Clinical Trials Register

Summary
EudraCT Number:	2017-001013-89
Sponsor's Protocol Code Number:	DAMTE
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:	2021-09-06
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

2017-001013-89

A.3

Full title of the trial

Double ASCT in MM: phase III study comparing between melphalan based regimen vs a new regimen consisting of melphalan and thiotepa

A.3.1

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

Double ASCT in MM: phase III study comparing between melphalan based regimen vs a new regimen consisting of melphalan and thiotepa

Confronto tra regimi di condizionamento (Melphalan vs Melphalan+Thiotepa) in pazienti con Mieloma Multiplo

A.3.2

Name or abbreviated title of the trial where available

DAMTE

A.4.1

Sponsor's protocol code number

DAMTE

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 "BIANCHI-MELACRINO-MORELLI"
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	ADIENNE
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 "Bianchi-Melacrino-Morelli"
B.5.2	Functional name of contact point	Segreteria CE
B.5.3	Address:
B.5.3.1	Street Address	Via Melacrino, sn
B.5.3.2	Town/ city	Reggio Calabria
B.5.3.3	Post code	89100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0965397347
B.5.5	Fax number	0965393325
B.5.6	E-mail	antonella.morabito@ospedalerc.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	TEPADINA - 15 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO(VETRO) - 10MG/ML 1 FLACONCINO DA 15MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ADIENNE 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	tiotepa
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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	ALKERAN - 50 MG/10 ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONCINO POLVERE + 1 FLACONCINO SOLVENTE DA 10 ML
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	alkeran
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028566
E.1.2	Term	Myeloma
E.1.2	System Organ Class	100000004864

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
to evaluate in double transplant program for MM patients if the conditioning regimen based on two alchilant drugs, Melphalan and Thiotepa, can increase the control of the disease in terms of survival free of disease progressioncelltransplantation (auto-HSCT), with two different conditioning regimens in the second auto-HSCT

: scopo dello studio è valutare nel programma di doppio trapianto per il trattamento del mieloma multiplo se un regime di condizionamento basato su 2 farmaci alchilanti, melfalan e tiotepa, entrambi attivi verso le cellule mielomatose, può aumentare il controllo della patologia in termini di sopravvivenza libera da progressione della malattia

E.2.2

Secondary objectives of the trial

Secondary
- Response rate - PR, VGPR, and CRat day +90 afterthe first ASCT
- Response rate - PR, VGPR, and CR at day +90 afterthe second ASCT
- duration of response
- Event Free Survival rate
- Overall Survival
- Incidence of TRM
- Incidence of hematologic and non-hematologic AEs after ASCT at month +3 after ASCT
- Incidence of hematologic and non-hematologic AEs not expected after ASCT at 24 months
- Hospitalization

Secondari
- Response rate - PR, VGPR, e CR a giorno +90 dopo il primo autotrapianto
- Response rate - PR, VGPR, e CR a giorno +90 dopo il secondo autotrapianto
- Durata della risposta
- Event Free Survival rate
- Overall Survival
- Incidenza di Transplant Related Mortality (TRM)
- Incidenza di eventi avversi ematologici e non ematologici dopo trapianto di CSE a + 3 mesi dopo il trapianto
- Incidenza di eventi avversi ematologici e non ematologici dopo trapianto di CSE a + 24 mesi dopo il trapianto
- Ospedalizzazione

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All individuals must meet all of the inclusion criteria in order to be eligible to participate in the study:
• Multiple myeloma diagnosis according to IMWG 2014
• Age =18
• Baseline cytogenetics data available
• Mobilized stem cells at least 4x106/Kg
• At least SD after the first auto-HSCT
• Second auto-HSCT if clinical and hematological disease progression, and not earlier than 3 months and not later than 6 months from the first disease progression evidence.
• Durie & Salmon stage II-III or I with disease progression.
• Karnofsky performance status = 60
• Willing and able to comply with all the protocol requirements.
• Adequate hepatic function, with serum (alanine aminotransferase) ALT = 3 times the upper limit of normal and serum direct bilirubin = 2 mg/dL (34 µmol/L) within 14 days prior to randomization
• DLCO =40%, TLC =40%, FEV1=40%
• Absolute neutrophil count (ANC) = 1.0 × 109/L within 14 days prior to randomization
• Platelet count = 50 × 109/L
• Creatinine clearance (CrCl) = 30 mL/minute within 7 days prior to randomization, either measured or calculated using a standard formula (eg, Cockcroft and Gault)
• Corrected serum calcium = 14 mg/dL (3.5 mmol/L)
• LVEF = 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
• For females of reproductive potential: use of highly effective contraception. Women of child-bearing potential and men must agree to take adequate contraceptive measures in order to avoid any pregnancies of their sexual partners during the course of the study (or for at least 3 months following the last dose of study drug, whichever is longer). Acceptable methods of birth control include oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device IUD) or intrauterine system (IUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/suppository. Abstinence is only considered an acceptable form of contraception when it is the usual life style of an individual*.
• Negative pregnancy test at Screening and at Baseline
• Not be breastfeeding
• For males of reproductive potential: use of condoms

Pazienti con complete response o near complete response candidati per doppio trapianto autologo.
- Diagnosi di mieloma multiplo in accordo con IMWG 2014
- età =18
- dati citogenetici disponibili alla visita Baseline
- almeno SR dopo il primo autotrapianto di CSE
- CSE mobilizzate almeno 4x106/Kg
- Secondo autotrapianto se progressione di malattia clinica ed ematologica e non oltre 3 mesi dopo la prima evidenza di progressione di malattia.
- Stage II-III or I Durie& Salmon con progression di malattia.
- Adeguata funzionalità organica (cuore, polmoni).
- Volontà e capacità di aderire ai requisiti del protocollo.

E.4

Principal exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:
• Diagnosis of smouldering or asymptomatic MM, plasmacell leukemia, solitary plasmocytoma of the bone o extramedullary plasmocytoma.
• Diagnosis of non-secretory MM.
• Patient not eligible for autologous transplant
• Non-adequate organ function (kindneys, liver)
• Previous allogeneic transplant
• Concomitant enrollment in a clinical study
• Concomitant use of a non authorized medication
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14days prior to randomization
• Known human immunodeficiency virus infection (HIV)
• Active hepatitis A, B or C infection
• Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
• DLCO <40%, TLC <40%, FEV1 <40% and/or receiving supplementary continuous oxygen
• Non hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
• Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0 (Appendix A)
• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and anti platelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
• Pregnancy or breastfeeding
• Unwillingness to use effective contraceptive measures up to 3 months after the end of study drug administration (females and males).
• For Women at risk to become pregnant during study participation: positive test for pregnancy (serum) at the time of enrollment

- Diagnosi di smouldering or MM asintomatico, leucemia plasmacellulare, plasmacitoma solitario o extramidollare.
- Diagnosis of non-secretory MM non secernente
- Pazienti di genere femminile incinta.
- Non adeguata funzionalità organica (cuore, polmoni )
- Precedente trapianto di CSE allogenico.
- Infezioni attive, incontrollate.

E.5 End points

E.5.1

Primary end point(s)

PFS at 24 months after the second auto-HSCT

PFS a 24 mesi dopo il secondotrapianto di CSE

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

E.5.2

Secondary end point(s)

Secondary
- EFS
- OS
- TRM
- AEs
- Hospitalization after ASCT procedure

- EFS
- OS
- TRM
- AEs
- Ospedalizzazione dopo trapianto autologo di CSE

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

Yes

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.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

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

LVLS: 24 mesi di follow up dopo il secondo autotrapianto di CSE dell’ultimo paziente

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)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

192

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

292

F.4.2

For a multinational trial

F.4.2.1

In the EEA

292

F.4.2.2

In the whole clinical trial

292

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)

regular follow up post HSCT

routine clinica per pazienti sottoposti a trapianto di cellule staminali

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

2018-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-28

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

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