Clinical Trials Register

Summary
EudraCT Number:	2019-004896-38
Sponsor's Protocol Code Number:	CL1-64315-004
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-09-18
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

France - ANSM

A.2

EudraCT number

2019-004896-38

A.3

Full title of the trial

Phase I/II, international, multicentre, open-label, non-randomised, non-comparative study evaluating the safety, tolerability and clinical activity of intravenously administered S64315, a selective Mcl-1 inhibitor, in combination with azacitidine in patients with acute myeloid leukaemia (AML)

A.3.1

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

Phase I/II trial of S64315 plus azacitidine in acute myeloid leukaemia

A.4.1

Sponsor's protocol code number

CL1-64315-004

A.5.4

Other Identifiers

Name:

IND

Number:

136541

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	Institut de Recherches Internationales Servier
B.1.3.4	Country	France
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	ADIR
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut de Recherches Internationales Servier
B.5.2	Functional name of contact point	Clinical Studies Department
B.5.3	Address:
B.5.3.1	Street Address	50 rue Carnot
B.5.3.2	Town/ city	SURESNES CEDEX
B.5.3.3	Post code	92284
B.5.3.4	Country	France
B.5.4	Telephone number	+33155724366
B.5.5	Fax number	+33155725412
B.5.6	E-mail	clinicaltrials@servier.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	S64315
D.3.2	Product code	S64315
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	S64315
D.3.9.3	Other descriptive name	S64315/MIK665
D.3.9.4	EV Substance Code	SUB184625
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	61.75
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	Vidaza
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe B.V.
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.3.4	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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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

Acute Myeloid Leukaemia (AML)

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukaemia (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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I dose escalation
To determine the safety profile and tolerability of S64315 in combination with azacitidine in patients with AML.

Phase II dose expansion
To evaluate the Objective Response rate (ORR) (including complete response (CR) and complete response with incomplete bone marrow recovery (CRi) rates) of S64315 in combination with azacitidine.

E.2.2

Secondary objectives of the trial

Phase I dose escalation
To determine pharmacokinetic (PK) profile of S64315 and azacitidine administered in combination, and potential metabolites.
To evaluate anti-leukemic activity of S64315 in combination with azacitidine.

Phase II dose expansion
To assess anti-leukemic activity of S64315 in combination with azacitidine in terms of overall survival (OS), duration of response (DOR), best overall response (BOR), progression-free survival (PFS), disease-free survival (DFS).
To assess the safety and tolerability of S64315 in combination with azacitidine.
To determine PK profile of S64315 and azacitidine administered in combination, and potential metabolites.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1-Patients aged ≥ 18 years

2-Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by WHO 2016 classification (Arber, 2016) excluding acute promyelocytic leukaemia (APL, French-American-British M3 classification) with: relapsed or refractory disease and without established alternative therapy, or secondary to MDS and without established alternative therapy or, newly diagnosed AML, not previously treated for AML and who are not candidate for intensive chemotherapy due to age or comorbidities.

3-Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

4-Adequate haematological, renal and hepatic functions based on the last assessment performed within 7 days prior to the first IMP administration.

E.4

Principal exclusion criteria

1-Previous myeloproliferative syndrome (MPS).

2-Patient previously treated with hypomethylating agents (HMAs) such as azacitidine or decitabine, during dose escalation phase I part.

3-Patients previously treated with any Mcl-1 inhibitor.

4-Patients who have not recovered from toxicity of previous anticancer therapy, including Grade ≥ 2 toxicity (except alopecia of any grade) according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 5.0, prior to the first IMP administration.

5-Severe or uncontrolled active acute or chronic infection.

6-Uncontrolled hepatitis B or C infection.

7-Known carriers of HIV antibodies, history of significant liver disease, active acute or chronic pancreatitis, active central nervous system disease.

8-Troponin (I or T) > ULN.

9-Clinically significant cardiac dysfunction (including NYHA class ≥II heart failure, Left Ventricular Ejection Fraction (LVEF) < 50% as assessed by echocardiography (ECHO) or Multi-Gated Acquisition (MUGA) scan).

10-QT prolongation defined as QTc interval (corrected with Fridericia’s formula) > 450 ms for males and > 470 ms for females, obtained from triplicate 12-lead ECG.

11-Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.

12-Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg).

E.5 End points

E.5.1

Primary end point(s)

Phase I - dose escalation:
Incidence of DLTs starting from the LID period to the end of the first cycle of treatment of S64315 in combination with azacitidine.
Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0.
Recording of any change or addition of a new concomitant treatment.
Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood coagulation, urinary analysis, hepatitis markers, TLS monitoring, cardiac markers follow up
Complete physical examination, ECOG performance status, vital signs measurements.
ECG parameters, cardiac function assessment.
Left ventricular ejection fraction (LVEF).
Dose interruptions, reductions and dose intensity.

Phase II - dose expansion:
ORR (including CR+ CRi)

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I - dose escalation:
DLT: D-13 to C1D28 (i.e. from the start of S64315 Lead in dose period to the end of 1st cycle of the combination of S64315 + azacitidine)
AE: D-13 up to the patient's last study visit
SAE: D-13 up to 30 calendar days after the patient's last study visit
Concomitant treatment: inclusion period to FU
Blood haematology and biochemistry: inclusion period, D-13, D-6, CxD1, CxD2, CxD9, CxD16, CxD23, WV
TLS monitoring: D-13, D-6, C1D1, CxD2, CxD9, CxD16, CxD23
ECG: inclusion period, D-13, D-6, C1D1, C1D9, C1D16, C1D23, CxD2, WV
ECHO, MUGA scan, LVEF: inclusion period, C2D1, C3D1, C4D1 then every 2 cycles, WV
S64315 administration schedule: D-13, D-6, CxD2, CxD9, CxD16, CxD23
Azacitidine administration schedule: CxD1 to CxD7

E.5.2

Secondary end point(s)

Phase I - dose escalation:
PK parameters of S64315 and azacitidine administered in combination, and potential metabolites if applicable, in plasma (e.g. Cinf, tinf, AUClast, tlast, Clast, AUC, t1/2,z, CL and Vd)
ORR (including CR/CRi), Best Overall Response (BOR), Duration of Response (DOR), Progression Free Survival (PFS), Overall survival (OS)
Anti-leukemic activity assessment using blood, BMA and BMB if available according to ELN 2017 response criteria (Döhner, 2017)

Phase II - dose expansion:
BOR, DOR, PFS, OS
Anti-leukemic activity assessment using blood/BMA and BMB if available according to ELN 2017 response criteria (Döhner, 2017)
Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0
Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood coagulation and urinary analysis, hepatitis markers, TLS monitoring, cardiac markers follow up
Complete physical examination, ECOG performance status, vital signs measurements
ECG parameters, cardiac function assessment
LVEF
Dose interruptions, reductions and dose intensity
PK parameters of S64315 and azacitidine administered in combination, and potential metabolites if applicable, in plasma

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I - dose escalation:
PK parameters of S64315: D-13, C1D2, C1D3, C1D9, C1D10
PK parameters of azacitidine: C1D1, C1D2, C1D3, C1D5, C1D7
Haematology anti-leukemic activity assessment: Inclusion period, C1D1, C1D2, CxD1, WV
BMA and BMB anti-leukemic activity assessment: Inclusion period, C2D1, C3D1, if suspected progression, WV
ORR, BOR, DOR, PFS, OS: from inclusion period to FU

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase I/II

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

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

Dose escalation phase 1 followed by a dose expansion phase 2

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

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

France

Spain

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

Last follow-up of the last patient (including a phone contact), or the date of the last contact attempt if the last patient is declared lost to follow-up.

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

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

180

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 discontinuation of the IMPs, patient’s treatment is left to the physician’s discretion.

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

2020-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-07

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

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