Clinical Trials Register

Summary
EudraCT Number:	2009-012973-37
Sponsor's Protocol Code Number:	IPR/21
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-10-18
Trial results	View 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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2009-012973-37

A.3

Full title of the trial

TK008:Randomized phase III trial of haploidentical HCTwith or without an add back strategy of HSV-Tk donor lymphocytes in patients with high risk acute leukemia

A.3.1

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

Randomized study evaluating in patients with high risk of acute leukemia, stem cells transplant from a partial compatible donor with or without HSV-TK infusion of genetically modified donor lymphocytes (HSV-Tk).

A.3.2

Name or abbreviated title of the trial where available

TK008

A.4.1

Sponsor's protocol code number

IPR/21

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00914628

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	MolMed S.pA.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MolMed S.p.A.
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	MolMed S.p.A.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	via Olgettina, 58
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390221277234
B.5.5	Fax number	00390221277239
B.5.6	E-mail	scialini.colombi@molmed.com

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/168
D.3 Description of the IMP
D.3.1	Product name	Haploidentical donor T-lymphocytes genetically modified to express HSV-TK genes
D.3.2	Product code	MM100
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	other anti-neoplastic agent
D.3.9.2	Current sponsor code	MM-100
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.8 x 10^7cell/Kg to 1.2 x10^7 cell/Kg
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)	Yes
	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	Yes
D.3.11.3.5.1	CAT classification and reference number	EMEA/CAT/667758/2009
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	Yes
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.2.1.2	Country which granted the Marketing Authorisation	France
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	Ganciclovir
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	GANCICLOVIR
D.3.9.1	CAS number	82410-32-0
D.3.9.4	EV Substance Code	SUB07881MIG
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	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	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.IMP: 3
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.2.1.2	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	Valganciclovir
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VALGANCICLOVIR
D.3.9.1	CAS number	175865-60-8
D.3.9.4	EV Substance Code	SUB00007MIG
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	450
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

High risk acute leukemias in 1st or subsequent complete remission or in relapse.

E.1.1.1

Medical condition in easily understood language

High risk acute leukemia

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10054291
E.1.2	Term	Acute leukemia (in remission)
E.1.2	System Organ Class	100000004864

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

To compare disease-free survival (DFS) in high risk leukemia patients who underwent haploidentical HCT followed by an add back strategy of HSV-Tk donor lymphocytes or standard haploidentical HCT

E.2.2

Secondary objectives of the trial

To compare overall survival (OS) in the two treatment arms
To compare the cumulative incidence of non-relapse mortality (NRM)
To compare the time to T-cell immune reconstitution
To compare the engraftment rate
To compare the cumulative incidence of grade II-IV acute GvHD
To compare the cumulative incidence of extensive chronic GvHD
To compare the cumulative incidence of relapse (CIR)
To compare incidence and duration of infectious episodes and infectious disease mortality
To evaluate the acute and long-term toxicity related to the HSV-Tk infusions
To assess quality of life (QoL) and Medical Care Utilization (MCU) in both arms

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: Pharmacoeconomy
Version: D
Data: 2012-06-13
Objective:to summarize and evaluate treatment group differences in total resource use, and more specifically, in resource use associated with diagnosis, monitoring and treatment of relevant events (i.e., acute and chronic GvHD, infectious episodes, etc).

Quality of life
Title:Evaluation of Quality of life
Version: D
Data: 2012-06-13
Objective: summarize and evaluate treatment group differences in patient convenience and satisfaction.

E.3

Principal inclusion criteria

Patients ≥ 18 years with HCT comorbidity index < 3 (Appendix I)
- Any of the following conditions:
- AML and ALL in 1st complete remission (CR) at high risk of relapse based on negative prognostic factors (for the definition of high-risk of relapse see Appendix H)
- AML and ALL in 2nd or subsequent CR
- secondary AML in CR
- AML and ALL in 1st or 2nd relapse or primary refractory
- Absence of timely and suitable fully HLA matched or one HLA locus mismatched family or unrelated donor and, at Investigator’s discretion, absence of other possible therapeutic alternatives
- Stable clinical conditions and life expectancy > 3 months
- PS ECOG < 2
- Serum creatinine < 1.5 x ULN
- Bilirubin < 1.5 x ULN; transaminases < 3 x ULN
- Left ventricular ejection fraction > 45%
- QTc interval < 450 ms
- DLCO > 50%
- Patients and donors, or independent witnesses must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects.

E.4

Principal exclusion criteria

- Patients with life-threatening condition or complication other than their basic condition
- Contraindication to haploidentical HCT as defined by the Investigator
- Patients with active CNS disease
- Pregnant or lactation. Patients both males and females with reproductive potential (i.e. menopausal for less than 1 year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of childbearing
potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration.

E.5 End points

E.5.1

Primary end point(s)

To compare disease-free survival (DFS) in high risk leukemia patients who underwent haploidentical HCT followed by an add back strategy of HSV-Tk donor lymphocytes or standard haploidentical HCT

E.5.1.1

Timepoint(s) of evaluation of this end point

Disease-Free Survival (DFS) Monthly (bone marrow aspiration: every 3 months, or as clinically indicated) for first 6 months after haplo-HCT and thereafter at month 9, 12 and yearly until disease relapse or death

E.5.2

Secondary end point(s)

• To compare overall survival (OS) in the two treatment arms
• To compare cumulative incidence of non-relapse mortality (NRM)
• To compare time to T-cell immune reconstitution
• To compare engraftment rate
• To compare cumulative incidence of grade II-IV acute GvHD
• To compare cumulative incidence of extensive chronic GvHD
• To compare cumulative incidence of relapse (CIR)
• To compare incidence and duration of infectious episodes and infectious disease mortality
• To evaluate the acute and long-term toxicity related to the HSV-Tk infusions
• To assess quality of life (QoL) and Medical Care Utilization (MCU) in both arms

E.5.2.1

Timepoint(s) of evaluation of this end point

•monthly up 6 months after haplo-HCT,then at month 9,12;yearly until relapse or death•monthly up 6 months, at month 9,12•weekly till IR, then monthly up 6 months, at month 9,12•weekly till IR,then monthly up 6 months, at month 9,12•weekly till IR, monthly up 6 months•weekly till IR, monthly up 6 months•Monthly (bone marrow aspiration:every 3 months or as clinically indicated) up 6 months, at month 9 and 12;yearly until disease relapse•weekly till IR, monthly up 6 months, at month 9,12;yearly until death•on a weekly basis up to IR, monthly up 6 months from the date of IR then at month 9,12;yearly for long-term toxicity•QoL:at screening, month 9,12;yearly till end of study.MCU on ongoing basis

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

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life assessment

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

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

Yes

E.8.2.3.1

Comparator description

Haploidentical haematopoietic stem cells transplantation (without HSV-Tk)

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

Israel

United States

E.8.7

Trial has a data monitoring committee

Yes

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

for Study completion date means the end of the last visit of the center because only when close out visit is performed all the data have been validated and study documentation rechecked

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

Number of subjects for this age range:

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:

150

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

130

F.4.2.2

In the whole clinical trial

170

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)

the plan is personal, according to patient clinical condition and hospital standard 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

2017-04-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-28

P. End of Trial
P.	End of Trial Status	Completed

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