Clinical Trials Register

Summary
EudraCT Number:	2013-003466-13
Sponsor's Protocol Code Number:	GMALL082013
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-05-05
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

Germany - BfArM

A.2

EudraCT number

2013-003466-13

A.3

Full title of the trial

Treatment optimization in adult patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma by individualised, targeted and intensified treatment - a phase IV-trial with a phase III-part to evaluate safety and efficacy of nelarabine in T-ALL patients

A.3.1

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

Optimization of therapy in adult patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma by individualised, targeted and intensified treatment

A.3.2

Name or abbreviated title of the trial where available

GMALL 08/2013

A.4.1

Sponsor's protocol code number

GMALL082013

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	Goethe University Frankfurt
B.1.3.4	Country	Germany
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	Deutsche Krebshilfe e.V.
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Frankfurt
B.5.2	Functional name of contact point	GMALL Studienzentrale
B.5.3	Address:
B.5.3.1	Street Address	Theodor-Stern-Kai 7
B.5.3.2	Town/ city	Frankfurt
B.5.3.3	Post code	60590
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496963016365
B.5.5	Fax number	00496963017463
B.5.6	E-mail	gmall@em.uni-frankfurt.de

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	Atriance
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/1/07/403
D.3 Description of the IMP
D.3.4	Pharmaceutical form	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.3.8	INN - Proposed INN	NELARABINE
D.3.9.1	CAS number	121032-29-9
D.3.9.4	EV Substance Code	SUB09188MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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: 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	Germany
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/3/08/569
D.3 Description of the IMP
D.3.4	Pharmaceutical form
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	PEGASPARGASE
D.3.9.1	CAS number	130167-69-0
D.3.9.4	EV Substance Code	SUB03666MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	3750
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

Newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma
Age 18 to 55 y

E.1.1.1

Medical condition in easily understood language

Newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma
Age 18 to 55 y

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic leukemia
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	10065923
E.1.2	Term	Lymphoblastic lymphoma
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

To improve event free survival (EFS), remission duration (RD), disease free survival (DFS) and overall survival (OS) compared with the previous trial GMALL 07/2003

E.2.2

Secondary objectives of the trial

1. To evaluate the role of CNS radiation and the role of chemotherapy alone in high risk ALL in molecular remission by randomised evaluation
R1: CNS rad + i.th. vs i.th.alone
R2: SCT vs chemotherapy in pts with molCR
2. To evaluate the feasibility of the entire treatment concept (i.e. adherence to schedule, administration of single and combination chemotherapy, maintenance therapy)
3. To evaluate feasibility and tolerability of nelarabine (IMP) as part of consolidation treatment in T-ALL
4. To perform prospective and concomitant monitoring of comorbidities and specifically defined serious adverse events
5. To evaluate an innovative overall approach to optimize treatment of a rare, biologically diverse disease by use of subgroup specific targeted and experimental substances within the main trial and in associated studies
6. To set up an interlinked biomaterial bank to prospectively evaluate molecular genetic risk factors and carry out scientific accompanying projects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Acute lymphoblastic leukemia (all subtypes except burkitt leukemia, blasts in BM ≥ 25%
or
• Lymphoblastic lymphoma (B- or T-lineage), blasts in BM <25%

• Age: ≥ 18 - ≤ 55 years

• Written Informed consent to participate in the study and the GMALL registry

• Women of childbearing potential (WOCBP) and male sexual partners of WOCBP must be willing to use an effective method of contraception (Pearl-Index < 1%) during the study and at least 6 months thereafter

E.4

Principal exclusion criteria

• Serious complications (leukemia associated) or concomitant diseases, such as
- severe uncontrollable complications (leukemia associated), i.e. sepsis, pneumonia with hypoxia, shock, bleeding at diagnosis
- renal insufficiency, if not caused by leukemia
- severe impairment of heart or liver function (if not caused by leukemic infiltration)
- severe obstructive or restrictive pulmonary disease
- known HIV infection or other uncontrolled infections
- any other condition that compromises the patient’s eligibility for intensive treatment as described by the study protocol

• Late relapse of childhood leukemia or concurrent malignancy

• Previous cytostatic treatment
- ALL directed (exceptions: standard prephase, application of steroids ≤ 7 days, once-only application of vincristine, cyclophosphamide or other substances as emergency medical intervention)
- directed to other malignancies within the last 10 years before diagnosis of ALL

• Pregnancy or breastfeeding

• Severe psychiatric disease or any severe concomitant condition under which the patient's understanding of importance and consequences of study participation and/or compliance and therapy according to study protocol cannot be expected

• At diagnosis: participation in another trial that interferes with the antileukemic treatment
(exceptions: trials aiming at supportive care, defined accompanying GMALL trials, and at a later timepoint trials with experimental substances, i. e. in case of molecular treatment failure)

E.5 End points

E.5.1

Primary end point(s)

Event free survival compared with GMALL 07/2003

E.5.1.1

Timepoint(s) of evaluation of this end point

at 5 years

E.5.2

Secondary end point(s)

1. time (days) until start of consolidation cycle I (for randomisation I)

2. disease free survival (for randomisation II)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Start date of consolidation cycle I

2. at 3,5 years

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

Yes

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

standard therapy

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

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

The originally planned follow-up period of 36 months will be shortened to 20 months. Thus, the last follow-up (i.e. LVLS) will be conducted in April 2024.
Justification: The primary endpoint of the trial has been met. Per recommendation of biostatisticians in line with data safety monitoring board further follow-up is not required. It is of utmost importance to prepare the final study report and essential publications.
This modification has no impact on patient safety or data integrity.

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

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:

900

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

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

900

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)

according to 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

2015-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-15

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

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