Clinical Trials Register

Summary
EudraCT Number:	2018-000386-36
Sponsor's Protocol Code Number:	DART4MM
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:	2021-02-10
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

2018-000386-36

A.3

Full title of the trial

A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next generation flow (NGF)

STUDIO PILOTA SULL’EFFICACIA DI DARATUMUMAB IN PAZIENTI AFFETTI DA MIELOMA MULTIPLO IN RISPOSTA MOLTO BUONA/MALATTIA MINIMA RESIDUA POSITIVE (>VGPR/MRD-POSITIVI) VALUTATA TRAMITE CITOFLUORIMETRIA A FLUSSO DI NUOVA GENERAZIONE (NGF)

A.3.1

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

A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next generation flow

A.3.2

Name or abbreviated title of the trial where available

DART4MM

A.4.1

Sponsor's protocol code number

DART4MM

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 UNIVERSITARIA SENESE
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	Janssen Cilag Spa
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	Azienda Ospedaliera Universitaria Senese
B.5.2	Functional name of contact point	UOC Ematologia
B.5.3	Address:
B.5.3.1	Street Address	Viale Bracci 16
B.5.3.2	Town/ city	Siena
B.5.3.3	Post code	53100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0577586798
B.5.5	Fax number	0577586185
B.5.6	E-mail	a.gozzetti@ao-siena.toscana.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	DARZALEX - 20 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 20 ML- 1 FLACONCINO
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	Darzalex
D.3.2	Product code	[JNJ-54767414]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Daratumumab
D.3.9.2	Current sponsor code	JNJ-54767414
D.3.9.3	Other descriptive name	Daratumumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	DARZALEX - 20 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 5 ML- 1 FLACONCINO
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	Darzalex
D.3.2	Product code	[JNJ-54767414]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Daratumumab
D.3.9.2	Current sponsor code	JNJ-54767414
D.3.9.3	Other descriptive name	Daratumumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Multiple Myeloma

MIELOMA MULTIPLO

E.1.1.1

Medical condition in easily understood language

Multiple Myeloma

MIELOMA MULTIPLO

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	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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective of the study is Daratumumab efficacy: in particular capacity to determine increase of response by MRD negativity, detected by NGF assessment on bone marrow specimens

Efficacia di Daratumumab nel determinare MRD negatività misurata con NGF su aspirato midollare dopo 8- e 24 settimane (al mese 2 e 6) ed ad altri successivi controlli (dopo 6-12-18-24 mesi).

E.2.2

Secondary objectives of the trial

Rate of acute and late toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria.

Percentuale di tossicità acuta e cronica in accordo con i criteri NCI CTCAE.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age 18-85 years at the time of signing the informed consent form
Able to adhere to the study visit schedule and other protocol requirements
>VGPR/MRD-positive by NGF measured by 2-tubes optimized 8-color antibody panel, (OneFlow PCST e PCD BD Biosciences)
At least 12 weeks from any therapy for myeloma
Eastern Cooperative Oncology Group performance status score of 0, 1, or 2
Laboratory values and electrocardiogram within protocol-defined parameters at screening
All previous MM therapy, including radiation, cytostatic therapy and surgery, must have been terminated at least 4 weeks prior to treatment in this study, without corticosteroid therapy.
Laboratory test results within these ranges:
Absolute neutrophil count greater / equal 1.0 x 109/L
Platelet count greater / equal 75 x 109/L
Creatinine clearance > 30 ml/h)
Total bilirubin less than / equal 1.5 mg/Dl
Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) less than / equal 2 x ULN
Disease free of prior malignancies for greater / equal 5 years with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast
Fertile patients must use effective contraception during and for 6 months after study treatment
Patients must sign on an Informed Consent Form
No study treatment or any other procedure within the framework of the trial (except for screening) will be performed in any patient prior to receipt of written informed consent.

Età 18-85 al momento della firma del consenso informato
Capace di aderire alle visite del protocollo di studio e alter richieste del protocollo
>VGPR/ MRD-positività determinate con NGF (OneFlow PCST e PCD BD Biosciences)
Eastern Cooperative Oncology Group performance status score di 0, 1, or 2
Terapie precedenti terminate da almeno 4 settimane, autotrapianto da 12 settimane
Valori di laboratorio entro I seguenti ranges:
Neutrofili assoluti maggiore / uguale 1.0 x 109/L
Conta piastrinica maggiore / uguale 75 x 109/L
Clearance creatinina > 30 ml/h)
Bilirubina totale minore / uguale 1.5 mg/dL
Aspartato aminotransferasi (AST; SGOT) e alanina aminotransferasi (ALT; SGPT) ¿ 2 x ULN
Remissione da precedenti neoplasie da maggiore / uguale 5 anni

E.4

Principal exclusion criteria

Received daratumumab or other anti-CD38 therapies previously
Nonsecretory multiple myeloma
Previously received an allogenic stem cell transplant or has received an autologous stem cell transplantation within 12 weeks
Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years
Absence of the Informed Consent Form signed by the patient
Pregnant or breast feeding females
Use of any other experimental drug or therapy within 28 days of baseline.
Known hypersensitivity to the study drugs
Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C.
Plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis

Precedente somministrazione di daratumumab o altro anticorpo anti –CD38
MM non secernente
Precedente trapianto allogenico
Patologia polmonare ostruttiva, asma
Mancanza di firma del consenso informato
Paziente in gravidanza o allattamento
Uso di altri farmaci sperimentali a 28 giorni dal baseline
Ipersensibilità conosciuta al farmaco
Positività conosciuta al virus HIV o epatite A, B or C
Leucemia plasmacellulare, macroglobulinemia di Waldenstrom, sindrome di POEMS , amiloidosi

E.5 End points

E.5.1

Primary end point(s)

MRD negativity will be measured at time 2 , 6, 12,18,24 months by Flow cytometry on bone marrow aspirate. MRD negativity will be defined as absence of monoclonal plasma cells with a sensitivity of 1x105 cells analyzed by Euro flow protocols.

percentuale di pazienti MRD negativi a 2,6,12,18,24 mesi.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 , 6, 12,18,24 mounths

2 , 6, 12,18,24 mesi

E.5.2

Secondary end point(s)

Complete remission rate (CR), Duration of response (DoR) and progression free survival (PFS).

percentuale di remissione completa(CR); Durata della risposta(DoR); Progressione libera da malattia(PFS) .

E.5.2.1

Timepoint(s) of evaluation of this end point

2,6,12,18 e 24 mounths

2,6,12,18 e 24 mesi

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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

Yes

E.8.1.7.1

Other trial design description

singolo braccio

singol arm

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

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

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

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

Patients will be followed up in follow-up as per normal clinical practice

I pazienti verranno seguiti in follow up come da normale pratica clinica

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

2018-12-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-15

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

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