Clinical Trials Register

Summary
EudraCT Number:	2011-005226-21
Sponsor's Protocol Code Number:	ARD12181
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:	2012-10-25
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

2011-005226-21

A.3

Full title of the trial

A Phase II, Multicenter, Open Label, Single Arm Study of SAR302503 in Subjects Previously Treated with Ruxolitinib and with a Current Diagnosis of Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Studio di fase II, multicentrico, in aperto, con un unico braccio di trattamento con SAR302503 in pazienti precedentemente trattati con Ruxolinitib e con diagnosi attuale di mielofibrosi primaria, di mielofibrosi post-policitemia vera o di mielofibrosi post-trombocitemia essenziale, di grado 2-intermedio o ad alto rischio.

A.3.1

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

Study of SAR302503 in Subjects with a Current Diagnosis of Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Studio con SAR302503 in pazienti con mielofibrosi primaria di mielofibrosi post-policitemia vera o di mielofibrosi post-trombocitemia essenziale

A.4.1

Sponsor's protocol code number

ARD12181

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1124-0967

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	SANOFI- AVENTIS RECHERCHE ET DÃ‰VELOPPEMENT
B.1.3.4	Country	France
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	sanofi-aventis Recherche et Développment
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	sanofi-aventis sp.a
B.5.2	Functional name of contact point	contact-point
B.5.3	Address:
B.5.3.1	Street Address	Viale Bodio, 37/b
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800.226343
B.5.5	Fax number	02.3939.4168
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi-aventis.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	EU/3/10/810 and EU/3/10/811
D.3 Description of the IMP
D.3.1	Product name	NA
D.3.2	Product code	SAR302503
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.3.9.2	Current sponsor code	SAR302503
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	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

Hematopoietic neoplasm

Neoplasia ematopoietica

E.1.1.1

Medical condition in easily understood language

Blood disease by which bone marrow produces too many red blood cells or too many platelets.

malattia del sangue nella quale il midollo osseo produce troppi globuli rossi o troppe piastrine.

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	LLT
E.1.2	Classification code	10018864
E.1.2	Term	Haematopoietic neoplasm NOS
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 evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-2 or high-risk primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles.

• Dimostrare l’efficacia di una dose giornaliera di SAR302503 in pazienti precedentemente trattati con Ruxolinitib e con diagnosi di mielofibrosi primaria (PMF), di mielofibrosi post-policitemia vera (post-PV MF) o di mielofibrosi post-trombocitemia essenziale (post-ET MF) di grado 2-intermedio o ad alto rischio in base alla riduzione del volume della milza al termine di 6 cicli di trattamento.

E.2.2

Secondary objectives of the trial

To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary To evaluate the durability of splenic response To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6 To evaluate the splenic response to SAR302503 through the first 6 treatment cycles To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden To evaluate the safety and tolerability of SAR302503 in this population To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted

• Misurare gli effetti di SAR302503 sui sintomi associati alla mielofibrosi utilizzando il diario “Myelofibrosis Symptom Assessment Form (MF-SAF)”. • Valutare la durata della risposta della milza. • Valutare la risposta della milza mediante palpazione a SAR302503 alla fine del ciclo 6 • Valutare la risposta della milza a SAR302503 durante i primi 6 cicli di trattamento • Valutare l’effetto di SAR302503 sull’allele mutato V617F della chinasi Janus 2 (JAK2) • Valutare il profilo di sicurezza e di tollerabilità di SAR302503 in questa popolazione • Valutare le concentrazioni plasmatiche di SAR302503 per l’analisi di farmacocinetica (PK), se giustificato

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

PHARMACOGENETIC:
Vers:1
Date:2011/10/20
Title:Pharmacogentic Substudy.
Objectives:To determine a possible relationship between genes and responses to treatment with Drug SAR302503, how the bosy processes Drug SAR302503 and possible side effects to Drug SAR302503.

FARMACOGENETICA:
Vers:1
Data:2011/10/20
Titolo:Farmacogenetica
Obiettivi:Determinare una possibile relazione tra i geni e le risposte al trattamento con SAR302503, determinare come il copro metabolizza il farmaco SAR302503 e i suoi possibili effetti collaterali.

E.3

Principal inclusion criteria

Diagnosis of PMF or Post-PV MF or Post-ET MF, according to the 2008 World Health Organization and IWG-MRT response criteria Subjects who previously received Ruxolitinib treatment for PMF or Post- PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 30 days prior to study entry MF classified as high-risk or intermediate-risk level 2 (IWG-MRT response criteria IPSS assess myelofibrosis score, Cervantes, et al, Blood 2009) Spleen ≥5 cm below costal margin as measured by palpation Male and female subjects ≥18 years of age Signed written informed consent.

I 01. Diagnosi di mielofibrosi primaria, o di mielofibrosi post-policitemia vera o di mielofibrosi post-trombocitemia essenziale in accordo ai criteri del 2008 della World Health Organization (appendice B) e ai criteri IWG-MRT (appendice C) I 02. pazienti che hanno ricevuto il trattamento con Ruxolitinib per il trattamento della mielofibrosi primaria, o della mielofibrosi post-policitemia vera o della mielofibrosi post-trombocitemia essenziale, , per almeno 14 giorni e che abbiano interrotto il trattamento da almeno 30 giorni prima di entrare nello studio I 03. Mielofibrosi di grado 2-intermedio o ad alto rischio (criteri modificati IWG-MRT valutazione IPSS punteggio MF (Cervantes et al., Blood 2009 [1])). I 04. Milza ingrossata, palpabile per almeno 5 cm al di sotto del margine costale. I 05. Almeno 18 anni di età. I 06. Consenso informato scritto a partecipare allo studio

E.4

Principal exclusion criteria

Splenectomy Eastern Cooperative Oncology Group (ECOG) performance status of >2 at study entry The following laboratory values within 14 days prior to the initiation of SAR302503: Absolute Neutrophil Count (ANC) <1.0 x 10exp9/L Platelet count <50 x 10exp9/L Serum creatinine >1.5 x Upper limit of normal (ULN) Serum amylase and lipase >1.5 x ULN Direct bilirubin ≥3.0 x ULN and subjects with total bilirubin between 1.5- 3.0 x ULN must be excluded if the direct bilirubin fraction is ≥25% of the total Subjects with known active (acute or chronic) Hepatitis A, B, or C; and Hepatitis B and C carriers Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN Subjects with any other prior malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 5 years Any chemotherapy (eg, hydroxyurea), immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), Anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 14 days prior to initiation of SAR302503; darbepoetin use within 28 days prior to initiation of SAR302503 Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of SAR302503

Splenectomia E 01. ECOG, performance status > 2 all’ingresso nello studio E 02. I seguenti valori di laboratorio entro 14 giorni prima dell’inizio di SAR302503: • conta assoluta dei neutrofili (ANC) <1,0 x 10esp9/l • conta delle piastrine <50 x 10esp9/l • creatinina sierica >1,5 volte il limite superiore di normalità (ULN). • amilasi sierica o lipasi >1,5 volte il limite superiore di normalità (ULN). E03 Bilirubina diretta: >uguale 3.0 x ULN e soggetti con bilirubina totale compresa tra 1,5 e 3 volte ULN devono essere esclusi se la frazione di biliorubina diretta è > uguale al 25% del totale. E 04. Nota epatite A, B o C acuta o cronica clinicamente in atto o condizione di portatore di epatite B e C. E 05. AST o ALT ≥ 2,5 volte il limite superiore di normalità (ULN) E 06. Storia anamnestica di malattia epatica cronica (ad esempio: epatopatia cronica alcolica, epatite autoimmune, colangite sclerosante, cirrosi biliare primitiva, emocromatosi, epatite steatosica non alcolica-NASH) E 07. I pazienti che abbiano altre neoplasie maligne precedenti non sono eleggibili, ad eccezione di neoplasie cutanee diverse dal melanoma adeguatamente trattato e dal carcinoma in situ della cervice, o di altre patologie tumorali, da cui il paziente è stato libero da malattia per almeno 5 anni. E 8. Pazienti sottoposti a terapia entro 14 giorni prima dell’inizio di SAR302503 con qualsiasi chemioterapico (ad esempio, idrossiurea), con qualsiasi terapia farmacologica immunomodulatoria (ad esempio, talidomide, interferone alfa), anagrelide, terapia immunosoppressiva, con corticosteroidi prednisone o equivalente assunti ad un dosaggio superiore a 10 mg al giorno, o terapia con fattori di crescita (ad esempio, eritropoietina), o ormoni (ad esempio, androgeni, danazolo); darbepoetina utilizzata nei 28 giorni precedenti l’inizio di SAR302503. E 19. Pazienti con insufficienza cardiaca congestizia non controllata (Classificazione 3 o 4 della New York Heart Association), angina, infarto miocardico, eventi cerebrovascolari, bypass aorto-coronarico, attacco ischemico transitorio o embolia polmonare nei 3 mesi precedenti l’inizio di SAR302503.

E.5 End points

E.5.1

Primary end point(s)

Response Rate (RR), defined as the proportion of subjects who have a ≥ 35% reduction from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI)

Percentuale di risposta (RR), definita come la percentuale di pazienti che hanno una riduzione del volume della milza >=35% alla fine del ciclo 6, in base alla misurazione data dalla Risonanza Magnetica (MRI) (o TAC nei pazienti con controindicazioni alla risonanza magnetica).

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months.

6 mesi.

E.5.2

Secondary end point(s)

Symptom Response Rate (SRR): Proportion of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF - Duration of spleen response, measured by MRI (or CT scan in subjects with contraindications for MRI) 6 months - Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6 - Response Rate by Cycle 6 (RR6), defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at any time up to Cycle 6 as measured by MRI (or CT scan in subjects with contraindications for MRI) - The effect of SAR302503 on the JAK2V617F allele burden - Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03 - Plasma concentrations of SAR302503

•Tasso di risposta sintomatologica (Symptom Response Rate - SRR): percentuale di pazienti con una riduzione ≥ 50% nel punteggio totale dei sintomi utilizzando l’MFSAF modificato, alla fine del ciclo 6 rispetto al basale.
• Durata della risposta splenica, misurata mediante risonanza magnetica (o tramite TAC in pazienti con controindicazioni ad eseguire la risonanza magnetica).
• Percentuale di pazienti con una riduzione ≥50% della lunghezza della milza alla palpazione, alla fine del ciclo 6 rispetto al basale.
• Tasso di risposta al ciclo 6 (Response Rate by Cycle 6 – RR6), definita come la percentuale di pazienti che presentano una riduzione ≥35% del volume della milza rispetto al basale, in qualsiasi momento fino al ciclo 6, in base alla misurazione effettuata mediante risonanza magnetica (RM) (o TAC in pazienti per i quali la RM è controindicata).
• Effetto di SAR302503 sul carico mutazionale di JAK2V617F
• Sicurezza e tollerabilità, valutate mediante i paramentri clinici, di laboratorio, gli elettrocardiogramma (ECG) e i segni vitali, il cui grado sarà classificato in base ai criteri CTCAE v4.03
• Concentrazioni plasmatiche di SAR302503

E.5.2.1

Timepoint(s) of evaluation of this end point

- For the 4 first secondary end points: 6 months - The effect of SAR302503 on the JAK2V617F allele burden: 2 years - Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03: approx 5 years Plasma concentrations of SAR302503: 4 years

Per i primi 4 endpoint secondari: 6 mesi; effetto di SAR302503 sull'allele JAK2V617F: 2 anni Sicurezza, come valutato dalla clinica, dal laboratorio, dall'ECG e dai segni vitali, graduato dal NCI CTCAE di SAR302503: circa 5 anni Concentrazione di plasma di SAR302503: 4 anni.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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)

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

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

United States

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

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:

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

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

2012-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-04-17

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