Clinical Trials Register

Summary
EudraCT Number:	2012-002253-30
Sponsor's Protocol Code Number:	SVT-RUXO#2012
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:	2012-08-31
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

2012-002253-30

A.3

Full title of the trial

A phase 2 study of Ruxolitinib in patients with splanchnic vein thrombosis associated with myeloproliferative neoplasm

Studio di fase II del Ruxolitinib in pazienti con Trombosi delle Vene Splancniche associata a Neoplasia Mieloproliferativa

A.3.1

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

A phase 2 study of Ruxolitinib in patients with splanchnic vein thrombosis associated with myeloproliferative neoplasm

Studio di fase II del Ruxolitinib in pazienti con Trombosi delle Vene Splancniche associata a Neoplasia Mieloproliferativa

A.3.2

Name or abbreviated title of the trial where available

SVT-RUXO

A.4.1

Sponsor's protocol code number

SVT-RUXO#2012

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	UNIVERSITA' DEGLI STUDI DI FIRENZE
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	Dipartimento di Ematologia dell’Università degli Studi di Firenze
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	CONSORZIO MARIO NEGRI SUD
B.5.2	Functional name of contact point	Lab epid clinica malattie cardiovas
B.5.3	Address:
B.5.3.1	Street Address	VIA NAZIONALE
B.5.3.2	Town/ city	S. MARIA IMBARO
B.5.3.3	Post code	66030
B.5.3.4	Country	Italy
B.5.4	Telephone number	0872 570407
B.5.5	Fax number	0872 570206
B.5.6	E-mail	pioggiarella@NEGRISUD.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	Jakafy
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis/Incyte
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	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	RUXOLITINIB
D.3.9.1	CAS number	1092939-17-7
D.3.9.2	Current sponsor code	INC424
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	5
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

splanchnic vein thrombosis associated with myeloproliferative neoplasm

TROMBOSI SPLANCNICA ASSOCIATA A NEOPLASIA MIELOPROLIFERATIVA

E.1.1.1

Medical condition in easily understood language

splanchnic vein thrombosis associated with myeloproliferative neoplasm

TROMBOSI SPLANCNICA ASSOCIATA A NEOPLASIA MIELOPROLIFERATIVA

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	10013238
E.1.2	Term	Disorder myeloproliferative
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary goal of this study is to evaluate the efficacy of Ruxolitinib in patients with splenomegaly due to an underlying myeloproliferative neoplasms associated with splanchnic vein thrombosis.

L’obiettivo primario di questo studio è valutare l’efficacia di Ruxolitinib in pazienti con splenomegalia dovuta a trombosi splancnica associata a una malattia mieloproliferativa .

E.2.2

Secondary objectives of the trial

The secondary objectives include the evaluation of safety of Ruxolitinib and QoL in this setting of patients, the assessment of a potential role of Ruxolitinib in splanchnic circulation

Gli obiettivi secondari includono la valutazione della sicurezza di Ruxolitinib e della qualità di vita in questo gruppo di pazienti, e la valutazione del potenziale ruolo di Ruxolitinib nel miglioramento della circolazione splancnica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Study patient population is represented by male or female subjects with splanchnic vein thrombosis (SVT) (including Budd-Chiari syndrome, mesenteric vein thrombosis, portal vein thrombosis, splenic vein thrombosis) in the setting of myeloproliferative neoplasms, ie polycythemia vera (PV), essential thrombocythemia (ET) (according to the WHO criteria), or myelofibrosis both primary (PMF) and secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF) (according to the WHO and IWG-MRT criteria, respectively), either JAK2V617F positive or negative, MPLW515L/K positive or negative, who are equal to or older than 18 and have a palpable spleen greater than 5 cm from the costal margin to the point of greatest splenic protrusion, with a platelet count >100x109/L and normal liver function.

La popolazione di pazienti in studio è rappresentata da soggetti di sesso maschile o femminile con trombosi venosa splancnica (SVT) (incluso sindrome di Budd-Chiari, trombosi della vena mesenterica, trombosi della vena porta, trombosi della vena splenica) associate a neoplasia mieloproliferativa, come policitemia vera (PV), trombocitemia essenziale (TE) (diagnosticate secondo criteri WHO), o mielofibrosi primaria (PMF) o secondaria a policitemia vera (PPV-MF) o a trombocitemia essenziale (PET-MF) (diagnosticate rispettivamente secondo criteri WHO e IWG-MRT), sia JAK2V617F positive che negative, MPLW515L/K positive che negative, con età maggiore o uguale a 18 anni e che abbiano una splenomegalia palpabile almeno 5 cm dall’arcata costale nel punto di maggior distanza, con conta piastrinica >100x109/L e funzionalità epatica nella norma.

E.4

Principal exclusion criteria

1.ALT or AST > 2.5 x ULN 2.Total bilirubin >2xULN 3.Active acute or chronic hepatitis A, B or C (Appendix III) 4.Presence of refractory ascites. 5.Presence of esophageal varices greater than grade 2 and/or a history of previous recurrent bleedings from varices, ie more than two episodes in the last 12 months. 6.Presence of TIPS (transjugular portosystemic shunt). 7.Creatinine level not greater than 1.5-fold the upper limit. 8.Other neoplastic disorders unless at least 3 years before and in complete remission except for treated, early-stage squamous or basal cell carcinoma of the skin. 9.Patient has hypersensitivity to Ruxolitinib or any of the eccipients. 10.Subjects with a life expectancy of less than 6 months 11.Subjects with inadequate bone marrow reserve as demonstrated by: •Absolute neutrophil count (ANC) that is ≤ 1x109/L •Platelet count that is < 100x109/L without the assistance of growth factors, thrombopoietic factors or platelet transfusions. 12.Patient has a percentage of blast cell in peripheral blood greater than 5% within 14 days before enrollment. 13.Subjects with any history of platelet counts < 50x109/L or ANC < 0.5x109/L except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason. 14.Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy, except for antiviral prophylaxis: subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. 15.Subjects HIV-positive. 16.Patients undergoing treatment with hematopoietic growth factor receptor-agonists (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF, romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to baseline. 17.Patients receiving any medications listed in the “prohibited medications” listing 18.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). 19.Patients receiving ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of study drug treatment. 20.Patient is currently eligible, has the option, and is willing to undergo stem cell transplantation. 21.Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 22.Subjects with cardiac disease which in the Investigator’s opinion may jeopardize the safety of the subject or the compliance with the protocol. 23.Subjects with currently uncontrolled or unstable angina. 24.Subjects with currently rapid or paroxysmal atrial fibrillation. 25.Subjects who have had splenic irradiation within 12 months prior to Screening.

ALT o AST >2,5 x ULN (Upper Limit Normal). Bilirubina sierica totale > 2 x ULN. Pazienti con epatite acuta o cronica di tipo A, B o C Ascite Refrattaria Presenza di varici esofagee superiori al grado 2 o storia di episodi ricorrenti (più di 2 episodi negli ultimi 12 mesi) di emorragia da varici. Presenza di TIPS (Transjugular Intrahepatic Portosystemic Shunts). Creatinina sierica ≥ 1,5 x ULN. Pazienti con altre neoplasie, a meno che non siano insorte almeno 3 anni prima e in remissione completa (eccetto il carcinoma della pelle a cellule basali o a cellule squamose trattato allo stadio precoce). Pazienti che hanno ipersensibilità al Ruxolitinib o ad uno qualsiasi degli eccipienti. Pazienti con un’aspettativa di vita inferiore a 6 mesi. Pazienti con conta assoluta dei neutrofili < 1x109/L. Pazienti con conta piastrinica <100x109/L. Pazienti che presentano una percentuali di blasti nel sangue periferico > 5% entro 14 giorni dall’arruolamento. Pazienti con storia di conta piastrinica <50x109/L o conta assoluta dei neutrofili < 0,5x109/L, eccetto durante il trattamento per disordini mieloproliferativi o il trattamento con terapia citotossica per qualunque altro motivo. Pazienti con infezioni batteriche, fungine o virali clinicamente significative che richiedono trattamento farmacologico, eccetto la profilassi virale. I soggetti con infezioni batteriche acute che richiedono la somministrazione di terapia antibiotica devono rimandare lo screening/arruolamento fino alla conclusione della terapia antibiotica. Pazienti che presentano storia di sieropositività all’HIV Pazienti in trattamento con fattori di crescita emopoietici (Eritropoietina [Epo], Fattore stimolante le colonie dei granulociti (GCSF, romiplostim, eltrombopag) entro 2 settimane dallo screening o 4 settimane dal baseline. Pazienti che assumono farmaci inseriti nella lista dei “farmaci proibiti” ( vedi protocollo, appendice IV) Pazienti che hanno disturbi gastrointestinali che possono in maniera significativa alterare l’assorbimento del INC424 (es. ulcera, nausea incontrollata, vomito, diarrea, sindrome da malassorbimento) Pazienti che stanno utilizzando farmaci sperimentali o che hanno ricevuto farmaci sperimentali per un periodo di tempo inferiore o uguale a 30 giorni dall’inizio dello studio. Pazienti elegibili che devono sottoporsi a trapianto di cellule staminali. Pazienti che presentano gravi condizioni di tipo medico o psichiatrico che possono interferire con la partecipazione in questo studio clinico. Pazienti con patologie cardiache che secondo lo Sperimentatore possono compromettere la sicurezza del soggetto o la compliance al protocollo. Pazienti con angina pectoris instabile o non controllata Pazienti con fibrillazione atriale parossistica Pazienti che nei 12 mesi precedenti lo screening sono stati sottoposti a irradiazione splenica.

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects achieving ≥ 50% reduction in spleen length at any time from baseline to week 24 and at week 24 as measured by palpation or ≥ 35% reduction in spleen volume by MRI (or CT for subjects unable to undergo MRI) at week 24.

La percentuale di pazienti che ottengono una riduzione della lunghezza della milza misurata alla palpazione ≥ 50% in qualsiasi momento dal baseline alla settimana 24 e alla settimana 24 o la riduzione del volume della milza ≥ 35%misurata con risonanza magnetica (o TC per pazienti che non possono effettuare RMN) alla settimana 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

24 settimane

E.5.2

Secondary end point(s)

1 To evaluate the safety of Ruxolitinib in patients with MPN-associated SVT through: a.Changes from baseline through end of treatment in physical examinations, heart rate/rhythm, blood pressure, respiratory rate, and clinical laboratory findings. b.The observation and report of any AEs (including laboratory abnormalities reported as AEs)that occur between the first study related procedure through 28 days following the last dose of investigational product administration. The intensity (severity) of AEs will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. 2 To assess ability of Ruxolitinib to improve at least one of these findings at week 24. a.Splanchnic circulation, on portal, splenic and/or mesenteric vein. b.Hyperdynamic arterial circulation; c.Stiffnes of epathic/splenic parenchyma. 3 To determine the effects of the treatment on the capacity of Ruxolitinib to induce a clinico-hematological response according to ELN criteria for Polycythemia Vera and Essential Thombocythemia and IWG-MRT criteria for Myelofibrosis. 4 To evaluate change and improvement in QoL by use of Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire response from Baseline at monthly interval.

1. Valutare la sicurezza di Ruxolitinib in pazienti con trombosi splancnica associata a malattia mieloproliferativa attraverso: a. Cambiamenti dal baseline alla fine del trattamento nell’esame obiettivo, frequenza e ritmo cardiaco, pressione arteriosa, frequenza respiratoria ed esami di laboratorio. b. L’osservazione e segnalazione di qualsiasi evento avverso (comprese anomalie di laboratorio riportate come EA) che si manifesti fra la prima procedura legata allo studio e 28 giorni dopo l’ultima dose del farmaco sperimentale. L’intensità (severità) degli eventi avversi verrà valutata utilizzando il National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Versione 4.03. 2. Determinare la capacità di Ruxolitinib di migliorare almeno uno di questi parametri alla settimana 24: a. Circolazione splancnica: vena porta, splenica o mesenterica. b. Circolazione arteriosa iperdinamica. c. Rigidità del parenchima epatico/splenico. 3. Valutare la capacità di Ruxolitinib di determinare una risposta clinico-ematologica in accordo con i criteri ELN per la Policitemia Vera e la Trombocitemia Essenziale e i criteri IWG-MRT per la Mielofibrosi. 4. Valutare cambiamenti e miglioramenti nella qualità di vita utilizzando il questionario Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) dalla baseline ad intervalli mensili.

E.5.2.1

Timepoint(s) of evaluation of this end point

week 2,4,6,8 and every 4 weeks thereafter, until Week 24.

2,4,6,8 settimane e successivamente ogni 4 settimane fino alla 24°

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