15.Pazienti che non vogliano o non siano in grado di aderire al protocollo

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is to measure the rate of CD34+/lin-Ph+ cells in the BM after 6 months of treatment. In order to obtain this result, BM blood of all enrolled patients (see Appendix 1) will be stored after 6 months of treatment with nilotinib. The isolated CD34+/lin- cells will be employed for standard FISH analysis. These endpoints will be obtained at the central laboratory of Niguarda Ca’ Granda Hospital, Milano, Italy.

L’endpoint primario di efficacia è la misurazione della percentuale di cellule CD34+/lin-Ph+ nel midollo osseo dopo 6 mesi di terapia, nei pazienti in CCyR. A tale scopo, al termine dei 6 mesi di trattamento con Nilotinib, si procederà al prelievo e conservazione di campioni di sangue midollare dei pazienti arruolati. Le cellule CD34+/lin- isolate, verranno sottoposte ad analisi FISH. Tali analisi verranno eseguite presso un laboratorio centralizzato (Ospedale Niguarda Ca’ Granda di Milano).

E.5.1.1

Timepoint(s) of evaluation of this end point

six months

6 mesi

E.5.2

Secondary end point(s)

Secondary endpoints will be reached performing: - the same analyzes on CD34+/lin- cells at diagnosis, at 3 and 12 months of treatment; - cytogenetic analysis to estimate the rate of CCyR at 3, 6 and 12 months; this analysis will be performed at each local laboratory; - molecular analysis to determinate the rate of MR (≤ 10%, ≤ 1%, MMR, MR4,5 IS) at 3, 6 and 12 months in the peripheral blood; the molecular analysis will be performed using the Labnet standardized laboratories in Lombardia.

Gli endpoint secondari saranno valutati mediante: - Analisi FISH delle cellule CD34+/lin- isolate dai campioni midollari prelevati al momento della diagnosi, a 3, 6 e 12 mesi dall’inizio della terapia; - Analisi citogenetica su campioni midollari per verificare l’ottenimento di CCyR a 3,6,12 mesi dal trattamento. Tale analisi verrà eseguita localmente, in ogni centro aderente, secondo routine. - Analisi molecolare per determinare la risposta molecolare (≤ 10%, ≤ 1%, MMR, MR4,5 IS) su SP a 3, 6 e 12 mesi; tali analisi verranno eseguite presso laboratori standardizzati LabNet.

E.5.2.1

Timepoint(s) of evaluation of this end point

three,six, twelve, twenty-four months

3,6,12,24 mesi

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

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)

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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:

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

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)

follow up of 24 months form the last visit

è previsto un periodo di follow up di 24 mesi, dall’ultima visita effettuata

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Rete Ematologica Lombarda

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-14

P. End of Trial
P.	End of Trial Status	Ongoing

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