Clinical Trials Register

Summary
EudraCT Number:	2015-001790-41
Sponsor's Protocol Code Number:	2215-CL-0201
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-03
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2015-001790-41

A.3

Full title of the trial

A Phase 3 Multicenter, Open-label, Randomized Study of ASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine and Azacitidine Alone in the Treatment of Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation in
Patients Not Eligible for Intensive Induction Chemotherapy

Wieloośrodkowe, otwarte badanie kliniczne fazy III oceniające monoterapię preparatem ASP2215 (giltertinib), terapię skojarzoną preparatem ASP2215 i azacytydyną oraz monoterapię azacytydyną w leczeniu świeżo rozpoznanej ostrej białaczki szpikowej z obecnością mutacji FLT3 u chorych, którzy nie kwalifikują się do intensywnej chemioterapii indukującej.

A.3.1

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

A Phase 3 Multicenter, Open-label, Randomized Study of ASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine and Azacitidine Alone in the Treatment of Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy

A.4.1

Sponsor's protocol code number

2215-CL-0201

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	Astellas Pharma Global Development, Inc. (APGD)
B.1.3.4	Country	United States
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	Astellas Pharma Global Development, Inc. (APGD)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astellas Pharma Europe B.V.
B.5.2	Functional name of contact point	Service Desk-Global Dev. Operations
B.5.3	Address:
B.5.3.1	Street Address	Sylviusweg 62
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 BE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715455050
B.5.6	E-mail	CTU@astellas.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1961
D.3 Description of the IMP
D.3.1	Product name	Gilteritinib
D.3.2	Product code	ASP2215
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GILTERITINIB
D.3.9.2	Current sponsor code	ASP2215
D.3.9.4	EV Substance Code	SUB177203
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	40
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 25 mg/mL powder for suspension for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene
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	Information not present in EudraCT
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Vidaza
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	Intravenous use 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy

E.1.1.1

Medical condition in easily understood language

AML is cancer of myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in bone marrow and interfere with production of normal blood cells.

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

Determine the efficacy superiority of ASP2215 plus azacitidine versus azacitidine as measured by overall survival (OS).

E.2.2

Secondary objectives of the trial

Determine the efficacy superiority of ASP2215 plus azacitidine versus azacitidine as measured by event-free survival (EFS).
The additional secondary objectives are to:
Evaluate the safety and efficacy of ASP2215 plus azacitidine versus azacitidine in terms of:
• Best Response
• Complete remission (CR) rate
• CRc rate
• CRh rate
• CR/CRh rate
• Transfusion conversion rate; transfusion maintenance rate
• Leukemia-free survival (LFS)
• Duration of remission
• Patient-reported fatigue (Brief Fatigue Inventory [BFI])
• Adverse events (AEs), clinical laboratory results, physical examinations, vital signs, ECGs, and Eastern Cooperative Oncology Group (ECOG) performance scores

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

Retrospective PGx Sub-study (Optional)

E.3

Principal inclusion criteria

1. Institutional Review Board-/Independent Ethics Committee- (IRB/IEC)-approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for United States [US] sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is considered an adult according to local regulation at the time of obtaining informed consent.
3. Subject has a diagnosis of previously-untreated AML according to World Health Organization (WHO) classification [Swerdlow et al, 2008] as determined by pathology review at the treating institution.
4. Subject is positive for FLT3 mutation (ITD or TKD [D835/I836] mutation) in bone marrow or whole blood as determined by central laboratory. NOTE: Requirement of FLT3 mutation assessment by central laboratory is only applicable to the randomization portion of the study.
5. Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
a. Subject is ≥ 65 years of age and ineligible for intensive induction chemotherapy per investigator’s discretion.
b. Subject is ≥ 18 to 64 years of age and has any of the following comorbidities:
i. Congestive heart failure (New York Heart Association (NYHA) class ≤ 3 ) or ejection fraction (EF) ≤ 50%;
ii. Creatinine > 2 mg/dL (177 μmol/L), dialysis or prior renal transplant;
iii. ECOG performance status ≥ 2;
iv. Prior or current malignancy that does not require concurrent treatment;
v. Subject has received a cumulative anthracycline dose above 400 mg/m2 of doxorubicin (or cumulative maximum dose of other another anthracycline)
vi. Known pulmonary disease with decreased diffusion capacity of lung for carbon monoxide (DLCO > 50%) and/or requiring oxygen ≤ 2 liters per minute
vii. Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor during screening and before randomization.
6. Subject must meet the following criteria as indicated on the clinical laboratory tests:
● Serum AST and ALT ≤ 3.0 x institutional upper limit of normal (ULN)
● Serum total bilirubin ≤ 1.5 x institutional ULN
● Serum potassium ≥ institutional LLN
● Serum magnesium ≥ institutional LLN
Repletion of potassium and magnesium levels during the screening period is allowed.
7. Subject is suitable for oral administration of study drug.
8. A female subject is eligible to participate if she is not pregnant and at least one of the following condictions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.1 Contraception Requirements]
OR
b) WOCBP agrees to follow the contraceptive guidance as defined in [Appendix 12.1 Contraception Requirements] starting at screening and continue through the study period, and for at least 180 days after the final study drug administration.
9. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration.
10. Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration.
11. A male subject with female partner(s) of childbearing potential must agree to use contraception as detailed in [Appendix 12.1 Contraception Requirements] starting at screening and continue through the study period, and for at least 120 days after the final study drug administration.
12. Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.
13. Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.

E.4

Principal exclusion criteria

1. Subject was diagnosed with acute promyelocytic leukemia (APL).
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
3. Subject has received previous therapy for AML, with the exception of the following:
● Emergency leukapheresis
● Hydroxyurea
● Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days
● Growth factor or cytokine support
● Steroids
4. Subject has clinically active central nervous system leukemia.
5. Subject has been diagnosed with another malignancy that requires concurrent treatment (with the exception of hormone therapy limited to those therapies that prevent recurrence and/or spread of cancer) or hepatic malignancy regardless of need for treatment.
6. Subject has clinically significant coagulation abnormality unless secondary to AML in the opinion of the investigator.
7. Subject has had major surgery within 4 weeks prior to the first study dose.
8. Subject has had radiation therapy within 4 weeks prior to the first study dose.
9. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A/P-gp.
12. Subject has congestive heart failure classified as New York Hearth Association Class IV.
13. Subject with mean Fridericia-corrected QT interval (QTcF) > 480 ms at screening based on central reading.
14. Subject with a history of Long QT Syndrome at screening.
15. Subject has known pulmonary function test with DLCO ≤ 50%, forced expiratory volume in the first second (FEV1) ≤ 60%, dyspnea at rest or any pleural neoplasm. (Transient use of supplemental oxygen is allowed.)
16. Subject has an active uncontrolled infection. If an infection is present, the patient must be receiving definitive therapy and have no signs of progressing infection. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
17. Subject is known to have human immunodeficiency virus infection.
18. Subject has active hepatitis B or C or other active hepatic disorder
● Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
● Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
● Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable.
19. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for study participation, including any contraindications of azacitidine listed in the country package insert.
20. Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or any
components of the formulations used.

E.5 End points

E.5.1

Primary end point(s)

- Overall Survival

E.5.1.1

Timepoint(s) of evaluation of this end point

up to 36 months

E.5.2

Secondary end point(s)

Key Secondary Efficacy Endpoint:
- Event-free survival

Secondary Efficacy Endpoints:
- Best Response
- CR, CRc, CRh, CR/CRh
- Transfusion conversion rate; transfusion maintenance rate
- Leukemia-free survival
- Duration of remission
- Patient reported fatigue from BFI
Safety Endpoints:AEs
- AEs
- Clinical laboratory results
- Physical examinations
- Vital sign measurements
- ECGs
- ECOG performance scores

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 43 months

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

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)

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

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)

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

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

Belgium

Brazil

Canada

France

Germany

Greece

Hungary

Italy

Japan

Korea, Republic of

Malaysia

Poland

Russian Federation

Spain

Taiwan

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

last subject last visit

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:

217

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Informed consent must be obtained from the subject or
legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).

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

145

F.4.2.2

In the whole clinical trial

287

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.
Note: Marketed product is not available in all participating countries

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

2016-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-23

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

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