Clinical Trials Register

Summary
EudraCT Number:	2017-005158-12
Sponsor's Protocol Code Number:	NCT-2017-0530
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-08-16
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

2017-005158-12

A.3

Full title of the trial

TEAM-Trial: Targeting Epigenetic therapy resistance in AML with Bortezomib: A multi-centre matched threshold crossing phase II approach

TEAM-Studie: Überwindung der epigenetischen Chemotherapie-Resistenz bei akuter myeloischer Leukämie (AML) mit Bortezomib : eine multizentrische Phase-II Studie mittels Matched Threshold Crossing (MTC)-Ansatz

A.3.1

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

TEAM-Trial: Overcoming the resistance to chemotherapy with the study drug Bortezomib in patients with akute myeloid leukemia : A multi-centre phase II Approach and evaluation with comparable patients

TEAM-Studie: Überwindung der Chemotherapie-Resistenz mit dem Studienmedikament Bortezomib bei Patienten mit Akuter Myeloischer Leukämie: eine multizentrische Phase-II Studie mit einer Auswertung mit vergleichbaren Patienten

A.3.2

Name or abbreviated title of the trial where available

TEAM-Trial

A.4.1

Sponsor's protocol code number

NCT-2017-0530

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	Ruprecht-Karls-University Heidelberg Medical Faculty, University Hospital
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	Pfizer Pharma GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Janssen -Cilag 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 Heidelberg, Internal Medicine V: Hematology, Oncology and Rheumatology
B.5.2	Functional name of contact point	Clinical Trials Office
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496221568006
B.5.5	Fax number	+496221565971
B.5.6	E-mail	team-trial.med5@med.uni-heidelberg.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	VELCADE
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag 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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	VELCADE
D.3.2	Product code	63020-0049
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BORTEZOMIB
D.3.9.1	CAS number	179324-69-7
D.3.9.4	EV Substance Code	SUB20020
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	3,5
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.2.1.1.1	Trade name	Mylotarg
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
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/3/00/005
D.3 Description of the IMP
D.3.1	Product name	Mylotarg
D.3.2	Product code	00008-4510
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	GEMTUZUMAB OZOGAMICIN
D.3.9.1	CAS number	220578-59-6
D.3.9.4	EV Substance Code	SUB20794
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	5
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)	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	Yes
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 confirmed diagnosis of Acute Myeloid Leukemia (AML)according to WHO-2016 classification (except acute promyelocytic leukemia) either de novo AML, AML after preceding myelodysplastic or myeloproliferative syndrome (MDS/MPD), and therapy related AML (t-AML) after previous cytotoxic therapy or radiation are eligible either refractory to first line chemotherapy or in first relapse, also after stem cell transplantation.

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia eligible either without response to first line chemotherapy or in first relapse, also after stem cell transplantation.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

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

Relapsed and refractory r/r-AML still carries a dismal prognosis. In this multicentre, phase II trial we will analyze efficacy of a novel therapy regimen for r/r-AML by combining high dose cytarabine, gemtuzumab ozogamicin (GA) and bortezomib (B).
Recent studies indicate that combination chemotherapy including high dose cytarabine (HiDAC) and gemtuzumab ozogamicin (GO), an antibody drug conjugate , at a dose of 3 mg/m² leads to improved response rates in refractory AML.

E.2.2

Secondary objectives of the trial

Therapy resistance in cancer is still poorly understood. Recently, we discovered an epigenetic therapy resistance mechanism in AML (Göllner et al, 2017). This mechanism might be relevant in up to 50% of relapsed/refractory AML patients. This epigenetic mediated resistance can be successfully overcome in in vitro models by proteasome inhibition. Proteasome inhibition with bortezomib appears to be a promising treatment strategy to restore chemo-sensitivity via EZH2 stabilisation.
Based on this data we combine the treatment efficacy of GO plus cytarabine based chemotherapy with the proteasome inhibitor bortezomib in the B-GA regimen. With such an approach we believe that we can substantially improve treatment results in r/r-AML. Part of the study is a pre-specified biomarker analysis for EZH2 restoration after bortezomib exposure in vitro and in vivo. Accordingly, we will be able to determine whether EZH2 restoration after bortezomib exposure is associated with response and outcome.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

See protocol chapter 5.3

E.4

Principal exclusion criteria

See protocol chapter 5.4

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint:
to assess efficacy (rates of CR/CRi) of B-GA according the ELN 2017 criteria in comparison to matched controls within the matched threshold crossing approach

E.5.1.1

Timepoint(s) of evaluation of this end point

Bone marrow aspiration will be performed at at baseline and for disease assessment after salvage therapy between day 22 and 56 at the time of peripheral blood cell regeneration after the chemotherapy induced nadir or at the time of clear signs of relapsed/refractory disease or at the time before a subsequent therapy e.g. allogeneic SCT is scheduled. At the latest assessment should be performed on day 56.

E.5.2

Secondary end point(s)

Secondary Endpoint:
Key secondary endpoint: safety and feasibility

Other secondary endpoints:
• to assess response in dependence of EZH2 protein levels
• to assess EFS, RFS and OS
• to assess MRD by flow cytometry
• to assess QoL

E.5.2.1

Timepoint(s) of evaluation of this end point

The key secondary endpoint safety will be assessed after 10, 22 and 35 patients based on SAE reporting whereby pulmonary events, prolonged thrombocytopenia and hepatotoxicity are of special interest.

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

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

feasibility,
response in dependence of EZH2 protein levels,
Event free survival, Relapse-free survival, Overall survival,
MRD by flow cytometry,
Quality of life

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

Yes

E.8.1.1

Randomised

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

Yes

E.8.1.7.1

Other trial design description

based on the Matched Threshold Crossing (MTC)-approach

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

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 duration of the trial for each patient is expected to range from 22 and 56 days followed by observational survival follow-up of up to 2 years

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:

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

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.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)

After the end of the study period patients will be routinely followed-up and treated regarding standard of care according to the discretion of the treating physician. A survival follow-up within the trial is intended.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Universitätsklinikum Dresden, Medizinische Klinik und Poliklinik, Studienallianz Leukämie (SAL)
G.4.3.4	Network Country	Germany

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-04-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-03-13

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