Clinical Trials Register

Summary
EudraCT Number:	2019-000439-14
Sponsor's Protocol Code Number:	CMBG453C12201
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:	2021-06-15
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

2019-000439-14

A.3

Full title of the trial

A phase II multi-center, single arm, safety and efficacy study of MBG453 in combination with azacitidine and venetoclax for the treatment of Acute
Myeloid Leukemia (AML) in adult patients unfit for chemotherapy

Studio di Fase II, multicentrico, a braccio singolo, della sicurezza d’impiego e dell’efficacia di MBG453 in associazione ad azacitidina e venetoclax per il trattamento della leucemia mieloide acuta (AML) in pazienti adulti non candidati alla chemioterapia

A.3.1

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

A study of MBG453 in combination with azacitidine and venetoclax in AML patients unfit for chemotherapy

Studio con MBG453 in associazione ad azacitidina e venetoclax in pazienti con AML non candidati alla chemioterapia

A.3.2

Name or abbreviated title of the trial where available

STIMULUS-AML1

A.4.1

Sponsor's protocol code number

CMBG453C12201

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	00
B.5.3.4	Country	Italy
B.5.4	Telephone number	0296543289
B.5.5	Fax number	029659066
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.3.1	Product name	-
D.3.2	Product code	[MBG453]
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.3.8	INN - Proposed INN	sabatolimab
D.3.9.2	Current sponsor code	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	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	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.2.1.1.1	Trade name	Venclyxto
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Deutschland GmbH & Co.
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/3/16/1617
D.3 Description of the IMP
D.3.1	Product name	Venetoclax
D.3.2	Product code	[-]
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	VENETOCLAX
D.3.9.2	Current sponsor code	venetoclax
D.3.9.4	EV Substance Code	SUB176260
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	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: 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.2.1.1.1	Trade name	-
D.2.1.1.2	Name of the Marketing Authorisation holder	-
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.3.2	Product code	[-]
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	azacitidina
D.3.9.1	CAS number	320-67-2
D.3.9.2	Current sponsor code	-
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	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 Myeloid Leukemia (AML) in adult patients unfit for chemotherapy

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia (AML)

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
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

safety run in+expansion:
Assess complete remission (CR) rate of MBG453, administered at 800 mg Q4W, in combination with azacitidine and venetoclax in subjects with AML not suitable for chemotherapy
Safety run in:
determine if MBG453 at 2 tested dose levels is not meeting overdose criteria when added to venetoclax+azain subjects with AML not suitable for chemotherapy

E.2.2

Secondary objectives of the trial

Secondary:
- assess effect of MBG453 in combination with venetoclax+azacitidine (aza) on MRD
- assess CR/CRi rate and durability of CR/CRi by determining the
Relapse Free Survival (RFS) in subjects who achieved CR/CRi
- assess durability of CR by determining the RFS in subjects who achieve CR
- assess EFS
- assess OS
- determine safety & tolerability of MBG453 in combination with venetoclax+aza
- characterize PK of MBG453 in combination with venetoclax+aza
- evaluate MBG453 immunogenicity in combination with venetoclax+aza
- assess effect of MBG453 in combination with venetoclax+aza on transfusion independence

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
1.Signed informed consent must be obtained prior to participation in the study.
2. Age = 18 years at the date of signing the informed consent form (ICF)
3. Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age =75, ECOG performance Status 2 or 3, or any of the following comorbidities: severe cardiac comorbidities (including congestive heart failure, LVEF = 50%, chronic stable Angina) , pulmonary comorbidity (DLCO = 65% or FEVI = 65%). moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN) , renal impairment (eGFR= 30 ml/min/1.73m^2 to 45 30 ml/min/1.73m^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessment and approved by the Novartis Medical monitor)
4..Not planned for hematopoietic stem-cell transplantation (HSCT)
5..Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3
Additional inclusion criteria as per full protocol may apply

E.4

Principal exclusion criteria

Exclusion Criteria:
1.Prior exposure to TIM-3 directed therapy
2. Subjects with therapy related AML.
3.History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients
4.Current use or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
5.Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine.
6.Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
7.Live vaccine administered within 30 days prior to randomization
Other protocol-defined Inclusion/Exclusion may apply.

E.5 End points

E.5.1

Primary end point(s)

1. Incidence of dose limiting toxicities (Safety run-in patients only)
2. Percentage of subjects achieving complete remission (CR)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
2. at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days)

E.5.2

Secondary end point(s)

1. Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi)
2. Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause
3. Time from date of first documented CR to the date of first documented relapse or death due to any cause
4. Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first
5. Time from start of treatment to death due to any cause (overall
survival)
6. Peak Serum Concentration (Cmax) MBG453
7. Trough Serum Concentration (Cmin) MBG453
8. Trough Plasma Concentration (Cmin) Venetoclax
9. Anti-drug Antibody (ADA) prevalence at baseline
10. ADA prevalence on-treatment
11. Percentage of MRD-negative subjects in the full study population and
in subjects achieving CR or CRi
12. Rate of subjects who achieve transfusion independence from baseline and while on treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

1-4. every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
5. date of start of treatment to date of death due to any reason (for up to 48 m from last patient first treatment)
6. Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days
7. Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months
8. Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days
9. prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days)
10. Throughout study until 150 day safety follow-up
11. every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
12. from start of treatment up to 48 months from last patient first treatment

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)

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

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

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

Australia

Canada

Japan

Korea, Democratic People's Republic of

Taiwan

United States

France

Germany

Italy

Spain

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

LPLV

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)

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

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)

all patients will have access to study treatment until deemed necessary and beneficial by investigator assessment

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

2021-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-11-17

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

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