Clinical Trials Register

Summary
EudraCT Number:	2020-004270-22
Sponsor's Protocol Code Number:	TMLI_HSM_001
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:	2021-08-17
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

2020-004270-22

A.3

Full title of the trial

PHASE II STUDY OF TOTAL MARROW AND LYMPHOID IRRADIATION (TMLI) GIVEN IN COMBINATION WITH CYCLOPHOSPHAMIDE AND ETOPOSIDE (VP-16) AS CONDITIONING FOR ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN PATIENTS WITH HIGH-RISK ACUTE LYMPHOCYTIC OR MYELOGENOUS LEUKEMIA

Tomoterapia sistemica e tomoterapia linfonodale (TMLI) in combinazione con ciclofosfamide (Cy) ed etoposide (VP16) come regime di condizionamento dei pazienti con leucemia acuta linfoide o mieloide ad alto rischio sottoposti a trapianto di midollo osseo allogenico (alloHCT): studio di fase II

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

TMLI

A.4.1

Sponsor's protocol code number

TMLI_HSM_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	IRCCS-A.O.U. SAN MARTINO-IST
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS OSPEDALE POLICLINICO SAN MARTINO
B.5.2	Functional name of contact point	CENTRO CLINICAL TRIALS
B.5.3	Address:
B.5.3.1	Street Address	Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0105558476
B.5.6	E-mail	luca.boni@hsanmartino.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.2.5	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	Ciclofosfamide
D.3.2	Product code	[Ciclofosfamide]
D.3.4	Pharmaceutical form	Powder and solvent for 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.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	Cy
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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.2.5	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	Etoposide
D.3.2	Product code	[VP-16]
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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.3.9.1	CAS number	33419-42-0
D.3.9.2	Current sponsor code	VP-16
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
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

Acute Lymphocytic or Myelogenous Leukemia

Leucemia acuta mieloide o linfoide

E.1.1.1

Medical condition in easily understood language

Acute Lymphocytic or Myelogenous Leukemia

Leucemia acuta mieloide o linfoide

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10024330
E.1.2	Term	Leukemia acute
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

Evaluate the anti-tumor activity of TMLI given in combination with cyclophosphamide (Cy) and etoposide (VP-16) as assessed by 2-year progression-free survival (PFS).

Valutare l’effetto anti tumorale della TMLI somministrata in combinazione con la ciclofosfamide (Cy) e l’etoposide (VP-16) mediante l’analisi della sopravvivenza libera da malattia a 2 anni post-trapianto.

E.2.2

Secondary objectives of the trial

Estimate overall survival (OS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.
Evaluate early/late toxicities/complications by organ/severity (including acute/chronic GVHD infection), and characterize by organ dose/dose volume.

Valutazione della sopravvivenza globale, della incidenza cumulativa di recidiva/progressione di malattia e la mortalità trapiantologica a 100 giorni, un anno e 2 anni post-trapianto.
Valutazione delle complicanze e delle tossicità precoci e tardive, sui singoli organi (inclusa la GvHD acuta e cronica e le complicanze infettive) e caratterizzazione del rapporto dose di radioterapia somministrata per organo/dose volumetrica effettiva

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age =18 to =60 years
• Karnofsky performance status must be =70%
• Patients with acute lymphocytic leukemia or acute myelogenous leukemia who are not in first remission or second remission, i.e. after failing induction therapy, or in relapse, or beyond second remission.
• All candidates for this study must have an HLA (A,B,C,DR) identical sibling who is willing to donate bone marrow or primed blood stem cells, a 10/10 allele matched unrelated donor.
• Patients must undergo cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm, and an ejection fraction of =50% established by MUGA or echocardiogram.
• Patients must have a serum creatinine of less than or equal to 1.3 mg/dL or creatinine clearance > 80ml/min.
• Patients must have bilirubin of less than or equal to 1.5mg/dL and should also have an SGOT and SGPT less than 5 times the upper limit of normal
• Pulmonary function tests including DLCO will be performed. FEV1and DLCO should be greater than 50% of predicted normal value.
• The time from the end last induction or re-induction attempt should be greater than or equal to 14 days.
• All patients must have a psychosocial evaluation prior to transplant as per COH SOP
• All subjects must have the ability to understand and the willingness to sign a written informed consent

• Età compresa tra 18 e 60 anni
• Karnofsky performance status e =70%
• Pazienti con leucemia acuta linfoide o mieloide non in prima o seconda remissione, ossia dopo il fallimento della terapia di induzione o in recidiva di malattia o in fase di malattia avanzata oltre la seconda remissione.
• I pazienti devono avere un donatore familiare HLA identico che può donare cellule staminali periferiche o midollari oppure un donatore non consanguineo HLA identico (10/10). I donatori mismatched per un singolo allele al locus A, B, C, DR, o DQ e KIR mismatch al locus C sono esclusi.
• I pazienti devono effettuare una valutazione cardiologica completa con ECG che non mostra alterazioni ischemiche e un ecocardiogramma che mostri una frazione di eiezione cardiaca superiore o uguale al 50%
• I pazienti devono avere un livello sierico di creatinina inferiore o uguale a 1.3 mg/dL o una clearance della creatinina > 80ml/min.
• I pazienti devono avere un livello sierico di bilirubina inferiore o uguale a 1.5 mg/dL o un livello di GOT e GPT inferiore a 5 volte il limite normale.
• I pazienti devono effettuare la valutazione della funzionalità respiratoria inclusa la DLCO. FEV1 e DLCO devono essere superiori al 50% del valore normale predetto.
• Il periodo tra l’ultima terapia di induzione o di re-induzione e l’inizio dello studio deve essere superiore o uguale a 14 giorni.
• Tutti i pazienti devono effettuare una valutazione psicologica prima del trapianto.
• Tutti i pazienti devono avere la capacità di comprendere e sottoscrivere un consenso informato
• Test di gravidanza negativo per le donne potenzialmente fertili

E.4

Principal exclusion criteria

• Patients who have received a prior autologous or allogeneic transplant are excluded
• Uncontrolled inter-current illness including, but not limited to ongoing or active or poorly controlled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and lactating women are excluded from this study.
• Patients who do not agree to practice effective forms of contraception.
• Patients who received radiation therapy that would exclude them from the use of total body irradiation are ineligible and individual patients who have received prior radiation must be presented to the study PI for eligibility determination.
• Patients with active 2nd malignancies other than AML, ALL or MDS.
• Any psychiatric, social or compliance issues that, in the treating physician opinion, will interfere with completion of the transplant treatment and follow up.

• I pazienti che hanno ricevuto un precedente trapianto autologo o allogenico sono esclusi.
• Infezioni in atto non controllate, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca, patologia polmonare non controllabile, patologia psichiatrica o situazioni sociali che potrebbero limitare la “compliance” richiesta dallo studio.
• Pazienti donne in gravidanza e in allattamento sono escluse dallo studio.
• Pazienti che non accettano di praticare nessuna forma di contraccezione.
• I pazienti che hanno ricevuto una pregressa radioterpia che li escluderebbe dallo studio, devono essere presentati al principale investigatore dello studio ed essere discussi per la eleggibilità.
• Pazienti con malattia attiva diversa da leucemia acuta mieloide, linfoide o sindrome mielodisplastica.
• Qualsiasi problematica psichiatrica o sociale che secondo l’opinione del clinico potrebbe interferire con il trattamento e il follow up post trapianto.

E.5 End points

E.5.1

Primary end point(s)

The primary study endpoint is 2-year progression-free survival (PFS). PFS will be estimated from the start of treatment to the date of death, disease relapse/progression, or date of last contact using the Kaplan-Meier method.

L’endpoint primario dello studio è la sopravvivenza libera da progressione (PFS) a 2 anni. La PFS sarà stimata dall'inizio del trattamento alla data di morte, ricaduta / progressione della malattia o data dell'ultimo contatto utilizzando il metodo Kaplan-Meier..

E.5.1.1

Timepoint(s) of evaluation of this end point

Two years

2 anni

E.5.2

Secondary end point(s)

CR proportion at day 30; Non- relapse mortality; Incidence of Infetion; Toxicitie and adverse events; Acute GVHD; Chronic GVHD; • Overall Survival; • EM and BM relapse/progression

Ottenimento della remissione completa al giorno +30; Mortalità trapiantologica; Incidenza di infezioni; Tossicità ed eventi avversi; GVHD acuta; GVHD cronica; • Sopravvivenza globale; • Recidiva o progressione midollare o extramidollare di malattia

E.5.2.1

Timepoint(s) of evaluation of this end point

26 months; 7 years; 27 months; 27 months; 27 months; 7 years; 7years; 7 years

26 mesi; 7 anni; 27 mesi; 27 mesi; 27 mesi; 7 anni; 7 anni; 7 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

E.6.5

Efficacy

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

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)

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)

Follow up post transplant

Regolare follow up trapiantologico

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

2021-06-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2024-12-17

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