Clinical Trials Register

Summary
EudraCT Number:	2017-000282-68
Sponsor's Protocol Code Number:	AML-PG03
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:	2020-11-04
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000282-68

A.3

Full title of the trial

A phase 2a study of the clinical activity and safety of actinomycin D in patients with NPM1-wild type AML (other than APL) aged = 70 years old and/or unfit for intensive chemotherapy, either newly diagnosed or previously treated with hypometylating agents

A.3.1

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

Studio di fase 2a sulla attivita’ clinica e sicurezza di Actinomicina D in pazienti con leucemia mieloide acuta senza mutazione del gene npm1 (ad eccezione della leucemia acuta promielocitica) di eta’ uguale o superiore a 70 anni e/o non idonei a chemioterapia standard, con malattia di nuova diagnosi o gia’ trattata con farmaci ipometilanti

A.3.2

Name or abbreviated title of the trial where available

AML-PG03

A.4.1

Sponsor's protocol code number

AML-PG03

A.5.4

Other Identifiers

Name:

AML-PG03

Number:

AML-PG03

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	PROF.BRUNANGELO FALINI,DR.SSA MARIA PAOLA MARTELLI,UNIVERSITA' DI PERUGIA
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	Dipartimento di medicina sez. ematologia UniPg
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	Dip. di Medicina
B.5.2	Functional name of contact point	Sez. di Ematologia
B.5.3	Address:
B.5.3.1	Street Address	P.le Menghini 1
B.5.3.2	Town/ city	S. Andrea delle Fratte PG
B.5.3.3	Post code	06132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0755783190
B.5.5	Fax number	0755783834
B.5.6	E-mail	maria.martelli@unipg.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	COSMEGEN - 0.5 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONCINO DA 0.5 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	LUNDBECK PHARMACEUTICALS IRELAND LTD
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	Dactinomicina, Actinomicina D, Cosmegen
D.3.2	Product code	[L01DA01 - Dactinomicina]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	DACTINOMICINA
D.3.9.1	CAS number	50-76-0
D.3.9.2	Current sponsor code	--
D.3.9.3	Other descriptive name	DACTINOMICINA
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

patients with NPM1-wild type AML (other than APL) aged >= 70 years old and/or unfit for intensive chemotherapy, either newly diagnosed or previously treated with hypometylating agents

pazienti affetti da leucemia acuta mieloide NPM1-wild type (ad eccezione della leucemia acuta promielocitica) di eta’ >= 70 anni e/o non idonei a terapia convenzionale, in prima linea o dopo trattamento con agenti ipometilanti.

E.1.1.1

Medical condition in easily understood language

patients with NPM1-wild type AML (other than APL) aged = 70 years old and/or unfit for intensive chemotherapy, either newly diagnosed or previously treated with hypometylating agents

pazienti con leucemia acuta mieloide NPM1-wild type (tranne leucemia acuta promielocitica) =70 anni e/o non idonei a terapia convenzionale, in prima linea o dopo trattamento con agenti ipometilanti

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10000880
E.1.2	Term	Acute myeloid leukaemia
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 determine the clinical efficacy of single agent actinomycin D administered intravenously in NPM1-wild type AML patients

Determinare l'efficacia clinica di Actinomicina D somministrata per via endovenosa come singolo farmaco in pazienti affetti da LAM NPM1-wild type

E.2.2

Secondary objectives of the trial

• To assess the safety of actinomycin D
• To determine the duration of response to actinomycin D
• To assess time to neutrophil (PMN>1000/¿l) and platelet (PLT>50000/¿l) recovery either after the first cycle or after each subsequent cycle
• To assess the need for transfusional support (platelets and blood red cells) during the first induction cycle and the subsequent cycles
• To assess the molecular response

• Valutare la sicurezza di actinomicina D
• Valutare la durata della risposta alla actinomicina D
• Valutare il tempo di risalita dei neutrofili (PMN>1000 mmc) e delle piastrine (PLT>50000 mmc) dopo il primo ciclo e cicli successivi
• Stabilire la necessità di supporto trasfusionale dopo il primo ciclo e cicli successivi
• Valutare il tasso di risposta molecolare

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria
In order to be enrolled into the study, patients must fulfil the following criteria:
1. Diagnosis of AML with NPM1-wild type genotype (lack of NPM1 mutations as detected at molecular analysis35 and/or at immunohistochemistry24).
2. Age =70 years, or age 18-70 years and being unsuitable for intensive chemotherapy. Ineligibility for intensive chemotherapy will be based on investigator assessment of patient characteristics such as age, performance status, concomitant co-morbidities and organ dysfunction (Döhner H et al., Blood 2014 Aug 28;124:1426-33).
3. Adequate renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of actinomycin D: serum creatinine =2.0 mg/dl; serum aspartate transaminase (AST) and serum alanine transaminase (ALT) =3 times the upper limit of normal (ULN), alkaline phosphatase =2.5 times ULN and bilirubin =1.5 times the ULN. Higher values are acceptable if they are directly related to the disease.
4. Negative pregnancy test (serum or urinary HCG) within 7 days prior to commencement of treatment in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for =1 year
5. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as indicated by their physician. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization.
- Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should also add a barrier method of contraception.
- Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 6 months after stopping treatment to avoid conception or embryo-fetal harm.
6. Signed informed consent. The consent must be obtained prior to performing any study-related procedure.

Criteri di inclusione

Possono essere considerati arruolabili i pazienti con le seguenti caratteristiche:
1. Diagnosi comprovata di leucemia acuta mieloide senza mutazione del gene NPM1 (esclusa la leucemia acuta promielocitica) sulla base dell’analisi molecolare o dell’analisi immunoistochimica
2. Età uguale o superiore a 70 anni, oppure età uguale o superiore a 18 anni e non eleggibilità per chemioterapia standard. L’ineIeggibilità sara’ valutata sulla base delle condizioni del paziente alla diagnosi, tenendo conto dell’eta’, del performance score, delle comorbidita’ e di eventuali altre disfunzioni d’organo (Döhner H et al., Blood 2014 Aug 28;124(9):1426-33
3. Funzione renale ed epatica adeguate, definite mediante esami di laboratorio da effettuare nei 7 giorni precedenti l’inizio del trattamento con actinomicina D: creatinina sierica =2.0 mg/dl; aspartato transaminasi sierica (AST) e alanina transaminasi sierica (ALT) =3 volte il valore soglia normale (ULN), fosfatasi alcalina =2.5 volte e bilirubina sierica =1.5 il valore normale. Valori superiori sono accettabili solo se direttamente correlati alla malattia leucemica.
4. Negatività del test di gravidanza (dosaggio HCG sierico e urinario) al massimo 7 giorni prima dell’inizio del trattamento chemioterapico nelle donne in eta’ fertile. Donne in eta’ non fertile potranno essere incluse se chirugicamente sterili o se in fase post-menopausale da almeno un anno.
5. Contraccezione efficace (fare riferimento al testo del protocollo per maggiori dettagli) in pazienti in eta’ fertile fino a 6 mesi dopo il termine della terapia.
6. Firma del consenso informato.

E.4

Principal exclusion criteria

Exclusion Criteria
A patient will be excluded if the answer to any of the following statements is "yes":
1. Diagnosis of acute promyelocytic leukemia or NPM1-mutated AML.
2. Central nervous system (CNS) leukemia involvement because actinomycin D does not cross the blood-brain barrier.
3. Concurrent administration of any anti-leukemic therapy (e.g. chemotherapy, experimental drug, etc.) other than actinomycin D.
4. Known hypersensitivity to actinomycin D
5. Active infection, any other concurrent disease or medical conditions that are deemed to
interfere with the conduct of the study as judged by the investigator.

6. Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women. Unwillingness to practice effective birth control
7. Inability to comply with other requirements of the protocol
8. Unwillingness to participate to the study

Criteri di esclusione
1. Leucemia acute promielocitica o leucemia acuta mieloide con mutazione del gene NPM1
2. Coinvolgimento del sistema nervoso centrale (CNS)
3. Concomitante somministrazione di qualsiasi altro farmaco anti-leucemico (es. chemioterapia, farmaci sperimentali, ecc.) diverso da actinomicina D.
4. Nota ipersensibilita’ ad actinomicina D
5. Infezione attiva, qualsiasi altra patologia concomitante o condizione medica che, a giudizio dello sperimentatore, si pensa possa interferire con la conduzione dello studio.
6. Gravidanza o allattamento in corso
7. Riluttanza ad adottare metodi contraccettivi efficaci
8. Incapacita’ di attenersi a quanto richiesto dal protocollo
9. Riluttanza a partecipare al protocollo.

E.5 End points

E.5.1

Primary end point(s)

The complete hematological response rate after two cycles of treatment. The complete hematological response rate is intended as the sum of complete response (CR) and complete response with incomplete marrow recovery (CRi), defined according to the criteria indicated below.

Tasso di risposta completa definito come somma delle remissioni complete (CR) e delle remissioni complete con incompleto recupero ematologico (CRi), valutato dopo due cicli di terapia (vedi flow-chart).

E.5.1.1

Timepoint(s) of evaluation of this end point

2 months

a 2 mesi

E.5.2

Secondary end point(s)

• The overall survival (OS)
• The disease free survival (DFS) as defined by relapse and death in remission.
• Cumulative incidence of relapse
• The molecular response as assessed by quantitative RT-PCR for WT1 copies on peripheral blood.
• Rate of adverse events (AE) and severe adverse events (SAE) as defined below.

• Tasso di sopravvivenza globale (overall survival, OS) e di sopravvivenza libera da malattia (disease free survival, DFS).
• Incidenza cumulativa di recidiva (CIR)
• Frequenza e severità degli eventi avversi (AE) e degli eventi avversi severi (SAE).
• Ia risposta molecolare misurata mediante l’analisi quantitativa in RT-PCR del numero di copie di WT1 nel sangue periferico

E.5.2.1

Timepoint(s) of evaluation of this end point

18 months

a 18 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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

An effort will be made to investigate the in vivo effects of actinomycin D on primary leukemic cells from the patients enrolled in this study.

Verranno studiati gli effetti in vivo dell'Actinomicina D nei campioni cellulari dei pazienti arruolati nello studio

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

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

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:

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)

clinical practice

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

2017-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-14

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials