Clinical Trials Register

Summary
EudraCT Number:	2017-004003-46
Sponsor's Protocol Code Number:	RealMM
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:	2021-06-15
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

2017-004003-46

A.3

Full title of the trial

A RANDOMIZED, MULTICENTER, OPEN LABEL STUDY COMPARING TWO STANDARD TREATMENTS, BORTEZOMIB-MELPHALAN-PREDNISONE (VMP) VS LENALIDOMIDE-DEXAMETHASONE (Rd) IN AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) INELIGIBLE COMMUNITY POPULATION AFFECTED BY MULTIPLE MYELOMA (MM)

Studio randomizzato, multicentrico, in aperto che compara due trattamenti standard, bortezomib-melfalan-prednisone (VMP) vs lenalidomide-desametasone (Rd) in pazienti non eleggibili al trapianto di cellule staminali (ASCT) affetti da mieloma multiplo (MM)

A.3.1

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

Studio randomizzato, multicentrico, in aperto che compara due trattamenti standard, bortezomib-melfalan-prednisone (VMP) vs lenalidomide-desametasone (Rd) in pazienti non candidabili al trapianto affetti da mieloma multiplo (MM)

A.3.2

Name or abbreviated title of the trial where available

VMPvsRD

A.4.1

Sponsor's protocol code number

RealMM

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	DIPARTIMENTO DI BIOTECNOLOGIE MOLECOLARI E SCIENZE PER LA SALUTE-UNIVERISITÀ DI TORINO
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	AIFA - Italian Medicines Agency
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	DIPARTIMENTO DI BIOTECNOLOGIE MOLECOLARI E SCIENZE PER LA SALUTE-UNIVERISIT¿ DI TORINO
B.5.2	Functional name of contact point	Clinical Trial Office
B.5.3	Address:
B.5.3.1	Street Address	Via Nizza 52
B.5.3.2	Town/ city	Torino
B.5.3.3	Post code	10126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0110243236
B.5.5	Fax number	0110133182
B.5.6	E-mail	clinical.trials@unito.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	VELCADE - 1 FLACONCINO DA 3.5 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	JANSSEN-CILAG INTERNATIONAL N.V.
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.3.1	Product name	Velcade
D.3.2	Product code	[Velcade]
D.3.4	Pharmaceutical form	Powder for solution 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	BORTEZOMIB
D.3.9.2	Current sponsor code	Non applicabile
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	1
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Farmaci antineoplastici
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	ALKERAN - 2 MG COMPRESSE RIVESTITE CON FILM25 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	ASPEN PHARMA TRADING 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.3.1	Product name	Melphalan
D.3.2	Product code	[Melphalan]
D.3.4	Pharmaceutical form	Film-coated 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	MELFALAN
D.3.9.2	Current sponsor code	Non applicabile
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	2
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Farmaco antineoplastico
D.IMP: 3
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	PREDNISONE TEVA - "5 MG COMPRESSE" 20 COMPRESSE IN BLISTER PVC-PVDC/ALU
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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.3.1	Product name	Prednisone
D.3.2	Product code	[Prednisone]
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	PREDNISONE
D.3.9.2	Current sponsor code	Non applicabile
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Corticosteroide
D.IMP: 4
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 - 25 MG CAPSULA RIGIDA - USO ORALE BLISTER (PCTFE/PVC/ALU) 21 CAPSULE
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	Yes
D.2.5.1	Orphan drug designation number	038016046
D.3 Description of the IMP
D.3.1	Product name	Lenalidomide 25 mg
D.3.2	Product code	[Lenalidomide 25 mg]
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 25 mg
D.3.9.2	Current sponsor code	Non applicabile
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	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENALIDOMIDE 15 mg
D.3.9.2	Current sponsor code	Non applicabile
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENALIDOMIDE 10 mg
D.3.9.2	Current sponsor code	Non applicabile
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENALIDOMIDE 5 mg
D.3.9.2	Current sponsor code	Non applicabile
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosoppressori
D.IMP: 5
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	SOLDESAM - 0.2% GOCCE ORALI, SOLUZIONE FLACONE 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIO FARMACOLOGICO MILANESE S.R.L.
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.3.1	Product name	Desametasone
D.3.2	Product code	[Desametasone]
D.3.4	Pharmaceutical form	Oral drops, solution
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	DESAMETASONE
D.3.9.2	Current sponsor code	Non applicabile
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Corticosteroridi

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 MM patients = 65 years old or ineligible for autologous stem cell transplant

Pazienti con nuova diagnosi di MM = 65 anni o non eleggibili al trapianto autologo di cellule staminali

E.1.1.1

Medical condition in easily understood language

Newly diagnosed Multiple Myeloma patients with or older than 65 years or ineligible for autologous
stem cell transplant

Pazienti con nuova diagnosi di Mieloma Multiplo con et¿ superiore o uguale a 65 anni o non eleggibili al trapianto autologo di cellule staminali

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
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 primary objective is to compare the
progression-free survival (PFS) of bortezomib-melphalan-prednisone (VMP) regimen vs lenalidomide-dexamethasone (Rd) treatment in real life, in unselected patient population.

L¿obiettivo primario dello studio ¿ di comparare la sopravvivenza libera da progressione (PFS) del
trattamento bortezomib-melfalan-prednisone (VMP) vs lenalidomide-dexamethasone (Rd) nella pratica clinica, in una popolazione di pazienti non selezionati.

E.2.2

Secondary objectives of the trial

¿To compare the overall response rate (ORR) between the VMP and Rd arms
¿To compare the duration of response (DOR) between the VMP and Rd arms
¿To compare the overall survival (OS) between the VMP and Rd arms
¿To compare the progression-free survival 2 (PFS2) between the VMP and Rd arms
¿To compare the time to next therapy (TNT) between the VMP and Rd arms
¿To compare the time to progression (TTP) between the VMP and Rd arms
¿To compare safety in terms of incidence of hematologic and non-hematologic adverse events between the VMP and Rd arms
¿To compare the rate of treatment discontinuation or death for toxicity between VMP and Rd arms
¿To validate frailty score in a real life population, using geriatric assessment and considering patients¿ non-Myeloma polydrug therapies
¿To compare Quality of Life (QoL) between VMP and Rd arms
¿To compare direct health related costs and indirect costs between VMP and Rd arms
¿To evaluate the risk of infectious complications between VMP and Rd arms

¿Confrontare tasso di risposta globale (ORR) tra bracci VMP e Rd
¿Confrontare durata della risposta (DoR) tra bracci VMP e Rd
¿Confrontare sopravvivenza globale (OS) tra bracci VMP e Rd
¿Confrontare periodo libero da progressione dalla seconda linea (PFS2) tra bracci VMP e Rd
¿Confrontare tempo alla terapia successiva (TNT) tra bracci VMP e Rd
¿Confrontare tempo alla progressione (TTP) tra bracci VMP e Rd
¿Confrontare sicurezza in termini di incidenza di eventi avversi ematologici o non-ematologici tra bracci VMP e Rd
¿Confrontare tasso di discontinuazione del trattamento o di morte per tossicit¿ tra bracci VMP e Rd
¿Validare scala di fragilit¿ in una popolazione reale, con l¿utilizzo della valutazione geriatrica e considerando le terapie polifarmacologiche dei pazienti
¿Confrontare qualit¿ di vita (QoL) tra bracci VMP e Rd
¿Comparare costi direttamente correlati alle cure ed i costi indiretti tra bracci VMP e Rd;
¿Confrontare rischio di complicanze infettive tra bracci VMP e Rd

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

Pharmacogenetics
Version: 1.2
Date: 03/08/2018
Title: CLONAL EVOLUTION
Objectives: The aim of the study is to achieve a fine characterization of the genetic peculiarities, which characterize the MM plasma cells of patients both before and after treatment with lenalidomide-based regimens, in order to assess whether an intra-clonal heterogeneity at the onset of MM and a clonal dynamics over time might be responsible of different patterns of MM disease evolution.

Other types of substudies
Specify title, date and version of each substudy with relative objectives: 1- Title: LIQUID BIOPSY (v. 1.2, 03.08.2018)
Objective: Characterize the EVs, in particular Exo and MVs, as a possible new prognostic biomarker and/or predicting in MM. The EVs will be quantified and analyzed by flow cytometry and their genetic content will be defined by sequencing.

2- Title: BONE DISEASE (v. 1.2, 03.08.2018)
Objective: To evaluate the effects of the two different regimens (PI-based and IMIDs-based) on bone turn over markers and multiple myeloma skeletal events at diagnosis and longitudinally at different time points. To study the role of chemokines and cytokines in bone metabolism alterations in patients affected by multiple myeloma, and to evaluate the effect of PIs and IMIDs, and response to therapy, on cytokines/chemokines levels.

3- Title: IMMUNE DYSREGULATION (v. 1.2, 03.08.2018)
Objective: To evaluate the effects of the two different regimens (PI-based and IMIDs-based) on immune dysregulation at diagnosis and longitudinally at different time points. To study the role of circulating biomarkers of myeloid-suppression-driven host¿s immune system status in patients affected by multiple myeloma, and to evaluate the effect of PIs and IMIDs, and response to therapy, based on these bio-markers levels.

Farmacogenetica
Versione: 1.2
Data: 03/08/2018
Titolo: EVOLUZIONE CLONALE
Obiettivi: Ottenere una buona caratterizzazione delle peculiarit¿ genetiche, che caratterizzano le plasmacellule MM dei pazienti sia prima che dopo il trattamento con lenalidomide, al fine di valutare se l'eterogeneit¿ intra-clonale all'esordio di MM e le dinamiche clonali nel tempo potrebbero essere responsabili di diversi modelli di evoluzione della malattia di MM.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: 1- BIOPSIA LIQUIDA (v. 1.2, 03.08.2018)
Obiettivi: Caratterizzare le endovescicole (EV), come possibile nuovo biomarcatore prognostico e/o predittivo in MM. Le EV saranno quantificate e analizzate mediante citometria a flusso e il loro contenuto genetico sar¿ definito mediante sequenziamento.

2- MALATTIA OSSEA (v. 1.2, 03.08.2018)
Obiettivi: Valutare gli effetti dei due regimi su marker di turn over osseo e eventi scheletrici del NDMM e in diversi momenti temporali. Studiare in pz con MM il ruolo di chemochine e citochine nelle alterazioni del metabolismo osseo, valutare l'effetto di PI e IMID e la risposta alla terapia sui livelli di citochine/chemochine.

3- DISGREGAZIONI IMMUNOLOGICHE (v. 1.2, 03.08.2018)
Obiettivi: Valutare gli effetti dei due regimi sulla disregolazione immunonologica alla diagnosi e in diversi momenti temporali. Studiare il ruolo dei biomarcatori circolanti sullo stato del sistema immunitario dell'ospite guidato dalla soppressione mieloide in pazienti affetti da MM e per valutare l'effetto di PI e IMID e risposta alla terapia, sulla base di questi livelli di biomarcatori.

E.3

Principal inclusion criteria

- Patients has given voluntary written informed consent before the performance of any study related procedure;
- Patients with newly diagnosed symptomatic multiple myeloma (NDMM) based on standard IMWG (International Myeloma Working Group) criteria (Appendix 12.2):
• Clonal bone marrow plasma cells =10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
¿ Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
¿ Renal insufficiency: creatinine clearance (CLcr)<40 mL per minute or serum creatinine >2mg/dL
¿ Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
¿ Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
¿ 60% or greater clonal plasma cells on bone marrow examination
¿ Serum involved/uninvolved free light chain ratio of 100 or greater
¿ >1 focal lesion (=5 mm each) detected by MRI (magnetic resonance imaging) studies
- According to physician’s opinion, patients can undergo either one of the two standard treatments and procedures;
- Females of childbearing potential (FBCP) must use an effective method for 28 days before the study treatment, during the treatment and for at least 3 months after the last dose of study drugs;
- Male subjects must use an effective barrier method if sexually active with FCBP during treatment and for at least 3 months after the last dose of study drug;
- Patients should be ineligible for ASCT, defined as:
- = 65 years old
- younger than 65 years but
- with abnormal cardiac, pulmonary, hepatic and renal function defined as [1]:
• LVEF (left ventricular ejection fraction) < 40%
• FEV1 (forced expiratory volume-1 second) < 40%
• Bilirubin > 1.5 UNL, AST/ALT >2.5 UNL
• Creatinine clearance < 60 mL/min.

- Pazienti che hanno fornito il consenso scritto prima di effettuare qualsiasi procedura prevista dallo studio;
- Pazienti con MM sintomatico di nuova diagnosi (NDMM) come definito dai criteri standard IMWG:
• Plasmacellule clonali nel midollo osseo = 10% o plasmacitoma osseo o extramidollare rilevato da una biopsia e una qualsiasi o più delle seguenti caratteristiche CRAB o eventi che definiscono il mieloma:
• Evidenza del danno dell'organo che può essere attribuito al disturbo proliferativo sottostante delle plasmacellule, in particolare:
• Ipercalcemia: calcio sierico >0.25 mmol/L (<1 mg/dL) maggiore del limite superiore del range normale o >2.75 mmol/L (>11 mg/dL).
• Insufficienza renale: clearance della creatinina (CLcr) <40 mL al minuto (misurata o stimata con equazioni validate) o creatinina sierica >2 mg/dL.
• Anemia: valore dell’Hb >20 g/L sotto il limite inferiore del range normale, o valore di Hb <100 g/L.
• Lesione ossee: una o più lesioni osteolitiche evidenziate da radiografia scheletrica, TAC o PET/TAC. Se il midollo osseo ha <10% di plasmacellule clonali, è necessaria più di una lesione ossea per distinguere dal plasmacitoma solitario con coinvolgimento minimo midollare.
• Uno o più dei seguenti biomarcatori:
• Plasmacellulle clonali >60% o maggiore dall’analisi del midollo osseo (la clonalità deve essere definita dalla restrizione della catena leggera ¿ / ¿ con citometria a flusso, immunoistochimica o immunofluorescenza. La percentuale di cellule plasmatiche del midollo osseo deve essere preferibilmente stimata da un campione bioptico; in caso di disparità tra aspirato e biopsia deve essere utilizzato il valore più alto)
• Rapporto delle catene libere leggere sieriche coinvolte/non coinvolte di 100 o oltre (valori basati sul test sierico Freelite. La catena libera leggera coinvolta deve essere = 100 mg/L).
• >1 lesione focale (=5 mm ciascuna) evidenziata da studi di risonanza magnetica.
- Pazienti che secondo il parere del medico possono essere sottoposti ad uno dei due trattamenti e procedure standard;
- Donne potenzialmente fertili devono usare un metodo contraccettivo efficace per 28 giorni prima del trattamento, durante la terapia e per almeno i 3 mesi successivi all’ultima dose di farmaci dello studio;
- I soggetti di sesso maschile devono utilizzare un metodo di barriera se sessualmente attivi con donne potenzialmente fertili durante il trattamento e per almeno i 3 mesi successivi all’ultima dose di farmaci dello studio;
- Pazienti devono essere non eleggibili a ASCT, definito come di seguito:
- = 65 anni
- più giovani ma che abbiano rifiutato la procedura del trapianto
oppure
con funzionalità cardiaca, polmonare, epatica e renale definite come [1]:
- LVEF (frazione di eiezione ventricolare sinistra) <40%,
- FEV1 (volume di espirazione forzata in 1 secondo) <40%,
- Bilirubina >1.5 UNL (limite superiore del range normale), AST/ALT >2.5 UNL,
- clearance della creatinina <60mL/min.

E.4

Principal exclusion criteria

- Hypersensitivity to any active substance or to any of the excipients (lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, boron, mannitol, nitrogen, crospovidone, colloidal anhydrous silica, hypromellose, titanium dioxide, macrogol, talc, sodium starch glycolate, sodium benzoate, propylene glycol, sodium dihydrogen phosphate, hydroxypropyl beta cyclodextrin, sodium saccharin, sodium EDTA, sodium hydroxide);
- Pregnant and lactating women;
- FBCP that do not follow the Pregnancy Prevention Plan requirements;
- Acute diffuse infiltrative pulmonary and pericardial disease;
- Acute viral infections (e.g. herpes simplex or ocular herpes simplex, herpes zoster, varicella);
- Systemic mycotic or bacterial infections, unless specific anti-infectious therapy is ongoing;
- Peptic ulcer;
- Psychosis;
- Administration of prophylactic vaccine from 8 to 2 weeks before starting treatment.

- Ipersensibilità a qualsiasi dei principi attivi o eccipienti (lattosio, cellulosa microcristallina, sodio croscarmelloso, magnesio stearato, boro, mannitolo, azoto, crospovidone, silice colloidale anidra, ipromellosa, titanio diidrossido, macrogol, talco, sodio amido glicolato, sodio benzoato, glicole propilenico, sodio diidrogeno fosfato diidrato, idrossipropril betaciclodestrina, saccarina sodica, sodio EDTA, sodio idrossido;
- Donne in gravidanza o allattamento;
- Donne potenzialmente fertili che non rispettano il Prgramma di Prevenzione della Gravidanza;
- Pneumopatia infiltrativa diffusa acuta e pericardiopatia;
- Infezioni virali acute (ad es herpes simplex o herpes oculare simplex, herpes zoster, varicella);
- Infezioni micotiche o batteriche sistemiche, a meno che sia in corso una specifica terapia anti-infettiva;
- Ulcera peptica;
- Psicosi;
- Un periodo da 8 settimane prima a 2 settimane dopo la somministrazione di un vaccino di profilassi.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) of bortezomib-melphalan-prednisone (VMP) regimen vs lenalidomide-dexamethasone (Rd) treatment in real life, in unselected patient population.

Sopravvivenza libera da progressione (PFS) del trattamento bortezomib-melfalan-prednisone (VMP)
vs lenalidomide-dexamethasone (Rd) nella pratica clinica, in una popolazione di pazienti non selezionati.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.5.2

Secondary end point(s)

To determine the overall response rate
(ORR) within the VMP and Rd arms.; To determine the duration of response (DOR) within the VMP and Rd arms; To determine the overall survival (OS)
within the VMP and Rd arms; To determine the progression-free survival 2 (PFS2) within the VMP and Rd arms; To determine the time to next therapy
(TNT) within the VMP and Rd arms; To determine the time to progression
(TTP) within the VMP and Rd arms; To evaluate safety in terms of incidence of hematologic and non-hematologic adverse events within the VMP and Rd arms; To assess the rate of treatment discontinuation or death for toxicity within the VMP and Rd arms; To assess the Quality of Life (QoL) of
enrolled patients; To compare health related costs; Validation of frailty score will be made by estimating efficacy and safety endpoints in patients stratified according to Myeloma Frailty Scor and by considering patients¿ non-Myeloma polydrug therapies; Infectious risk complications will be evaluated in terms of incidence, severity, type of infection, need for hospitalization, deferral or suspension of study treatment with possible impact on PFS

Determinare il tasso di risposta globale (ORR) nei bracci di trattamento VMP e Rd.; Determinare la durata della risposta (DoR) nei bracci di trattamento VMP e Rd; Determinare la sopravvivenza globale (OS) nei bracci di trattamento VMP e Rd; Determinare il periodo libero da progressione dalla seconda linea (PFS2) nei bracci di trattamento VMP e Rd; Determinare il tempo alla terapia successiva (TNT) nei bracci di trattamento VMP e Rd; Determinare il tempo alla progressione (TTP) nei bracci di trattamento VMP e Rd; Valutare la sicurezza in termini di incidenza di eventi avversi ematologici o non-ematologici nei bracci di trattamento VMP e Rd; Valutare la percentuale di interruzione dal trattamento o morte per tossicit¿ all'interno dei bracci VMP e Rd; Valutare la qualit¿ di vita (QoL) dei pazienti arruolati; Comparare i costi correlati alle cure; Validare la scala di fragilit¿ in una popolazione reale, con l¿utilizzo della valutazione geriatrica e considerando le terapie con pi¿ combinazioni di farmaci a cui vengono sottoposti i pazienti che non sono per curare il mieloma; Le complicazioni del rischio infettivo saranno valutate in termini di incidenza, gravit¿, tipo di infezione, necessit¿ di ospedalizzazione, sospensione o sospensione del trattamento di studio con possibile impatto sulla PFS

E.5.2.1

Timepoint(s) of evaluation of this end point

5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years; 5 years

5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 anni; 5 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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Comparare due trattamenti standard (VMP vs RD)

Compare two standard treatments (VMP vs RD)

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

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

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

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.1.1.1

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

350

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

350

F.4.2

For a multinational trial

F.4.2.1

In the EEA

350

F.4.2.2

In the whole clinical trial

350

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)

At the end of the study the patient will continue to be followed by his medical doctor.

Al termine dello studio il paziente continuer¿ ad essere seguito dal proprio medico.

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

2018-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-18

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

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Orphan Designation Number:
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