Clinical Trials Register

Summary
EudraCT Number:	2015-005248-33
Sponsor's Protocol Code Number:	CML1415
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-12-06
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-005248-33

A.3

Full title of the trial

SUSTRENIM Study – GIMEMA CML1415 Sustained treatment-free remission in BCR-ABL+ chronic myeloid leukemia: a prospective study comparing Nilotinib versus Imatinib with switch to Nilotinib in absence of optimal response

A.3.1

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

Sustained treatment –free period in the course of a disease when symptoms become less sever in BCR-ABL+ chronic myeloid leukemia: a prospective study comparing a drug called Nilotinib versus another called Imatinib with switch to Nilotinib in absence of optimal response

A.3.2

Name or abbreviated title of the trial where available

SUSTRENIM

A.4.1

Sponsor's protocol code number

CML1415

A.5.4

Other Identifiers

Name:

Clinical Trial number

Number:

02602314

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	Fondazione GIMEMA Franco Mandelli ONLUS
B.1.3.4	Country	Italy
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	Novartis Pharma
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	GIMEMA Data Center
B.5.2	Functional name of contact point	GIMEMA Data Center
B.5.3	Address:
B.5.3.1	Street Address	via Casilina, 5
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00182
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390670390526
B.5.5	Fax number	+390670390540
B.5.6	E-mail	gimema@gimema.it

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	Tasigna – 150 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm LTD
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	Tasigna
D.3.4	Pharmaceutical form	Capsule, hard
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	NILOTINIB
D.3.9.1	CAS number	641571-10-0
D.3.9.3	Other descriptive name	Nilotinib
D.3.9.4	EV Substance Code	SUB25225
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	150
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	Glivec – 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm LTD
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	Glivec
D.3.4	Pharmaceutical form	Capsule, hard
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	Imatinib mesylate
D.3.9.1	CAS number	152459-95-5
D.3.9.3	Other descriptive name	IMATINIB
D.3.9.4	EV Substance Code	SUB25387
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic myeloid leukemia (CML) in chronic phase (CP)

E.1.1.1

Medical condition in easily understood language

Chronic myeloid leukemia is a type of cancer that starts in certain blood-forming cells of the bone marrow.

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10009015
E.1.2	Term	Chronic 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

The study will investigate in newly diagnosed CP-CML patients the efficacy of NIL frontline therapy vs IM followed by switch to NIL in the case of absence of optimal response as defined by the ELN criteria using two primary end-points:
- To evaluate the rates of molecular response (MR4.5) at 24 months
- To evaluate the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse 12 months after entering the TFR phase. The molecular relapse is defined as loss of MMR, or confirmed loss of MR3.0

E.2.2

Secondary objectives of the trial

Monitoring the molecular response.
Progression-free survival (PFS) in the two arms of the study.
Overall Survival in the two arms of the study.
Rates of major molecular response (MR3.0) during the study in the two arms of the study.
The dynamics of molecular response
The relationship between baseline characteristics and the primary objectives
The relationship between early molecular response and the primary objectives
To assess the safety profile of both arms.
To determine the rate and the time-distribution of the discontinuation causes of the first-line TKI.
To investigate quality of life (QoL) differences between treatment arms over time

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

Quality of life
To investigate quality of life differences between treatment arms over time

Translational research
Deep phenotypic and molecular characterization of INDIVIDUAL LSC within the LSC pool of newly diagnosed CML patients;
Deep understanding of the cellular pathways involved in CML LSC persistence and genomic instability;
Deep understanding of the physio-pathogenesis of CML by detecting pre-existing mutated (DNMT3A) ancestral clones, leading to leukemia by the addition of following alterations (Bcr-Abl);
To define BM microenvironment markers that nurture and determine stem cell fate in leukemia associated-niches;
To define MSC’s genetic profile in CML patients;
To evaluate the role of BM molecular microenvironment underling the variable degree of response to TKI treatment in patients with CP of CML vs. patients with advanced phase CML;
To verify the prognostic value of the biological factors that have been assessed in vitro experiments by designing an in vivo mouse model;
Flow-cytometry quantification and monitoring of peripheral blood CML LSCs during Sustrenim Study.

E.3

Principal inclusion criteria

•Patients with a confirmed diagnosis of BCR/ABL+ CML in chronic phase
o Documented chronic phase CML must meet all the following criteria:
 < 15% blasts in peripheral blood
 < 30% blasts plus promyelocytes in peripheral blood
 < 20% basophils in the peripheral blood
 ≥ 100 x 109/L (≥ 100,000/mm3) platelets
•Age ≥18
•ECOG performance status of 0-2
•Evidence of typical BCR-ABL transcripts which are amenable to standardized RQ-PCR
•Adequate end organ function as defined by:
o Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab).
Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert’s disease) grade < 3
o SGOT (AST) and SGPT (ALT) ≤ 3 x ULN
o Serum amylase and lipase ≤ 2 x ULN
o Alkaline phosphatase ≤ 2.5 x ULN
o Serum creatinine < 1.5 x ULN
•Written informed consent prior to any study procedures

E.4

Principal exclusion criteria

•Previous treatment with BCR-ABL inhibitors for more than 30 days.
•Expression of any atypical BCR-ABL transcripts, instead of the classical P210-encoding type with the e13a2 or the e14a2 junction at screening.
•Previous anticancer agents (hydroxyurea, anagrelide, interferon) for CML for more than three months.
•Poorly controlled diabetes mellitus (defined as HbA1c >8%)
•Prior documented history of coronary heart disease, including myocardial infarction, coronary bypass, coronary stent, and symptomatic angina as defined at page 30 in Exclusion Criteria.
•Uncontrolled hypertension
•History of peripheral arterial occlusive disease.
•History of acute pancreatitis within 12 months of study entry, or a past medical history of chronic pancreatitis.
•Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers which cannot be either discontinued or switched to a different medication prior to starting study drug.
•Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and for which cannot be either safely discontinued or switched to a different medication prior to starting study drug.
•Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
•Patients unable to understand and to comply with study instructions and requirements.
•Refusal to give informed consent.

E.5 End points

E.5.1

Primary end point(s)

- To evaluate the rates of molecular response (MR4.5) at 24 months
- To evaluate the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse 12 months after entering the TFR phase.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 24 months for the rates of molecular response (MR4.5) and at 12 months after entering the TFR phase for the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse.

E.5.2

Secondary end point(s)

- To determine the depth of molecular response by 4 years.
- To estimate progression-free survival (PFS) in the two arms of the study at 60 months.
- To estimate the Overall Survival in the two arms of the study at 60 months.
- To determine the rates of major molecular response (MR3.0) at 1, 2, 3, and 4 year in the two arms of the study.
- The dynamics of molecular response
- The relationship between baseline characteristics and the achievement of MR4.5 (after treatment NIL frontline therapy vs IM followed by switch to NIL) and the sustained treatment free remission rate (≥MR3.0);
- The relationship between early molecular response and the achievement of MR4.5 (after treatment NIL frontline therapy vs IM followed by switch to NIL) and the sustained treatment free remission rate (≥MR3.0)
- To assess the safety profile of either NIL and IM arms.
- To determine the rate and the time-distribution of the discontinuation of the first-line TKI, for side-effects, toxicity and AEs.
- To investigate quality of life (QoL) differences between treatment arms over time.

E.5.2.1

Timepoint(s) of evaluation of this end point

During the study

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)

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)

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

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

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

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:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

450

F.4.2.2

In the whole clinical trial

450

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)

None

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

2019-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-30

P. End of Trial
P.	End of Trial Status	Completed

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