Clinical Trials Register

Summary
EudraCT Number:	2019-002089-11
Sponsor's Protocol Code Number:	CMBG453B12301
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:	2020-02-25
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

2019-002089-11

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled phase III multi-center study of azacitidine with or without MBG453 for the treatment of patients with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

A.3.1

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

A study of azacitidine with or without MBG453 for the treatment of patients with intermediate, high or very high risk myelodysplastic syndrome (MDS), or Chronic Myelomonocytic Leukemia-2 (CMML-2)

A.4.1

Sponsor's protocol code number

CMBG453B12301

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	Novartis Pharma AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farma
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1 -
B.5.3.2	Town/ city	Origgio (VA)
B.5.3.3	Post code	0
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390296541
B.5.5	Fax number	0039029659066
B.5.6	E-mail	info.studiclinici@novartis.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	MBG453
D.3.4	Pharmaceutical form	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.3.8	INN - Proposed INN	Not yet defined
D.3.9.2	Current sponsor code	MBG453
D.3.9.3	Other descriptive name	MBG453
D.3.9.4	EV Substance Code	SUB178459
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	100
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.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	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	Azacitidine
D.3.4	Pharmaceutical form	Powder for suspension 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	AZACITIDINE
D.3.9.1	CAS number	320-67-2
D.3.9.4	EV Substance Code	SUB05624MIG
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	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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

adult subjects with intermediate, high or very high risk (per IPSS-R prognostic risk categories) myelodysplastic syndrome or with Chronic Myelomonocytic Leukemia - 2 (CMML-2)

E.1.1.1

Medical condition in easily understood language

intermediate, high or very high risk myelodysplastic syndrome or with Chronic Myelomonocytic Leukemia - 2

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10028536
E.1.2	Term	Myelodysplastic syndromes
E.1.2	System Organ Class	100000004851

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10009018
E.1.2	Term	Chronic myelomonocytic 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

To compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm

E.2.2

Secondary objectives of the trial

Key Secondary:
1:compare time to definitive deterioration of fatigue in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm
2: compare RBC transfusion-free intervals in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
3: compare improvement of fatigue in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
4: compare improvement of physical functioning in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
5: compare improvement of emotional functioning in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
Other:
•assess response rate in each treatment arm
•assess PFS in each treatment arm
•assess leukemia-free survival in each treatment arm
•assess safety profile of MBG453 when given in combination with azacitidine
•assess improvement in RBC/Platelets transfusion independence in each treatment arm
•characterize the PK of MBG453
•evaluate immunogenicity of MBG453
•assess overall QoL in each treatment arm

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

Actigraphy substudy:
Activity monitoring sensors (Actigraphy) will be used in the study to record daily physical activity and sleep quality and will be offered to a subset of subjects as an additional, optional assessment.

E.3

Principal inclusion criteria

Key inclusion criteria:
• Signed informed consent must be obtained prior to participation in the study
• Age ≥ 18 years at the date of signing the informed consent form (ICF)
• Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R):
• Very high (> 6 points)
• High (> 4.5 - ≤ 6 points)
• Intermediate (> 3 - ≤ 4.5 points)
Or
Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with WBC < 13 x 10^9/L
• Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
• Not eligible for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
• Not eligible for hematopoietic stem cell transplantation according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Please refer to protocol for further details and any additional inclusion criteria.

E.4

Principal exclusion criteria

Key exclusion criteria:
• Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is allowed except if the drug was administered within 4 months prior to randomization
• Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML-2 with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
• Investigational treatment received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
• Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
• Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016)
• Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification
(Arber et al 2016)
• History of organ or allogeneic hematopoietic stem cell transplant
Please refer to protocol for further details and any additional exclusion criteria.

E.5 End points

E.5.1

Primary end point(s)

OS is the time from randomization until death due to any cause. If the subject is not known to have died, then OS will be censored at the latest date the subject was known to be alive (on or before cut-off date).

E.5.1.1

Timepoint(s) of evaluation of this end point

Estimated at 28 months and 33 months after first patient randomized and up to 5 years after the first patient randomized

E.5.2

Secondary end point(s)

Key secondary endpoints:
1. Time from randomization to at least 3 points worsening from baseline in FACIT-fatigue scores with no subsequent improvement above this threshold or death due to any cause, whichever occurs first
2. Cumulative time of intervals with no evidence of RBC transfusion for at least 8 weeks at any point after randomization
3. Percent of subjects with at least 3 point confirmed improvement from baseline in FACIT-fatigue scores
4. Percent of subjects with at least 10 point confirmed improvement from baseline in physical functioning using EORTC QLQ-C30
5. Percent of subjects with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC QLQ-C30
Other endpoints:
a) Percentage of CR/mCR/PR/HI according to IWG-MDS as per investigator assessment; Percentage of SD according to IWG-MDS as per investigator assessment
b) Time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from complete remission (CR) according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment
c) Time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia, or death due to any cause
d) Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs (per CTCAE version 5)
e) Number and percent of transfusion dependent subjects at baseline who become RBC/platelets transfusion independent after randomization as per IWG-MDS criteria
f) Serum concentrations and pharmacokinetic parameters for MBG453
g) Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
h) Change from baseline in EQ-5D-5L scores and VAS scores over time; Change from baseline to C12D1 of Global Health Status/QoL scores using EORTC QLQ-C30

E.5.2.1

Timepoint(s) of evaluation of this end point

1&3 C3D1 & every 2 cycles, EOT & every 12wks. Estimated at 33mths & up to 5yrs after first patient (FP) rando. 2 Throughout trial. Est at 28 & 33mths and up to 5yrs after FP rando. 4&5 C3/C6/C9D1, after C15 every 3 cycles, EOT & every 12wks. Est at 33mths & up to 5yrs after FP rando.
a/b/c C7/C13D1 & every 12 cycles up to 5yrs after FP rando. d AEs, throughout trial. Hematology, D1+D8 of each cycle until EOT & every 12wks. Chemistry, D1 of each cycle until C7 & C9 & every 2 cycles after until EOT. Vital signs, D1+D8 of each cycle until EOT. e Throughout trial up to 5yrs after FP rando. f/g PK & IG, D8 of each cycle until C6, C9, C12 & every 6 cycles after, EOT, 30 & 150 days after EOT. Soluble Tim-3, D8 of C1/C3/C6. h C3D1, after every 3 cycles, EOT & every 12wks. Analysis at C12D1.

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

Yes

E.6.7

Pharmacodynamic

Yes

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)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

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

Argentina

Australia

Austria

Belgium

Brazil

Canada

Chile

China

Colombia

Czech Republic

Finland

France

Germany

India

Israel

Italy

Japan

Korea, Republic of

Lebanon

Lithuania

Malaysia

Mexico

Netherlands

Oman

Portugal

Russian Federation

Saudi Arabia

Singapore

Spain

Switzerland

Taiwan

Thailand

Turkey

United Kingdom

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

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

350

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

113

F.4.2.2

In the whole clinical trial

500

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)

At the end of the study, every effort will be made, in alignment with local regulations, to continue provision of MBG453 outside this study through an alternative setting to subjects who are receiving treatment with MBG453 and in the opinion of the investigator are still deriving clinical benefit. Options for continued treatment with MBG453 may include access to commercially available drug, or managed access program, or a roll-over study.

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

2020-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-15

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

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