Clinical Trials Register

Summary
EudraCT Number:	2019-003836-22
Sponsor's Protocol Code Number:	FLG-V001
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-22
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

Finland - Fimea

A.2

EudraCT number

2019-003836-22

A.3

Full title of the trial

TWO-STAGE, TWO-ARM, OPEN-LABEL PHASE II STUDY OF VENETOCLAX IN COMBINATION WITH AZACYTIDINE IN ACUTE MYELOID LEUKEMIA PATIENTS SELECTED USING EX VIVO DRUG SENSITIVITY SCREENING

Vaiheen II kaksiosainen, kaksihaarainen avoin tutkimus, jossa venetoklaksia annetaan yhdessä atsasitidiinin kanssa akuuttia myelooista leukemiaa sairastaville potilaille, joiden hoito valitaan koeputkessa tehdyn lääkeherkkyystutkimuksen perusteella.

A.3.1

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

STUDY OF VENETOCLAX IN COMBINATION WITH AZACYTIDINE IN ACUTE MYELOID LEUKEMIA PATIENTS SELECTED USING EX VIVO DRUG SENSITIVITY SCREENING

Lääketutkimus, jossa venetoklaksia annetaan yhdessä atsasitidiinin kanssa akuuttia myelooista leukemiaa sairastaville potilaille, joiden hoito valitaan koeputkessa tehdyn lääkeherkkyystutkimuksen perusteella.

A.3.2

Name or abbreviated title of the trial where available

VenEx

A.4.1

Sponsor's protocol code number

FLG-V001

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	HUS Helsinki University Hospital
B.1.3.4	Country	Finland
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	Helsinki University
B.4.2	Country	Finland
B.4.1	Name of organisation providing support	FiCAN South
B.4.2	Country	Finland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HUS Helsinki University Hospital
B.5.2	Functional name of contact point	Mika Kontro
B.5.3	Address:
B.5.3.1	Street Address	Haartmaninkatu 4, PO Box 372
B.5.3.2	Town/ city	Helsinki
B.5.3.3	Post code	00290
B.5.3.4	Country	Finland
B.5.6	E-mail	mika.kontro@helsinki.fi

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	Venclyxto
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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 leukemia in patients who are non-fit for standard induction therapy (except acute promyelocytic leukemia) and present with de novo, secondary, released or refractory AML

E.1.1.1

Medical condition in easily understood language

Newly diagnosed, relapsed, resistant or secondary acute myeloid leukemia

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10000880
E.1.2	Term	Acute myeloid 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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate usability of ex vivo drug sensitivity testing for patient selection and to validate the ex vivo/in vivo drug sensitivity correlation.

E.2.2

Secondary objectives of the trial

-To evaluate resistance mechanisms of venetoclax in primary patient samples
-To evaluate venetoclax based combinations in resistant samples to overcome resistance
-To unravel biomarkers (i.e. gene expression, protein levels and phosphorylation status of specific proteins, etc.) for sensitivity/resistance
-To evaluate the correlation of venetoclax blood concentrations on treatment responses

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

Substudy included in protocol
-To evaluate resistance mechanisms of venetoclax in primary patient samples
-To evaluate venetoclax based combinations in resistant samples to overcome resistance
-To unravel biomarkers (i.e. gene expression, protein levels and phosphorylation status of specific proteins, etc.) for sensitivity/resistance
-To evaluate the correlation of venetoclax blood concentrations on treatment responses

E.3

Principal inclusion criteria

1. Written informed consent
2. Patients who present with one of the following (except acute promyelocytic leukemia)
a. De novo or secondary AML patients who are non-fit for standard induction therapy (see below)
b. Relapsed or refractory AML patients following at least 1 line of prior therapies (see below)

3. Ex vivo sensitivity testing performed to assess venetoclax sensitivity
a. Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.
b. Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.

4. Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age

5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.

6. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.

7. Participant must have adequate liver function as demonstrated by
a. alanine aminotransferase (ALT) ≤ 4.0 × ULN
b. bilirubin ≤ 1.5 × ULN

8. Specific inclusion criteria for participants non-fit for standard chemotherapy
Participant must be:
≥ 70 years of age;
OR
≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the criteria following:
• Clinically significant comorbidities, as reflected by at least 1 of:
- Left ventricular ejection fraction (LVEF) < 50%.
- Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
- Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
- Chronic stable angina or congestive heart failure controlled with medication.
- Alanine aminotransferase (ALT) 3.0-4.0 × ULN

• Other contraindication(s) to anthracycline therapy (must be documented)
• Adverse risk karyotype associated with poor outcome with standard chemotherapy
• Patient’s refusal from intensive chemotherapy

9. Specific inclusion criteria for relapsed patients
Participant must be:
≥ 55 years of age with non-CBF AML relapse
OR
≥ 18 to 54 years of age and meeting at least one of the criteria following:
• Not candidate for intensive chemotherapy (see the criteria 8.)
• The duration of remission < 12 months.
• Relapse after allogeneic transplantation.
• 2nd (or higher) relapse.

10. Specific inclusion criteria for refractory patients
The patients who fail to achieve a complete or partial remission after induction chemotherapy (two cycles of chemotherapy containing cytarabine or clofarabine, in compilation with topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone)

E.4

Principal exclusion criteria

1. Participant has acute promyelocytic leukemia (APL)
2. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %
3. ECOG >3 (see also inclusion criteria 4)
4. Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)
5. Participant with known HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with anti-viral medication.
6. Participant has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which participants are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
7. Evidence of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participation in this study (including but not limited to):
a. Participant has a chronic respiratory disease that requires continuous oxygen use
b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)
c. Malabsorption syndrome or other condition that precludes enteral route of administration.
d. Uncontrolled GVHD.
8. Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.

E.5 End points

E.5.1

Primary end point(s)

CR/CRi rate before Cycle 4

E.5.1.1

Timepoint(s) of evaluation of this end point

Bone marrow examinations before C4

E.5.2

Secondary end point(s)

The correlation of ex vivo sensitivity and specific responses (OS, DOR, EFS, MRD status)
The correlation of venetoclax blood concentrations specific responses (OS, DOR, EFS, MRD status)

E.5.2.1

Timepoint(s) of evaluation of this end point

Entire 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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

To evaluate usability of ex vivo drug sensitivity testing for patient selection and to validate the ex vivo/in vivo drug sensitivity correlation.

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

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

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.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

2019-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-11

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

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