Clinical Trials Register

Summary
EudraCT Number:	2016-004440-12
Sponsor's Protocol Code Number:	CPKC412A2408
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-10-20
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

Spain - AEMPS

A.2

EudraCT number

2016-004440-12

A.3

Full title of the trial

An open-label, multi–center, Phase IIIb study to assess the safety and efficacy of midostaurin (PKC412) in patients 18 years of age or older with newly-diagnosed FLT3-mutated Acute Myeloid Leukemia (AML) who are eligible for “7+3” or “5+2” chemotherapy

Estudio de fase IIIb, abierto y multicéntrico, para evaluar la seguridad y eficacia de midostaurina (PKC412) en pacientes adultos con Leucemia Mieloide Aguda (LMA) con mutación FLT3 de Nuevo diagnóstico, que son candidatos a quimioterapia "7+3" o"“5+2"

A.3.1

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

A clinical trial of midostaurin in adult patients ≥ 18 years old with newly diagnosed acute myeloid leukemia (AML). Patients must have a mutation known as FLT3 and eligible for 7+3 or 5+2 chemotherapy

Estudio para evaluar la seguridad y eficacia de midostaurina (PKC412) en combinación con quimioterapia estándar durante la
inducción y consolidación seguido por 12 meses de monoterapia en pacientes con Leucemia Mieloide Aguda con mutación FLT3 de nuevo diagnóstico.

A.4.1

Sponsor's protocol code number

CPKC412A2408

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	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
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	Novartis Pharma AG
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	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Javier Malpesa
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34933064464
B.5.5	Fax number	34933064615
B.5.6	E-mail	eecc.novartis@novartis.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/3/04/214
D.3 Description of the IMP
D.3.1	Product name	midostaurin (INN)
D.3.2	Product code	PKC412
D.3.4	Pharmaceutical form	Capsule, soft
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	midostaurin
D.3.9.1	CAS number	120685-11-2
D.3.9.2	Current sponsor code	PKC412
D.3.9.3	Other descriptive name	MIDOSTAURIN
D.3.9.4	EV Substance Code	SUB21040
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	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

newly diagnosed FLT3 mutated acute myeloid leukemia

Pacientes de nuevo diagnóstico con mutación del receptor tirosina quinasa tipo Fms (FLT3) y con Leucemia Mieloide Aguda (LMA)

E.1.1.1

Medical condition in easily understood language

newly diagnosed acute myeloid leukemia

Pacientes de nuevo diagnóstico con Leucemia Mieloide Aguda (LMA)

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.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To further assess the safety of midostaurin in induction, consolidation and maintenance therapy, including, the “7+3” regimen, daunorubicin (60-90mg/m2/day), the substitution of daunorubicin by idarubicin and cytarabine (100-200 mg/m2/day) and also allowing the “5+2” reduced dose regimen.

Evaluar más en profundidad la seguridad de midostaurina en terapia de inducción, consolidación y mantenimiento, incluyendo el regimen "7+3", dosis más alta de Daunorubicina (60-90 mg/m2/día), la sustitución de Daunorubicina por Idarubicina (12 mg/m2/día) y dosis más baja de Citarabina (100-200 mg/m2/día) y permitir el régimen de dosis reducido "5+2".

E.2.2

Secondary objectives of the trial

To assess the clinical efficacy of midostaurin in combination with chemotherapy regimens in induction and consolidation and the clinical efficacy of midostaurin maintenance phase (measured by CR/CRi rate).

Evaluar la eficacia clínica de midostaurina en combinación con regímenes de quimioterapia en inducción y consolidación y la eficacia clínica de midostaurina en la fase de mantenimiento (medido mediante la tasa RC/RCi).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 years of age or older at the time of signing informed consent.
3. Patients must have a documented unequivocal diagnosis of AML according to WHO 2008 classification. A bone marrow or blood blast count of ≥20% is required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16)) where blast count may be <20%, and excluding M3 (acute promyelocytic leukemia).
4. Patients with secondary AML are eligible, e.g. patients with antecedent history of treatment for prior malignancy. AML patients with a history of antecedent treatment for myelodysplasia (MDS), e.g. azacitidine or decitabine, remain eligible for treatment on this study. These agents must have been discontinued for a period of at least 30 days or 5 half-lives of the drug (whichever is greater) before midostaurin can be administered.
5. Patients must have started “7+3” or “5+2” first induction chemotherapy regimen.
6. Patients must have a documented FLT3 mutation (ITD or TKD).
7. Patients must have an ECOG Performance Status of ≤ 2
8. Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours prior to the first dose of midostaurin
9. Patients must have Total Bilirubin ≤ 2.5 x ULN.
10. Patients must have Serum Creatinine ≤ 2.5 x ULN.
11. Patients must be able to communicate well with the investigator to understand and comply with the requirements of the study.
12. Women of child-bearing potential must have a negative pregnancy test before starting use of midostaurin.

Los pacientes elegibles para inclusión en este estudio tienen que cumplir todos los criterios siguientes:
1. El consentimiento informado por escrito debe obtenerse antes de realizar cualquier procedimiento de selección.
2. Los pacientes deben tener 18 años de edad o más en el momento de firmar el consentimiento informado.
3. Los pacientes deben tener un diagnóstico inequívoco documentado de LMA de acuerdo con la clasificación de la OMS de 2008. Es necesario un recuento de blastos en médula ósea o en sangre >/= 20%, excepto para LMA con t(15;17), t(8;21), inv(16) o t(16;16) en que el recuento de blastos pueda ser < 20%, y, excluyendo M3 (leucemia promielocítica aguda).
4. Los pacientes con LMA secundaria son elegibles, p.ej., los pacientes con historia previa de tratamiento para neoplasia previa. Los pacientes con LMA con historia previa de tratamiento para mielodisplasia (SMD), p.ej., azacitidina o decitabina, siguen siendo elegibles para tratamiento en este estudio. Estos agentes deben haber sido interrumpidos durante un periodo de al menos 30 días o 5 vidas medias del fármaco (lo que sea más largo) antes de poder administrar midostaurina.
5. Los pacientes deben haber iniciado un primer régimen de quimioterapia de inducción "7+3" o "5+2".
6. Los pacientes deben tener una mutación FLT3 documentada [ITD (duplicación interna en tándem) o TKD (dominio tirosina quinasa)].
7. Los pacientes deben tener un estado funcional ECOG </= 2.
8. Los pacientes que precisen quimioterapia intratecal deben tener un lavado mínimo de 48 horas antes de la primera dosis de midostaurina.
9. Los pacientes deben tener una Bilirrubina Total </= 2,5 x LSN.
10. Los pacientes deben tener una Creatinina en Suero </= 2,5 x LSN.
11. Los pacientes deben ser capaces de comunicarse bien con el investigador para entender y cumplir con los requisitos del estudio.
12. Las mujeres en edad fértil deben tener una prueba de embarazo negativa antes de empezar a utilizar midostaurina.

E.4

Principal exclusion criteria

Patients eligible for this study must not meet any of the following criteria:
1. Prior therapy for AML with the following exceptions:
a. emergency leukapheresis
b. emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days
c. cranial RT for CNS leukocytosis (one dose only)
d. growth factor/cytokine support
2. Patients with Left Ventricular Ejection Fraction (LVEF) less than 45% (by echocardiogram or MUGA) or symptomatic congestive heart failure (Class III or IV) according to New York Heart Association (NYHA) classification
3. Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolved to < Grade 1 within screening timeframe)
4. Patients with any uncontrolled illness, including, but not limited to, acute or chronic pancreatitis or uncontrolled infection
5. QTc >470 msec on screening ECG.
6. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment.
7. Participation in a prior investigational interventional (drug) study with administration of the investigational product within 30 days or 5 half-lives of the investigational product, whichever is longer.
8. Pregnancy statements and contraception requirements:
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 4 months after stopping medication. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
• Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system , or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should also add a barrier method of contraception, particularly as it is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives.
Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.
9. Patients enrolled in this study are not permitted to participate in additional parallel study drug or device studies.

Los pacientes elegibles para este estudio no deben cumplir ninguno de los criterios siguientes:
1. Terapia previa para LMA con las siguientes excepciones:
a. leucaféresis de urgencia
b. tratamiento de urgencias para hiperleucocitosis con hidroxiurea durante </= 7 días
c. Radioterapia (RT) craneal para leucocitosis del SNC (sólo una dosis)
d. apoyo con factores de crecimiento/citoquinas
2. Pacientes con Fracción de Eyección Ventricular Izquierda (FEVI) de menos del 45% (mediante ecocardiograma o MUGA) o insuficiencia cardiaca congestiva sintomática (Clase III o IV) según la clasificación de la Asociación del Corazón de Nueva York (NYHA).
3. Pacientes con algún infiltrado pulmonar incluyendo los que se sospecha que son de origen infeccioso (a menos que se resuelva a < Grado 1 durante el periodo de selección).
4. Pacientes con alguna enfermedad no controlada, incluyendo, pero no limitada a, pancreatitis aguda o crónica, o infección no controlada.
5. QTc>470 mseg en el ECG de la selección.
6. Antecedentes de hipersensibilidad a algún fármaco o metabolito de clase química similar al tratamiento del estudio.
7. Participación en un estudio (fármaco) en investigación intervencionista previo con administración del producto en investigación en los 30 días o 5 vidas medias del producto en investigación, lo que sea más largo
8. Declaraciones de embarazo y requisitos de anticonceptivos:
Mujeres en edad fértil, definidas como toda mujer fisiológicamente capaz de quedarse embarazada, a menos que esté utilizando métodos anticonceptivos altamente eficaces durante la dosificación y durante al menos 4 meses después de suspender la medicación. Los métodos anticonceptivos altamente eficaces incluyen:
-Abstinencia total (cuando ello concuerda con el estilo de vida preferido y habitual de la persona). Abstinencia periódica (p.ej., métodos del calendario, ovulación, sintotérmicos, postovulación) y coitus interruptus no son métodos anticonceptivos aceptables
-Esterilización femenina (haber sufrido ooforectomía bilateral quirúrgica con o sin histerectomía), histerectomía total, o ligadura de trompas al menos seis semanas antes de tomar el tratamiento del estudio. En caso de ooforectomía sola, únicamente cuando el estado reproductivo de la mujer haya sido confirmado mediante seguimiento de la evaluación del nivel hormonal.
- Esterilización masculina (al menos 6 meses antes de la selección). La pareja masculina vasectomizada debería ser la única pareja de dicha persona.
- Uso de métodos anticonceptivos hormonales orales, inyectados o implantados o colocación de un dispositivo intrauterino o sistema intrauterino, u otras formas de anticonceptivos hormonales que tengan eficacia comparable (tasa de fallos < 1%), por ejemplo, anillo vaginal hormonal o anticonceptivo hormonal transdérmico.
En caso de uso de anticonceptivos orales las mujeres también deberían añadir un método anticonceptivo de barrera, en particular debido a que actualmente se desconoce si midostaurina puede reducir la eficacia de los anticonceptivos hormonales.
Los hombres sexualmente activos a menos que utilicen un preservativo durante el coito con mujeres en edad fértil o mujeres embarazadas y durante al menos 4 meses después de suspender el tratamiento para evitar la concepción o la lesión embriofetal.
9. Los pacientes reclutados en este estudio no pueden participar en estudios paralelos adicionales de fármacos o dispositivos.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with AEs, Grade 3&4 AEs, SAEs, AEs leading to discontinuation, and deaths.

Proporción de pacientes con AEs, Grado 3& 4 AEs, SAEs, AEs importantes para su discontinuación y muertes

E.5.1.1

Timepoint(s) of evaluation of this end point

at end of study

Al final del estudio

E.5.2

Secondary end point(s)

Proportion of patients with CR/CRi as per local assessment

Proporción de pacientes con RC/RCi por evaluación local

E.5.2.1

Timepoint(s) of evaluation of this end point

at end of study

Al final del estudio

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

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

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)

Information not present in EudraCT

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

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

LPLV

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:

210

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

300

F.4.2.2

In the whole clinical trial

300

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)

Not applicable (no planned extension)

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

2017-11-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-25

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

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