Clinical Trials Register

Summary
EudraCT Number:	2014-001303-52
Sponsor's Protocol Code Number:	DTIC
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-04-11
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

2014-001303-52

A.3

Full title of the trial

Treatment of relapsed/refractory leukemia with intravenous administration of Dacarbazine

Trattamento della leucemia acuta mieloide recidivata/refrattaria con somministrazione endovenosa di Dacarbazina

A.3.1

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

Treatment of relapsed/refractory leukemia with intravenous administration of Dacarbazine

Trattamento della leucemia acuta mieloide recidivata/refrattaria con somministrazione endovenosa di Dacarbazina

A.3.2

Name or abbreviated title of the trial where available

DTIC protocol

A.4.1

Sponsor's protocol code number

DTIC

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 Ospedaliero-Universitaria di Parma
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	medac pharma srl
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Fondo dipartimento università degli studi di Parma
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	Segreteria Comitato Etico
B.5.2	Functional name of contact point	Giulia De Luca
B.5.3	Address:
B.5.3.1	Street Address	via Gramsci 14
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43126
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390521704775
B.5.5	Fax number	00390521704702
B.5.6	E-mail	gideluca@ao.pr.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	DACARBAZINA
D.2.1.1.2	Name of the Marketing Authorisation holder	medac GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	DACARBAZINA
D.3.4	Pharmaceutical form	Powder 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	DACARBAZINA CITRATO
D.3.9.1	CAS number	64038-56-8
D.3.9.3	Other descriptive name	DACARBAZINE CITRATE
D.3.9.4	EV Substance Code	SUB01547MIG
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	1000
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

Relapsed/Refractory acute myeloid leukemia patients

Pazienti affetti da leucemia acuta mieloide recidivata/refrattaria

E.1.1.1

Medical condition in easily understood language

Relapsed/Refractory acute myeloid leukemia patients

Pazienti affetti da leucemia acuta mieloide recidivata/refrattaria

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10000889
E.1.2	Term	Acute myeloid leukemia without mention of remission
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

To assess the efficacy of Dacarbazine in relapsed/refractory acute myeloid leukemia (AML) patients with MGMT-deficient

Valutare l’efficacia di Dacarbazina nei pazienti affetti da leucemia acuta mieloide recidivata/refrattaria i cui blasti esprimono bassi livelli di MGMT

E.2.2

Secondary objectives of the trial

To establish the safety, the short-term response (within 1 cycle of treatment), the time of disease control and the fasibility of bone marrow transplantation in eligibles pazients following the Dacarbazine administration

Stabilire la sicurezza, la risposta a breve termine (entro 1 ciclo di trattamento), il tempo di controllo della malattia e la fattibilita’ del trapianto nei pazienti elegibili, a seguito della somministrazione di Dacarbazina

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients aged between 18 and 65 years
• Signed written informed consent prior to beginning protocol specific procedures according to ICH/EU/GCP and national/local laws
• Diagnosis of refractory acute myeloid leukaemia (after 1 cycle of induction therapy and 1 salvage therapy) or relapsed acute myeloid leukemia (after 1 salvage therapy)
• Levels of MGMT associated with leukaemic blasts (obtained from bone marrow or peripheral blood): MGMT/β-Actin ratio (Western Blot analysis) not higher than 0.4 or MGMT activity (enzymatic determination) not exceeding 200 fM/mg protein
• WHO performance status 0-3
• Adequate renal (serum creatinine < 2 x the institutional ULN) and liver (total serum bilirubin < 2 x ULN; serum ALT and AST ≤ 3 x ULN) function, unless considered due to organ leukemic involvement
• -Left Ventricular Ejection Fraction (LVEF) >50%, as determined by echocardiogram
• Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection
• Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule
• Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of study drugs (post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential)

• Pazienti di eta’ compresa tra 18 e 65 anni
• Firma del consenso informato prima dell’inizio delle procedure specifiche del protocollo in accordo con ICH/EU/GCP e con le leggi nazionali e locali
• Diagnosi di leucemia acuta mieloide refrattaria (a seguito di un ciclo chemioterapico di induzione e uno di salvataggio) o recidivata (a seguito di un ciclo chemioterapico di salvataggio)
• Livelli di espressione di MGMT a livello dei blasti leucemici (ottenuti da sangue periferico o sangue midollare): rapporto MGMT/ β-actina (analisi Western Blot) non superiore a 0,4 oppure attvita’ enzimatica di MGMT (determinazione enzimatica) non superiore a 200 fM/mg di proteina
• Performance status secondo WHO 0-3
• Adeguata funzionalita’ renale (creatinina sierica < 2 ULN) ed epatica (bilirubina sierica totale < 2 ULN; AST e ALT ≤ 3 ULN), tranne casi in cui l’alterata funzionalita’ epatica e renale sia dovuta a localizzazione di malattia
• Frazione di eiezione ventricolare sinistra (LVEF) > 50%, determinata da un esame ecocardiografico
• Assenza di gravi malattie neurologiche e psichiatriche, di grave insufficienza cardiaca e di infezioni non controllate
• Assenza di qualsiasi condizione psicologica, famigliare, sociale e geografica che possa ostacolare il protocollo e il follow-up
• Test di gravidanza negativo nelle pazienti di sesso femminile entro 48h dalla somministrazione del farmaco (donne in menopausa devono presentare una amenorrea da almeno 12 mesi)

E.4

Principal exclusion criteria

• Patients aged less than 18 or more than 65 years
• Acute promyelocytic leukaemia
• Blast crisis of chronic myeloid leukaemia
• AML supervening after other myeloproliferative disease
• Previous treatment with any other experimental drug within 3 weeks prior to study entry
• Levels of MGMT associated with leukaemic blasts (obtained from bone marrow or peripheral blood): MGMT/β-Actin ratio (Western Blot analysis) higher than 0.4 or MGMT activity (enzymatic determination) exceeding 200 fM/mg protein
• Inadequate renal or liver function (metabolic abnormalities > 3 times the normal upper limit)
• Severe heart failure requiring diuretics
• Ejection fraction < 50%
• Uncontrolled infections
• WHO performance status = 4
• Severe concomitant neurological or psychiatric diseases
• Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug

• Pazienti di eta’ inferiore a 18 anni o superiore a 65 anni
• Leucemia Acuta Promielocitica
• Crisi blastica di mieloide cronica
• Leucemia Acuta Mieloide secondaria a malattia mieloproliferativa
• Precedente trattamento con farmaci sperimentali entro 3 settimane dall’arruolamento nel protocollo
• Livelli di espressione di MGMT a livello dei blasti leucemici (ottenuti da sangue periferico o sangue midollare): rapporto MGMT/ β-actina (analisi Western Blot) superiore a 0,4 oppure attvita’ enzimatica di MGMT (determinazione enzimatica) superiore a 200 fM/mg di proteina
• Inadeguata funzionalita’ epatica e renale (anomalie metaboliche 3 volte superiori al valore normale di laboratorio)
• Grave insufficienza cardiaca in terapia con farmaci diuretici
• Frazione di eiezione ventricolare < 50%
• Infezione non controllata
• Performance status secondo WHO=4
• Concomitanti gravi malattie neurologiche e psichiatriche
• Pazienti in stato di gravidanza o pazienti fertili che non adottano sicure misure contraccettive

E.5 End points

E.5.1

Primary end point(s)

Rate of complete remission (CR+CRi) after induction therapy

Percentuale di remissioni complete (CR+Cri) a seguito della terapia di induzione

E.5.1.1

Timepoint(s) of evaluation of this end point

1-2 MONTHS

1-2 mesi

E.5.2

Secondary end point(s)

• Stima della sopravvivenza globale (OS)
• Stima della sopravvivenza libera da malattia (DFS) dalla remissione completa
• Stima del tempo libero da complicanze (EFS) dall’arruolamento nello studio
• Valutazione della tossicita’
• Percentuale delle remissioni complete e stima della OS, DFS, EFS in rapporto alle caratteristiche del paziente come eta’, performance status, conta dei globuli bianchi, caratteristiche morfologiche, citogenetiche e molecolari

• Estimation of overall survival (OS)
• Estimation of Disease Free Survival (DFS) from CR evaluation
• Estimation of Event Free Survival (EFS) from study entry
• Toxicity according to CTCAE version 4.0 (Appendix C)
• Rate of CR patients and estimation OS, EFS, and DFS according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features

E.5.2.1

Timepoint(s) of evaluation of this end point

2 YEARS

2 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)

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

Yes

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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

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.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)

USUAL CARE

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

2014-06-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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