Clinical Trials Register

Summary
EudraCT Number:	2011-005322-22
Sponsor's Protocol Code Number:	RV-MDS-PI-0550-REV/AZA
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:	2012-05-24
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

2011-005322-22

A.3

Full title of the trial

A Phase II Study exploring the feasibility of Azacitidine and Lenalidomide use (combination vs sequential treatment) for Higher-Risk Myelodysplastic Syndromes (MDS) (IPSS Risk: High or INT-2)

Studio di fase II sulla fattibilita' dell'utilizzo di Azacitidina e Lenalidomide (somministrati in combinazione o sequenzialmente) per il trattamento delle Sindromi Mielodisplastiche (MDS) ad alto rischio (rischioIPSS alto o intermedio-2)

A.3.1

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

A Phase II Study exploring the feasibility of Azacitidine and Lenalidomide use (combination vs sequential treatment) for Higher-Risk Myelodysplastic Syndromes (MDS) (IPSS Risk: High or INT-2)

Studio di fase II sulla fattibilita' dell’utilizzo di Azacitidina e Lenalidomide (somministrati in combinazione o sequenzialmente) per il trattamento delle Sindromi Mielodisplastiche (MDS) ad alto rischio (rischioIPSS alto o intermedio-2)

A.3.2

Name or abbreviated title of the trial where available

RV-MDS-PI-0550-REV/AZA

A.4.1

Sponsor's protocol code number

RV-MDS-PI-0550-REV/AZA

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 DI BOLOGNA POLICLINICO S. ORSOLA M. MALPIGHI
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	CELGENE International
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOU di Bologna, Policlinico S.Orsola-Malpighi
B.5.2	Functional name of contact point	U.O. Ematologia (Baccarani):Finelli
B.5.3	Address:
B.5.3.1	Street Address	Via Albertoni 15
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	051/6364077
B.5.5	Fax number	051/6364037
B.5.6	E-mail	carlo.finelli@nibo.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	REVLIMID*21CPS 10MG
D.2.1.1.2	Name of the Marketing Authorisation holder	CELGENE Srl
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
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	10
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	Yes
D.2.1.1.1	Trade name	VIDAZA*1FL 100MG
D.2.1.1.2	Name of the Marketing Authorisation holder	CELGENE EUROPE LIMITED
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	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZACITIDINE
D.3.9.1	CAS number	320-67-2
D.3.9.4	EV Substance Code	SUB05624MIG
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

Higher-Risk Myelodysplastic Syndromes (MDS) (IPSS Risk: High or INT-2)

Pazienti affetti da Sindromi Mielodisplastiche (MDS) ad alto rischio (rischio IPSS alto o intermedio-2)

E.1.1.1

Medical condition in easily understood language

Higher-Risk Myelodysplastic Syndromes (MDS) (IPSS Risk: High or INT-2)

Pazienti affetti da Sindromi Mielodisplastiche (MDS) ad alto rischio (rischio IPSS alto o intermedio-2)

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	10002311
E.1.2	Term	Anemia refractory
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10028532
E.1.2	Term	Myelodysplasia
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

To evaluate the feasibility of the combination Azacitidine + Lenalidomide vs the sequential use of Azacitidine and Lenalidomide in high risk Myelodysplastic Syndromes (MDS) (IPSS score risk : High or INT-2) patients.

• Valutazione della fattibilità della somministrazione combinata di Azacitidina e Lenalidomide vs la somministrazione sequenziale di Azacitidina e Lenalidomide nelle Sindromi Mielodisplastiche (MDS) ad alto rischio (rischio IPSS alto o intermedio-2)

E.2.2

Secondary objectives of the trial

A. The safety of the combination regimen vs the sequential use, considered as the incidence of adverse event (graded according to WHO) and clinically significant abnormal laboratory values following therapy B. The quality of responses C. The progression to AML in the 2 different treatment strategies D. OS benefits between in the combination and the sequence arms To determine: • The relationship of cytogenetic abnormalities and response to treatment • Biomarkers of the response

A.Valutazione della sicurezza del regime di combinazione vs il regime sequenziale,in termini di incidenza di eventi avversi (classificati secondo la WHO) e di alterazioni laboratoristiche clinicamente significative B.Valutazione della qualità della risposta al trattamento C.Valutazione della evoluzione in Leucemia Acuta Mieloide (AML) con le due differenti strategie di trattamento D.Valutazione del beneficio clinico,in termini di durata della sopravvivenza,ottenuto con le due differenti strategie di trattamento E.Determinazione della correlazione fra anomalie citogenetiche e risposta al trattamento F.Determinazione di eventuali parametri biologici correlati alla risposta alla terapia

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:finale
Date:2011/09/08
Title:Genetic substudy is included in the core protocol
Objectives:Genetic substudy is included in the core protocol

FARMACOGENETICA:
Vers:finale
Data:2011/09/08
Titolo:Sottostudio di genetica è parte integrante del protocollo
Obiettivi:Sottostudio di genetica è parte integrante del protocollo

E.3

Principal inclusion criteria

A. Male and female patients ≥ 18 years B. Signed informed consent C. Confirmed diagnosis of MDS according to WHO 2008 classification D. IPSS risk Int-2 or High proved by bone marrow aspiration, biopsy and cytogenetics E. Karnofsky score > 60% at study entry F. Adequate renal, pulmonary and hepatic function, intended as follows: • Bilirubin ≤ 2.5 times upper limit of normal (ULN) (unless elevation is due primarily to elevated unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis, but not to liver dysfunction) • AST and ALT ≤ 3.5 times ULN • Creatinine ≤ 2 times ULN G. HIV negativity H. Females of childbearing potential (FCBP) must undergo pregnancy testing based on the frequency outlined in Appendix 1 and pregnancy results must be negative. I. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods as specified in Appendix 1 J. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP as specified in Appendix 1 K. Males must agree not to donate semen or sperm during the duration specified in Appendix 1

• Maschi e femmine di età ≥ 18 anni • Firma del consenso informato • Diagnosi confermata di Sindrome Mielodisplastica (MDS) (secondo la Classificazione WHO 2008) ad alto rischio (rischio IPSS Alto o Intemedio-2) ottenuta mediante aspirato e biopsia osteomidollare e studio citogenetico • Performance Satus basale (valutata mediante il Karnofsky score): > 60% • Funzionalità renale, polmonare ed epatica adeguate, valutate con I seguenti criteri: o Bilirubina ≤ 2.5 volte il limite superiore della norma (ULN) (ad esclusione di iperbilirubinemia indiretta attribuibile a sindrome di Gilbert o ad emolisi, e non a malattia epatica) o AST e ALT ≤ 3.5 volte il ULN o Creatinina ≤ 2 volte il ULN • HIV negatività • Tutti i pazienti dovranno rispettare il piano di prevenzione della gravidanza seguendo le procedure descritte dettagliatamente nell’ Appendice 1 del protocollo

E.4

Principal exclusion criteria

A. Prior treatment with Azacitidine or Lenalidomide. B. Any prior chemotherapy or radiotherapy for another malignancy within 6 months C. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions may enroll at any time: • Basal cell carcinoma of the skin • Carcinoma in situ of the cervix • Incidental histologic finding of prostate cancer (Tumor Node Metastasis (TNM) stage of T1a or T1b) D. Concurrent chemotherapy for another malignancy E. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. F. Any of the following laboratory abnormalities: • Serum aspartate aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 3.5 x upper limit of normal (ULN) • Serum bilirubin levels > 2.5 x ULN; serum bilirubin levels > 2.5 x ULN are acceptable if these can be attributed to active hemolysis (as indicated by positive direct Coombs’ testing, decreased haptoglobin level, elevated indirect bilirubin and/or lactate dehydrogenase), or ineffective erythropoiesis (as indicated by bone marrow findings) • Creatinine > 2 times ULN G. Uncontrolled hyperthyroidism or hypothyroidism. H. Absence of patient’s written informed consent I. Current uncontrolled severe infections

• Precedente trattamento con Azacitidina o Lenalidomide. • Precedente chemioterapia o radioterapia per altra neoplasia nei 6 mesi precedenti • Precedenti neoplasie (ad eccezione della MDS) , a meno che il paziente non mantenga la remissione da ≥ 3 anni. (eccezioni: carcinoma basocellulare della cute, carcinoma in situ della cervice uterina, reperto istologico incidentale di carcinoma prostatico, con stadioTNM : T1a o T1b) • Necessità di concomitante chemioterapia per altra neoplasia • HIV positività, infezioni attive da HBV o HCV • AST e/o ALT > 3.5 volte il ULN, o Bilirubina > 2.5 volte il ULN (ad esclusione di iperbilirubinemia indiretta attribuibile a sindrome di Gilbert o ad emolisi, e non a malattia epatica) • Creatinina > 2 volte il ULN • Ipertiroidismo o ipotiroidismo non controllati dalla terapia • Assenza di Consenso Informato scritto firmato • Gravi infezioni in atto, non controllate dalla terapia

E.5 End points

E.5.1

Primary end point(s)

The Overall Response Rate: defined as the Rate of Complete Remission (CR), Partial Remission (PR) and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson BD et al, Blood 2000, and Blood 2006)

• Efficacia della terapia, in termini di percentuale di pazienti che mostrano una risposta favorevole al trattamento, cioè che ottengono o la Remissione Completa (CR), o la Remissione Parziale (PR) o il Miglioramento Ematologico (Hematologic Improvement, HI), secondo i criteri dell’ International Working Group (IWG) (Cheson BD et al, Blood 2006)

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months (maximum period for the treatment)

24 mesi (durata massima di trattamento)

E.5.2

Secondary end point(s)

A. The rate of Complete Remission (CR), following the International Working Group (IWG) criteria (Cheson BD et al, Blood 2006) B. The duration of responses C. The overall survival

A. Percentuale di pazienti che raggiungono la Remissione Completa (CR), definita secondo i criteri dell’ International Working Group (IWG) (Cheson BD et al, Blood 2006) B. Durata delle risposte al trattamento C. Durata della sopravvivenza (Overall Survival, OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

48 months (24 months follow-up forseen)

48 mesi (previsti 24 mesi di follow-up)

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

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

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

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

terapia in combinazione vs. sequenziale

combination treatment vs. sequential

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

Last patient last treatment: march 2015. Last patient last follow-up visit: march 2017.

Last patient last treatment: marzo 2015. Last patient last follow-up visit: marzo 2017.

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)

NA-normal routine treatment care

NA-normale iter assistenziale

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

2012-06-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-15

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

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