Clinical Trials Register

Summary
EudraCT Number:	2019-003362-41
Sponsor's Protocol Code Number:	Leuk-CTL-001
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:	2020-10-07
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

2019-003362-41

A.3

Full title of the trial

Phase I/IIa clinical trial on the safety and preliminary efficacy of donor-derived anti-leukemia cytotoxic T lymphocytes for the prevention of leukemia relapse in children given haploidentical hematopoietic stem cell transplantation

Studio di fase I/IIa sulla sicurezza e l'efficacia preliminare dell'infusione di linfociti T citotossici anti-leucemia del donatore per la prevenzione della ricaduta di malattia dopo trapianto pediatrico di cellule staminali emopoietiche da donatore HLA-aploidentico

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Anti-leukemia T cell therapy after haplo-HSCT

Terapia cellulare con linfociti T antileucemia dopo HSCT aplo

A.4.1

Sponsor's protocol code number

Leuk-CTL-001

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	FONDAZIONE I.R.C.C.S. POLICLINICO SAN MATTEO
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	Fondazione Regionale per la Ricerca Biomedica
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Ministero della Salute
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	Fondazione IRCCS Policlinico San Matteo
B.5.2	Functional name of contact point	Ematologia - Oncoematologia Pediatr
B.5.3	Address:
B.5.3.1	Street Address	viale Golgi 19
B.5.3.2	Town/ city	Pavia
B.5.3.3	Post code	27100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0382502848
B.5.5	Fax number	0382501251
B.5.6	E-mail	m.zecca@smatteo.pv.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	No
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	linfociti T citotossici anti-leucemia
D.3.2	Product code	[CTL anti-leucemia]
D.3.4	Pharmaceutical form	Suspension 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.3.9.2	Current sponsor code	ND
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50000 to 8000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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

Leukemia relapse prevention given haploidentical hematopoietic stem cell transplantation

Prevenzione di ricaduta di leucemia acuta dopo trapianto di cellule staminali emopoietiche da donatore HLA-aploidentico

E.1.1.1

Medical condition in easily understood language

Leukemia relapse prevention given haploidentical hematopoietic stem cell transplantation

Prevenzione di ricaduta di leucemia dopo trapianto di cellule staminali emopoietiche da donatore HLA-aploidentico

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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000844
E.1.2	Term	Acute lymphoblastic 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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective will be safety, evaluated as the incidence of acute GVHD. Acute GVHD will be diagnosed and graded according to the NIH criteria. Grade II-IV acute GVHD will be expressed as cumulative incidence (CI) considering disease relapse and death in remission without GVHD as competing events. A CI of acute GVHD = 25% will be considered as acceptable treatment toxicity.

L’obiettivo principale di sicurezza sarà l’incidenza di GVHD acuta. La GVHD acuta sarà diagnosticata e stadiata secondo i criteri NIH. La GVHD acuta di grado II-IV sarà valutata come incidenza cumulativa (CI), considerando la recidiva di malattia e il decesso in remissione senza GVHD acuta come eventi in competizione. Una CI di GVHD acuta = 25% sarà considerata accettabile.

E.2.2

Secondary objectives of the trial

Relapse (REL): REL, defined as the time from HSCT to the date of disease relapse will be calculated at 3, 6, 9, 12 18 and 24 months after HSCT and expressed as CI considering death in remission as a competing event. The CI of REL in treated patients will be compared with that of recipients of haplo-HSCT with the same disease characteristics and prognosis, give conventional infusions of unmanipulated, donor-derived T lymphocytes (DLI). Preliminary efficacy of the treatment will be a CI of REL = of the CI of REL observed in the control group.
Other secondary objectives:
1. Non-relapse mortality (NRM) will be calculated at 3, 6, 9, 12 18 and 24 months after HSCT.
2. Overall survival (OS) will be calculated at 3, 6, 9, 12 18 and 24 months after HSCT.
3. Event-free survival (EFS) will be calculated at 3, 6, 9, 12 18 and 24 months after HSCT.
4. Event-free and chronic GVHD-free survival will be calculated at 3, 6, 9, 12 18 and 24 months after HSCT.
5. Infectious complications.
...

Obiettivo di efficacia preliminare - ricaduta (REL): REL, definita come tempo dal TCSE alla data della ricaduta di malattia, sarà calcolata a 3, 6, 9, 12 18 e 24 mesi dopo il TCSE ed espressa come incidenza cumulativa considerando il decesso in remissione come evento in competizione.
La CI di REL nei pazienti trattati sarà paragonata a quella del gruppo di controllo, costituito da riceventi pediatrici di aplo-TCSE con le stesse caratteristiche di malattia e prognosi, che hanno ricevuto terapia con infusioni di T linfociti del donatore non manipolate (DLI) allo stesso dosaggio e schema previsto per i CTL antileucemia. L’efficacia preliminare del trattamento sarà considerata per una CI di REL inferiore a quella osservata nel gruppo di controllo.
Altri obiettivi secondari:
...

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age inferior or equal to 18 years and superior or equal to 1 months
2) Life expectancy > 12 weeks
3) Patients affected by life-threatening acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) with high risk of relapse after HSCT, namely:
Patients affected by ALL:
- in first morphological remission but with a positive minimal residual disease = 1 x 10-3 before HSCT;
- in second morphological remission after a high-risk relapse (patients belonging to the S3-S4 BFM risk group), independently of the level of minimal residual disease;
- in second morphological remission with any positivity of minimal residual disease before HSCT;
- in third or subsequent morphological remission, independently of the level of minimal residual disease;
- patients not in morphological remission at time of HSCT.
Patients affected by AML:
- in first morphological remission and with a flow cytometry MRD at the end of induction therapy = 0.1%;
- in first morphological remission and with high-risk disease according to cytogenetics aberrations;
- in first morphological remission after a primary induction failure;
- in second morphological remission;
- in third or subsequent morphological remission;
- patients not in morphological remission at time of HSCT.
4) Pre-HSCT Lansky / Karnofsky score = 40%.
5) HIV negativity.
6) Written informed consent signed by the parents or legal guardians (in case of patients < 18 years) or by the patients (in the case of patients = 18 years).

1) Età minore o uguale a 18 anni e maggiore o uguale a 1 mese
2) Aspettativa di vita > 12 settimane
3) Pazienti affetti da leukemia acuta linfoblastica (ALL) o leukemia mieloide acuta (AML) con alto rischio di recidiva dopo TCSE:
Pazienti con ALL:
- in prima remissione morfologica ma con MRD positiva = 1 x 10-3 prima del TCSE;
- in seconda remissione morfologica dopo ricaduta ad alto rischio (pazienti appartenenti al gruppo di rischio BFM S3-S4), indipendentemente dal livello di MRD;
- in seconda remissione morfologica con qualsiasi positività per MRD prima del TCSE;
- in terza o successiva remissione morfologica, indipendentemente dal livello di MRD;
- pazienti non in remissione morfologica al TCSE.
Pazienti con AML:
- in prima remissione morfologica e con MRD in citofluorimetria alla fine della terapia di induzione = 0.1%;
- in prima remissione morfologica e con malattia ad alto rischio in base al dato della citogenetica;
- in prima remissione morfologica dopo una primary induction failure;
- in seconda remissione morfologica;
- in terza o successiva remissione morfologica;
- pazienti non in remissione morfologica al TCSE.
4) Lansky / Karnofsky score = 40% prima del trapianto.
5) Negatività per HIV.
6) Consenso informato scritto firmato dai genitori o dai tutori legali (in caso di pazienti < 18 years) o dal paziente (nel caso di paziente = 18 anni).

E.4

Principal exclusion criteria

1) Ongoing active superior or equal to grade II acute GvHD or chronic extensive GvHD due to a previous allograft
2) Current clinically active infectious disease (including positive HIV serology or viral RNA)
3) Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%)
4) Liver dysfunction (AST/ALT superior or equal to 3 times institutional upper limit normal value –ULN- or bilirubine > 3 times ULN)
5) Renal dysfunction: serum creatinine > 1.5 times ULN or calculated creatinine clearance < 60 ml/min/1.73 m2
6) End stage irreversible multi-system organ failure.
7) Other active malignancy.
8) Pregnant or breast feeding female patient
9) Lack of parents’/guardian’s written informed consent for minors or lack of written informed consent for patients aged 18 y.

1) GvHD acuta attiva di grado maggiore o uguale a II o GvHD cronica estesa per un precedente trapianto;
2) Infezione clinicamente attiva al momento dell’arruolamento (incluso sierologia o NAT per HIV positiva)
3) Malattia cardiovascolare severa (aritmie che richiedono trattamento cronico, insufficienza cardiaca congestizia o frazione di eiezione del ventricolo sin <40%)
4) Disfunzione epatica (AST/ALT maggiore o uguale a 3 volte al limite superiore del range istituzionale–ULN- o bilirubina > 3 volte ULN)
5) Disfunzione renale: creatinine sierica > 1.5 volte ULN o clearance della creatinina calcolata < 60 ml/min/1.73 m2
6) Multi-system organ failure irreversibile.
7) Neoplasie attive diverse dalla malattia di base.
8) Paziente di sesso femminile in gravidanza o allattamento.
9) Assenza del consenso informato scritto firmato dai genitori/tutore legale per i minori, o assenza del consenso informato scritto per i pazienti di 18 anni.

E.5 End points

E.5.1

Primary end point(s)

Acute GVHD

GVHD acuta

E.5.1.1

Timepoint(s) of evaluation of this end point

Incidence of acute GVHD

Incidenza di GVHD acuta

E.5.2

Secondary end point(s)

Disease relapse

Ricaduta di malattia

E.5.2.1

Timepoint(s) of evaluation of this end point

The time from HSCT to the date of disease relapse

Tempo dal trapianto di cellule staminali al momento della ricaduta di malattia

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase I clinical trial following previous individual therapeutic use of anti-leukemia T cells

Sperimentazione clnica di fase I successiva a precedente utilizzo ad uso nominale di terapia con lin

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-10-07.

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

</= 18 years

</= 18 anni

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)

Standard of 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

2020-08-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-23

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

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