Clinical Trials Register

Summary
EudraCT Number:	2018-002964-25
Sponsor's Protocol Code Number:	GO40800
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-06-14
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

2018-002964-25

A.3

Full title of the trial

A PHASE IB/II STUDY, EVALUATING THE SAFETY AND EFFICACY OF IDASANUTLIN IN COMBINATION WITH CYTARABINE AND DAUNORUBICIN IN PATIENTS NEWLY DIAGNOSED WITH ACUTE MYELOID LEUKEMIA (AML) AND THE SAFETY AND EFFICACY OF IDASANUTLIN IN THE MAINTENANCE OF FIRST AML COMPLETE REMISSION.

ESTUDIO EN FASE Ib/II PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE IDASANUTLINA EN COMBINACIÓN CON CITARABINA Y DAUNORUBICINA EN PACIENTES CON DIAGNÓSTICO RECIENTE DE LEUCEMIA MIELÓGENA AGUDA (LMA) Y LA SEGURIDAD Y LA EFICACIA DE IDASANUTLINA EN EL MANTENIMIENTO DE LA PRIMERA REMISIÓN COMPLETA DE LA LMA

A.3.1

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

A Study Evaluating the Safety and Efficacy of Idasanutlin in Combination with Cytarabine and Daunorubicin in Patients Newly Diagnosed with Acute Myeloid Leukemia and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission.

Estudio que evalua la seguridad y eficacia de Idasanutlin en combinación con citarabina en pacientes con diagnostico reciente de leucemia mielogena aguda y la seguridad y eficacia de idasanutlin en el mantenimiento de la primera remisión completa de la LMA

A.4.1

Sponsor's protocol code number

GO40800

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03850535

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
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	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34913257300
B.5.5	Fax number	+34913248195
B.5.6	E-mail	spain.start_up_unit@roche.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/3/14/1328
D.3 Description of the IMP
D.3.1	Product name	idasanutlin
D.3.2	Product code	RO5503781/F17-01
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	IDASANUTLIN
D.3.9.1	CAS number	1229705-06-9
D.3.9.2	Current sponsor code	RO5503781, RO5503781-000
D.3.9.3	Other descriptive name	n/a
D.3.9.4	EV Substance Code	SUB186708
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	50
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1328
D.3 Description of the IMP
D.3.1	Product name	idasanutlin
D.3.2	Product code	RO5503781/F16-01
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	IDASANUTLIN
D.3.9.1	CAS number	1229705-06-9
D.3.9.2	Current sponsor code	RO5503781, RO5503781-000
D.3.9.3	Other descriptive name	n/a
D.3.9.4	EV Substance Code	SUB186708
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	200
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: 3
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/3/14/1328
D.3 Description of the IMP
D.3.1	Product name	idasanutlin
D.3.2	Product code	RO5503781/F13-01
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	IDASANUTLIN
D.3.9.1	CAS number	1229705-06-9
D.3.9.2	Current sponsor code	RO5503781, RO5503781-000
D.3.9.3	Other descriptive name	n/a
D.3.9.4	EV Substance Code	SUB186708
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	300
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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	ARA-cell®
D.2.1.1.2	Name of the Marketing Authorisation holder	STADApharm GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	cytarabine
D.3.9.3	Other descriptive name	CYTARABINE
D.3.9.4	EV Substance Code	SUB06880MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	4000 to 80
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: 5
D.1.2 and D.1.3	IMP Role	Comparator
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	Daunorubicin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Parenteral Medicines, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	daunorubicin
D.3.9.1	CAS number	20830-81-3
D.3.9.3	Other descriptive name	DAUNORUBICIN
D.3.9.4	EV Substance Code	SUB06917MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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 (AML)

Leucemia Mielógena Aguda (LMA)

E.1.1.1

Medical condition in easily understood language

AML is a type of cancer in which the bone marrow is being filled with abnormal myeloblasts (progenitors for red blood cells, platelets and white blood cells).

LMA es un tipo de cáncer en el que la medula espinal se llena de mieloblastos anormales (progenitores de los globulos rojos, plaquetas y globulos blancos)

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To determine the recommended Phase II dose (RP2D) for idasanutlin when given in combination with cytarabine and daunorubicin during the dose-escalation phase
• To evaluate the safety and tolerability of idasanutlin when given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance
• To compare the differences in patient-reported treatment-related symptoms
• To evaluate the efficacy of idasanutlin when given in combination with cytarabine and daunorubicin as induction treatment.

• Determinar la dosis recomendada en la fase II (DRF2) para idasanutlina cuando se administra en combinación con citarabina y daunorubicina durante la fase de incremento de la dosis
• Evaluar la seguridad y la tolerabilidad de idasanutlina cuando se administra en combinación con citarabina y daunorubicina en la inducción, en combinación con citarabina en la consolidación y en monoterapia en la fase de mantenimiento
• Comparar las diferencias en los síntomas relacionados con el tratamiento notificados por el paciente
• Evaluar la eficacia de idasanutlina cuando se administra en combinación con citarabina y daunorubicina como tratamiento de inducción

E.2.2

Secondary objectives of the trial

• To characterize the PK profiles of idasanutlin (and its metabolites, if appropriate), cytarabine, and daunorubicin
• To assess potential PK interactions among idasanutlin, cytarabine, and daunorubicin
• To evaluate health status utility scores of patients treated with idasanutlin.

•Caracterizar los perfiles FC de idasanutlina (y sus metabolitos, si procede), citarabina y daunorubicina.
•Evaluar el potencial de interacciones FC entre idasanutlina, citarabina y daunorubicina
•Evaluar las puntuaciones de utilidad del estado de salud de los pacientes tratados con idasanutlina

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria for All Study Phases
- Age >=18 years
- Eastern Cooperative Oncology Group (ECOG) performance status <=2
- Adequate hepatic and renal function
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs with a failure rate of <1% per year during the treatment period and for at least 6 months after the final dose of idasanutlin, cytarabine, or daunorubicin. Women must refrain from donating eggs during this same period.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive, measures, and agreement to refrain from donating sperm that together result in a failure rate of <1% per year during the treatment period and for 6 months after the final dose of idasanutlin, cytarabine, or daunorubicin. Men must refrain from donating sperm during this same period.

Inclusion Criteria for Patients in the Dose-Escalation and Expansion Phases
- Documented/confirmed newly diagnosed AML not previously treated according to WHO

Inclusion Criteria for Patients in the Post-Consolidation Phase
- Documented/confirmed AML according to WHO in remission after induction, within 21 days of end of last chemotherapy consolidation cycle, and were minimum residual disease (MRD) positive at the end of induction as per local laboratory assessment.

Criterios de inclusión para todas las fases del estudio
-Edad >=18 años
-Estado general según el Grupo Oncológico Cooperativo del Este <=2
Función hepática y renal adecuada
-Para las mujeres en edad fértil: aceptación de practicar la abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o usar medidas anticonceptivas y aceptación de abstenerse de donar óvulos, con una tasa de fracaso <1 % al año durante el periodo de tratamiento y durante al menos 6 meses después de la última dosis del fármaco del estudio. Las mujeres deben abstenerse de donar óvulos durante este mismo periodo.
-Para los hombres: aceptación de practicar la abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o usar medidas anticonceptivas y aceptación de abstenerse de donar esperma, que juntos den como resultado una tasa de fracaso <1 % al año durante el periodo de tratamiento y durante 6 meses después de la última dosis del fármaco del estudio. Los hombres deben abstenerse de donar semen durante este mismo periodo.

Criterios de inclusión para los pacientes en las fases de incremento de dosis y de expansión
-LMA de diagnóstico reciente documentada/confirmada no tratada previamente, de acuerdo con la OMS
Criterios de inclusión para los pacientes en la fase posterior a la consolidación:
-LMA documentada/confirmada de acuerdo con la OMS en remisión después de la inducción, en el plazo de 21 días desde el final del último ciclo de consolidación con quimioterapia y con ERM positiva al final de la inducción según la evaluación del laboratorio local (evaluación de ERM específica de la LMA cuantitativa validada con un umbral 0,1 %)

E.4

Principal exclusion criteria

Exclusion Criteria for All Study Phases
- Clinical evidence of CNS leukemia
- Any Grade >=2 non-hematologic toxicities prior to starting therapy
- Current treatment with any other investigational or commercial agents or therapies administered with the intention to treat their malignancy with the exception of hydroxyurea (HU) or 6-mercaptopurine (6-MP)
- Treatment-related AML
- Acute promyelocytic leukemia
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study, impair the ability of the investigator to evaluate the patient, or impair the patient’s ability to complete the study
- Echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan showing ejection fraction <=40%
- Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study treatment, such as hereditary coagulation disorders, insulin-dependent diabetes mellitus not optimally controlled with medical management (e.g., presence of ketoacidosis), or active GI conditions affecting absorption
- Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon the induction of neutropenia, that is, patients who are or should be on antimicrobial agents for the treatment of active infection
- Febrile patients within 72 hours of study treatment initiation
- Patients with a history of active or chronic infectious hepatitis unless serology demonstrates clearance of infection
- Patients who are unable to interrupt treatment with moderate to strong CYP2C8 inducers and inhibitors
- Patients who are unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-platelet agents during treatment phase
- Patients who have a history of clinically significant liver cirrhosis
- Patients with extramedullary AML with no evidence of systemic involvement
- Pregnant or breastfeeding patients
- Known history of HIV-positive status
- Patients who might refuse to receive blood products and/or have a hypersensitivity to blood products
- Prior treatment with an MDM2 antagonist
- Patients with clinically relevant QTc prolongation, a family history of long QT syndrome

Exclusion Criteria for Patients in the Phase Ib Dose-Escalation Phase
- Adverse risk patients as per ELN 2017 criteria

Exclusion Criteria for Patients in Phase Ib Post-Consolidation Phase
- Any ongoing Grade >=2 hematologic adverse events prior to starting therapy
- Previous HSCT

Exclusion Criteria for Patients in the Dose-Escalation Phase and Patients in the Favorable/Intermediate-Risk Cohort of the Expansion Phase
- Secondary AML, defined as AML evolving from AHD.

Criterios de exclusión para todas las fases del estudio
-Signos clínicos de leucemia del SNC
-Cualquier toxicidad no hematológica de grado >=2 antes de iniciar el tratamiento
-Tratamiento actual con otros agentes en investigación o comercializados o tratamientos administrados con la intención de tratar la neoplasia maligna con la excepción de hidroxiurea (HU) o 6-mercaptopurina (6-MP).
-LMA relacionada con el tratamiento
-Leucemia promielocítica aguda
-Antecedentes de otra neoplasia maligna que pudiera afectar al cumplimiento del protocolo o a la interpretación de los resultados
-Cualquier afección médica grave o no controlada u otras afecciones que pudieran afectar a su participación en el estudio, a la capacidad del investigador para evaluar el paciente, o a la capacidad del paciente para completar el estudio
-Ecocardiograma (ECO) o ventriculografía isotópica (multiple-gated acquisition, MUGA) que muestre fracción de eyección <=40 %
-Enfermedades no malignas que no están controladas o cuyo control podría verse obstaculizado por este tratamiento del estudio, tales como trastornos hereditarios de la coagulación, diabetes mellitus insulinodependiente no controlada de forma óptima con tratamiento médico (p. ej., presencia de cetoacidosis) o trastornos digestivos activos que afecten a la absorción
-Infección que el investigador considere clínicamente no controlada o de riesgo inaceptable para el paciente tras la inducción de neutropenia, es decir, pacientes que reciben o deben recibir fármacos antimicrobianos para el tratamiento de una infección activa
-Pacientes febriles en un plazo de 72 horas antes de iniciar el tratamiento del estudio
-Pacientes con antecedentes de hepatitis infecciosa activa o crónica, a menos que la serología demuestre la desaparición de la infección
-Pacientes que no pueden interrumpir el tratamiento con inductores e inhibidores de moderados a potentes de CYP2C8
-Pacientes que no puedan interrumpir temporalmente el tratamiento con anticoagulantes/antiagregantes plaquetarios por vía oral o parenteral durante la fase de tratamiento.
-Pacientes con antecedentes de cirrosis hepática clínicamente significativa
-Pacientes con LMA extramedular sin signos de afectación sistémica
-Mujeres embarazadas o en período de lactancia
-Antecedentes conocidos de VIH positivo
-Pacientes que pueden negarse a recibir hemoderivados o tienen hipersensibilidad a los mismos
-Tratamiento previo con un antagonista de MDM2
-Pacientes con una prolongación del QTc clínicamente relevante, antecedentes familiares de síndrome de QT largo.

Criterios de exclusión para los pacientes en la fase de incremento de la dosis de fase Ib solamente:
-Pacientes de riesgo adverso según Europa LeukemiaNet 2017

Criterios de exclusión para los pacientes en la fase posterior a la consolidación de fase Ib solamente:

-Cualquier acontecimiento adverso hematológico de grado >=2 antes de iniciar el tratamiento
-TCMH anterior

Criterios de exclusión para los pacientes en la fase de incremento de la dosis y los pacientes en la cohorte de riesgo favorables/intermedio de la fase de expansión solamente:
-LMA secundaria, que se define como LMA derivada de THP

E.5 End points

E.5.1

Primary end point(s)

1. Incidence of dose-limiting toxicities (DLTs) during the first cycle of study treatment
2. Incidence and severity of adverse events, including DLTs, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
3. Change from baseline in targeted vital signs
4. Change from baseline in ECG parameters
5. Change from baseline in targeted clinical laboratory test results
6. Presence, frequency of occurrence, severity, and/or degree of interference with daily function of symptomatic treatment toxicities (nausea, vomiting, and diarrhea), as assessed through use of the NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)
7. Change from baseline in symptomatic treatment toxicities, as assessed through use of the PRO-CTCAE
8. Proportion of patients with a complete remission (CR) at the end of induction treatment.

1. Incidencia de las toxicidades limitantes de dosis (TLM) durante el primer ciclo del tratamiento del estudio.
2. Incidencia y severidad de los acontecimientos adversos, incluyendo las TLMs, con la severidad de acuerdo al National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
3. Cambio desde basal en los signos vitales objetivo
4. Cambio desde basal en los parámetros del ECG
5. Cambio desde basal en los resultados clínicos de laboratorio objetivo
6. Presencia, frecuencia de ocurrencia, severidad y / o grado de interferencia con las funciones diarias de las toxicidades sintomáticas del tratamiento (nausea, vomitos y diarrea), valorados a través del uso del NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)
7. Cambio desde basal en el tratamiento sintomatico de las toxicidades valorado a través del uso del PRO-CTCAE
8. Proporcion de pacientes con una remisión completa (CR) al final del tratamiento de inducción.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to Day 56 of Cycle 1
2. Up to 2 years
3-5. Baseline, Day 1 of all cycles
6. Day 1 of all cycles
7. Baseline, Day 1 of all cycles
8. At the end of induction treatment.

1. Hasta como maximo el dia 56 del ciclo 1
2. hasta un máximo de 2 años
3-5. Basal, dia 1 de todos los ciclos.
6. Dia 1 de todos los ciclos.
7. Basal, dia 1 de todos los ciclos
8. Al final del tratamiento de inducción.

E.5.2

Secondary end point(s)

1. Proportion of patients with a CR, complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet count recovery (CRp) at the end of induction treatment
2. Proportion of patients with a CR or complete remission with partial hematologic recovery (CRh) at the end of induction treatment
3. Proportion of patients with a negative MRD status at the end of induction treatment
4. Event-free survival
5. Overall survival
6. Relapse-free survival in patients who achieve remission (CR, CRi, CRp, or CRh)
7. Change from baseline in patient-reported disease-related symptoms and health-related quality of life at specified timepoints, as assessed through use of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (EORTC QLQ-C30) (selected scales), and European Organisation for Research and Treatment of Cancer (EORTC) Item Library (selected symptoms)
8. Change from baseline in EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) index-based and visual analogue scale (VAS) scores at specified timepoints
9. Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, and daunorubicin at specified timepoints.

1. Proporción de pacientes con RC, remisión completa con recuperación incompleta del hemograma (RCi), o remisión completa con recuperación incompleta de trombocitos (RCt) al final del tratamiento de inducción
2. Proporción de pacientes con RC o remisión completa con recuperación hematológica parcial (RCh) al final del tratamiento de inducción
3. Proporción de pacientes con un estado negativo para la ERM al final del tratamiento de inducción
4. Supervivencia libre de eventos
5. Supervivencia global
6. Supervivencia libre de recaidaen pacientes que alcanzan remisión (CR, CRi, CRp o CRh).
7. Cambio desde el inicio en los síntomas relacionados con la enfermedad notificados el paciente y la calidad de vida relacionada con la salud en momentos específicos, según la evaluación mediante el uso de la Evaluación Funcional del Tratamiento de Enfermedades Crónicas (FACIT)-Fatiga, el Cuestionario de la calidad de vida principal de 30 ítems de la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ-C30 de la EORTC) (escalas seleccionados) e Item Library de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC)
8. Cambio con respecto al inicio en el cuestionario de 5 niveles y 5 dimensiones de EuroQOL (EQ-5D-5L) basado en un índice y las puntuaciones de la escala analógica visual en momentos especificados
9. Concentraciones plasmaticas de idasanutlina (y metabolitos si es apropiado), citarabina y daunorubicina en tiempos especificados

E.5.2.1

Timepoint(s) of evaluation of this end point

1-3. At the end of induction treatment
4-6. Up to 6 years
7-8. Baseline, Day 1 of all cycles
9. Idasanutlin: Day 1, Day 3, Day 5 of induction cycle 1; Day 1 and Day 5 of consolidation cycle 1; Day 1 and Day 5 of maintenance cycle 1
Cytarabine: Day 1, Day 3, Day 5 of induction cycle 1; Day 1 and Day 5 of consolidation cycle 1
Daunorubicin: Day 1, Day 3, Day 5 of induction cycle 1.

1-3. Al final del tratamiento de inducción
4-6. Hasta un maximo de 6 años
7-8. Basal, dia 1 de todos los ciclos
9. Idasanutlina: Dia 1, Dia 3, Dia 5 de induccion del ciclo 1; Dia 1 y Dia 5 de consolidación del ciclo 1; Dia 1 y Dia 5 de mantenimiento del ciclo 1
Citarabina: Dia 1, Dia 3, Dia 5 de inducción del ciclo 1; Dia 1 y Dia 5 de consolidacion del ciclo 1
Daunorubicina: Dia 1, Dia 3, Dia 5 de induccion del ciclo 1.

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

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

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)

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

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.8.2.4

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

France

Italy

Spain

United States

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

UVUP

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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'

Ninguno

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

2019-06-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-24

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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