Clinical Trials Register

Summary
EudraCT Number:	2017-001600-29
Sponsor's Protocol Code Number:	ARO-013
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-04-04
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2017-001600-29

A.3

Full title of the trial

Phase III Randomized, Double-blind, Placebo-controlled Study Investigating the Efficacy of the Addition of Crenolanib to Salvage Chemotherapy Versus Salvage Chemotherapy Alone in Subjects ≤ 75 Years of Age with Relapsed/Refractory FLT3 Mutated Acute Myeloid Leukemia

III. fázisú, randomizált, kettős vak, placebo-kontrollált vizsgálat a crenolanibbal kiegészített illetve az egyedül alkalmazott mentő kemoterápia hatékonyságának összehasonlítására a 75 éves vagy annál idősebb, relabált/refrakter FLT3 mutáns akut mieloid leukémiában szenvedő betegeknél

A.3.1

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

Study at several locations, randomized, double-blind with crenolanib plus chemotherapy in comparison with chemotherapy alone in patients with relapsed/refractory mutated AML

A.4.1

Sponsor's protocol code number

ARO-013

A.5.4

Other Identifiers

Name:

IND Number

Number:

067968

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	Arog Pharmaceuticals, Inc.
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	Arog Pharmaceuticals, Inc.
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	Arog Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	5420 LBJ Freeway, Suite 410
B.5.3.2	Town/ city	Dallas, TX
B.5.3.3	Post code	75240
B.5.3.4	Country	United States
B.5.4	Telephone number	+1214593 0500
B.5.5	Fax number	+1214594 0002
B.5.6	E-mail	vjain@arogpharma.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	Crenolanib
D.3.2	Product code	AR-868,596-26
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	Crenolanib Besylate
D.3.9.1	CAS number	670220-93-6
D.3.9.2	Current sponsor code	AR-868,596-26
D.3.9.3	Other descriptive name	CRENOLANIB
D.3.9.4	EV Substance Code	SUB185102
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	20
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	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	Crenolanib
D.3.2	Product code	AR-868,596-26
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	Crenolanib Besylate
D.3.9.1	CAS number	670220-93-6
D.3.9.2	Current sponsor code	AR-868,596-26
D.3.9.3	Other descriptive name	CRENOLANIB
D.3.9.4	EV Substance Code	SUB185102
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed/Refractory FLT3 Mutated Acute Myeloid Leukemia (AML)

E.1.1.1

Medical condition in easily understood language

Relapsed/Refractory Mutated Blood Cancer

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	20.0
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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10060558
E.1.2	Term	Acute myeloid leukemia recurrent
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

To evaluate the effect of adding crenolanib versus placebo to salvage chemotherapy, consolidation (HiDAC and/or allo-HCT) and as single-agent maintenance therapy on event-free survival (EFS)

E.2.2

Secondary objectives of the trial

To evaluate the effect of adding crenolanib versus placebo to salvage chemotherapy, consolidation (HiDAC and/or allo-HCT) and as single-agent maintenance therapy on:

• Overall survival (OS)
• Relapse-free survival (RFS)
• Complete remission (CR) rate
• Composite complete remission (CRc) rate
• MRD-negative complete remission (CR MRD-) rate

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Confirmed diagnosis of AML according to WHO 2016 classification
2. Presence of FLT3-ITD and/or D835 mutation(s)
3. Subjects must be primary refractory or relapsed to 1st line intensive treatment for AML or refractory or relapsed after second line of treatment for AML as defined by:
3a. Primary refractory is defined as no CR or CRi after two courses of intensive induction chemotherapy.
3b. Relapse after first line treatment for AML is defined as the first hematologic relapse after one line of treatment for AML that includes at least one course of intensive chemotherapy with or without a tyrosine kinase inhibitor.
3c. Relapse after second line treatment for AML is defined as a hematologic relapse after two lines of treatment for AML. Subjects may be refractory to or relapse after the first line treatment but must have achieved a CR/CRi after second line treatment and subsequently relapse. First line treatment must include at least one course of intensive chemotherapy. Second line treatment may be one of the following:
i. Intensive or non-intensive salvage therapy with or without tyrosine kinase inhibitor or other targeted therapy
ii. Tyrosine kinase inhibitor alone
iii. Hypomethylating agent
iv. One experimental therapy for treatment of AML
3d. Refractory after second line treatment for AML is defined as no CR or CRi after second line of treatment for AML. Subjects who are refractory after a second line treatment for AML must have must have achieved a CR/CRi after first line treatment and subsequently relapsed. First line treatment must include at least one course of intensive chemotherapy. Second line treatment may be one of the following:
i. Non-intensive salvage therapy with or without tyrosine kinase inhibitor or other targeted therapy
ii. Tyrosine kinase inhibitor alone
iii. Hypomethylating agent
iv. One experimental therapy for treatment of AML
4. Eligible for pre-selected induction chemotherapy specified in the protocol
5. Age ≥ 18 years and ≤ 75 years
6. Adequate hepatic function
7. Adequate renal functions
8. ECOG performance status ≤ 3
9. Female subjects with reproductive potential must have negative serum or urine pregnancy test.
10. Adequate contraception, if heterosexually active
11. Written informed consent before any study-specific procedure is performed

E.4

Principal exclusion criteria

1. Subjects with any of the following current or previous diagnoses:
• Treatment related AML secondary to prior chemotherapy
• AML secondary to prior myelodysplastic syndrome (MDS)
• AML secondary to prior myeloproliferative syndrome (MPN) including polycythemia vera, essential thrombocythemia, myelofibrosis, mastocytosis and chronic myeloid leukemia
• Acute promyelocytic leukemia (APL)
• AML secondary to MDS/MPN syndromes including chronic myelomonocytic leukemia
• DNA fragility or bone marrow failure syndromes
• Blastic plasmacytoid dendritic cell neoplasm
• Acute leukemia of ambiguous lineage
• B-lymphoblastic leukemia/lymphoma
• T-lymphoblastic leukemia/lymphoma, including early T-cell precursor lymphoblastic leukemia (ETP-ALL)
2. Known clinically active central nervous system (CNS) leukemia
3. Subjects who have received more than 1 prior allogeneic HSCT.
4. Subjects who are refractory to first-line (induction and re-induction) and a second-line (1st salvage) treatment for AML.
5. Severe liver disease
6. Active infections including known mycobacterial infections. Subjects with positive blood cultures for virus, bacteria, or fungi, or sepsis will not be eligible.
7. Inadequate pulmonary function (subjects requiring assisted ventilation will not be eligible)
8. Hemodynamically unstable (subjects requiring pressor support will not be eligible)
9. Active infection with hepatitis B virus (HBV), defined as a positive test for HBV surface antigen (HBsAg), and/or active infection with hepatitis C virus (HCV), defined as a positive test for HCV ribonucleic acid (RNA)
10. Clinically significant bleeding diathesis and coagulation disorder independent of leukemia
11. Subjects with a “currently active” second malignancy other than non-melanoma skin cancers.
12. Inadequate cardiac function, including greater than Grade 2 decreased ejection fraction, clinically significant prolonged QTc interval, congestive heart failure class III or IV by the NYHA, unstable angina (angina symptoms at rest), new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months
13. Any disorder that compromises the subject’s ability to give written informed consent and/or to comply with study procedures
14. Any substance abuse, severe and/or uncontrolled medical, social or psychiatric conditions that may prevent the subject from completing the study, interfere with the evaluation of safety and/or efficacy, or interfere with the interpretation of the study results
15. Grade 2 or above graft-versus-host disease (GvHD), including acute, chronic, or overlap; or escalation of therapy for GvHD within 14 days prior to randomization
16. Major surgical procedures within the 28 days prior to randomization (does not include line placement as needed for chemotherapy administration).
17. Prior anti-leukemia therapy within the 14 days prior to randomization. Prior use of quizartinib or gilteritinib must be discontinued 21 days prior to randomization. Prior use of hydroxyurea or other palliative treatment for leukocytosis is allowed.
18. Previous treatment with crenolanib or prior participation in clinical trial involving crenolanib.
19. Concurrent use of other investigational agents.
20. Female subject who is pregnant or breastfeeding, or planning to become pregnant while receiving treatment and within 6 months after ending treatment
21. Known or suspected hypersensitivity to the study drugs and/or any excipients

E.5 End points

E.5.1

Primary end point(s)

Event free survival

E.5.1.1

Timepoint(s) of evaluation of this end point

From the date of randomization to the date of failure to achieve a complete remission, relapse or death of any cause (whichever occurs first)

E.5.2

Secondary end point(s)

• Overall survival (OS)
• Relapse-free survival (RFS)
• Complete remission (CR) rate
• Composite complete remission (CRc) rate
• MRD-negative complete remission (CR MRD-) rate

E.5.2.1

Timepoint(s) of evaluation of this end point

• OS: from the date of randomization to the date of death of any cause for all randomized subjects
• RFS: from the date of achievement of CRc to the date of relapse or death of any cause
• CR, CRc, CR MRD-: throughout 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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Czech Republic

France

Germany

Hungary

Italy

Poland

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

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

122

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

160

F.4.2.2

In the whole clinical trial

322

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 finishing all study relevant procedures, therapy and follow-up period, the patient will be followed in terms of routine aftercare and treated if necessary by the primary responsible hematology/oncology center.

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

2018-06-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-30

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

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