Clinical Trials Register

Summary
EudraCT Number:	2019-000373-23
Sponsor's Protocol Code Number:	CINC424H12201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2019-10-02
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

Spain - AEMPS

A.2

EudraCT number

2019-000373-23

A.3

Full title of the trial

A randomized, open-label, phase I/II open platform study evaluating safety and efficacy of novel ruxolitinib combinations in myelofibrosis patients

Estudio de fase I/II, aleatorizado, abierto y de plataforma abierta en el que se evalúa la seguridad y eficacia de nuevas combinaciones de ruxolitinib en pacientes con mielofibrosis.

A.3.1

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

A safety, pharmacokinetics and preliminary efficacy study of novel ruxolitinib combination treatments in patients with myelofibrosis

Estudio de la seguridad, farmacocinética y eficacia preliminar de los nuevos tratamientos de combinación de ruxolitinib en pacientes con mielofibrosis.

A.3.2

Name or abbreviated title of the trial where available

ADORE

A.4.1

Sponsor's protocol code number

CINC424H12201

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	Trial Monitoring Organization (TMo)
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	+3490 0353036
B.5.5	Fax number	NA
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	Yes
D.2.1.1.1	Trade name	Jakavi
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ruxolitinib
D.3.2	Product code	INC424
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	ruxolitinib
D.3.9.1	CAS number	1092939-17-7
D.3.9.2	Current sponsor code	INC424
D.3.9.3	Other descriptive name	RUXOLITINIB PHOSPHATE
D.3.9.4	EV Substance Code	SUB32897
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	5
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/3/12/1034
D.3 Description of the IMP
D.3.1	Product name	crizanlizumab
D.3.2	Product code	SEG101
D.3.4	Pharmaceutical form	Concentrate 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	CRIZANLIZUMAB
D.3.9.2	Current sponsor code	SEG101
D.3.9.4	EV Substance Code	SUB188615
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Yes
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	MBG453
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	Not yet defined
D.3.9.2	Current sponsor code	MBG453
D.3.9.3	Other descriptive name	MBG453
D.3.9.4	EV Substance Code	SUB178459
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	Yes
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	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	siremadlin
D.3.2	Product code	HDM201
D.3.4	Pharmaceutical form	Capsule, hard
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	siremadlin
D.3.9.3	Other descriptive name	HDM201
D.3.9.4	EV Substance Code	SUB129457
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	10
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	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	siremadlin
D.3.2	Product code	HDM201
D.3.4	Pharmaceutical form	Capsule, hard
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	siremadlin
D.3.9.3	Other descriptive name	HDM201
D.3.9.4	EV Substance Code	SUB129457
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: 6
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	siremadlin
D.3.2	Product code	HDM201
D.3.4	Pharmaceutical form	Capsule, hard
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	siremadlin
D.3.9.3	Other descriptive name	HDM201
D.3.9.4	EV Substance Code	SUB129457
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.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

PMF or PPV- MF, or PET- MF

MFP, MF-PPV o MF-PTE

E.1.1.1

Medical condition in easily understood language

Myelofibrosis (a type of blood cancer)

Mielofibrosis (un tipo de cáncer sanguíneo)

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	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1:
To characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of each
combination partner used with ruxolitinib

Parts 2 & 3:
To evaluate the preliminary efficacy of each novel ruxolitinib combination treatment arm

Parte 1:
Caracterizar la seguridad, la tolerabilidad y la dosis recomendada para la fase 2 (RP2D) de cada elemento de combinación utilizado con ruxolitinib

Parte 2 y 3:
Evaluar la eficacia preliminar de los nuevos tratamientos de combinación de ruxolitinib

E.2.2

Secondary objectives of the trial

Part 1,2&3
•characterize PK profile of rux administered in combo w. HDM201,SEG101&MBG453
•emergence of anti-SEG101 or anti-MBG453 antibodies following one or more IV infusions
•evaluate long-term safety and tolerability of rux combo treatments in each arm based on frequency,duration&severity of AE,abnormalities in vital signs & lab test values
Part 2&3
•assess proportion of subjects in each arm who achieve Hb improvement of ≥ 2.0 or ≥ 1.5 g/dL from baseline (BL) to end of C6 &end of C12
•evaluate changes in symptoms of MF in each arm using MFSAF v4.0 and EORTC QLQ-C3 PROs from BL
•evaluate changes in spleen size in each arm measured by change in spleen length&spleen volume from BL
•evaluate effect of each rux combo treatment in delaying progression of MF & estimate time to PFS event
•evaluate effect on bone marrow fibrosis in each arm by determining proportion of subjects achieving improvement in bone marrow fibrosis of ≥ 1 gr from BL to end of C6 & subsequent 6 cycles

Parte 1, 2 y 3: -Caracterizar el perfil farmacocinético de rux administrado en combo con HDM201,SEG101yMBG453 -Evaluar la aparición de anticuerpos anti-SEG101 y anti-MBG453 después de 1 o más perfusiones i.v -Evaluar seguridad y tolerabilidad a largo plazo de los ttos de combo de rux en cada grupo, según la frecuencia, duración y gravedad de AA, constantes vitales y valores analíticos. Parte 2 y 3 evaluar:
-Proporción de sujetos en cada grupo que alcancen una mejora de Hb >/=2 g/dl o >/=1,5 g/dl desde la basal hasta el final del c6 y del c12
-Cambios en los síntomas de MF en cada grupo desde la basal
-Cambios en el tamaño del bazo en cada grupo según cambio de longitud y volumen desde la basal
-Efecto de cada tto de combo de rux en el retraso de la progresión de MF y el PFS
-Efecto sobre la fibrosis de médula ósea en cada grupo de tto determinando la proporción de sujetos que alcanzan una mejora de grado ≥1 desde la basal hasta el final del c6 y los 6 ciclos sucesivos

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-essential thrombocythemia (ET) (PET-MF) or post-polycythemia vera (PV) myelofibrosis (PPV-MF) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria
• Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted).
• Have been treated with ruxolitinib for at least 24 weeks prior to first dose of study treatment
• Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 25 mg twice a day (BID)) for ≥ 8 weeks prior to first dose of study treatment.
• Hemoglobin < 10 g/dL
• Part 1: Platelet counts ≥ 75 000/μL
• Part 2 and Part 3: Platelet counts ≥ 50 000/μL

Additional inclusion criteria as per full protocol may apply.

-Sujetos con un diagnóstico de mielofibrosis primaria (MFP) de acuerdo con los criterios de 2016 de la Organización Mundial de la Salud (OMS), o un diagnóstico de mielofibrosis post-trombocitemia esencial (MF-PTE) o mielofibrosis post-policitemia vera (MF-PPV) de acuerdo con los criterios de 2007 del International Working Group for Myelofibrosis Research and Treatment (IWG-MRT).
-Un bazo palpable de al menos 5 cm desde el margen costal izquierdo (MCI) hasta el punto de mayor protrusión esplénica o hasta alcanzar un volumen de agrandamiento del bazo de al menos 450 cm3 según la RM o TC en la basal (se puede aceptar una RM/TC de hasta 8 semanas antes de la primera dosis del tratamiento del estudio).
-Haber sido tratados con ruxolitinib al menos 24 semanas antes de la primera dosis del tratamiento del estudio.
-Mantener (sin ajustes de la dosis) la dosis pautada de ruxolitinib (entre 5 y 25 mg dos veces al día (b.i.d.) durante >/= 8 semanas antes de la primera dosis del tratamiento del estudio.
-Hemoglobina <10 g/dl.
-Parte 1: Recuento de plaquetas >/=75 000/µl.
-Partes 2 y 3: Recuento de plaquetas >/= 50 000/µl.

Para más criterios de inclusión ver protocolo

E.4

Principal exclusion criteria

• Not able to understand and to comply with study instructions and requirements.
• Received any investigational agent for the treatment of MF (except ruxolitinib) within 30 days of first dose of study treatment or within 5 half-lives of the study treatment, whichever is greater
• Peripheral blood blasts count of > 10%.
• Received a monoclonal antibody (Ab) or immunoglobulin-based agent within 1 year of screening, or has documented severe hypersensitivity reactions/immunogenicity (IG) to a prior biologic
• Splenic irradiation within 6 months prior to the first dose of study drug
• Received blood platelet transfusion within 28 days prior to first dose of study treatment.
• Subjects with known TP53 mutation or deletion of TP53

Additional exclusion criteria as per full protocol may apply.

-Incapaz de comprender y cumplir las instrucciones y requisitos del estudio.
-Haber recibido un fármaco en investigación durante el tratamiento de la MF (excepto ruxolitinib) durante los 30 días anteriores a la primera dosis del tratamiento del estudio o durante las 5 semividas del tratamiento del estudio, aquel periodo que
sea más largo.
-Recuento de blastos en sangre periférica >10 %.
-Haber recibido un anticuerpo monoclonal (Ac) o un fármaco basado en la inmunoglobulina durante el año anterior a la selección, o haber documentado reacciones graves de hipersensibilidad/inmunogenicidad (IG) a un tratamiento biológico anterior.
-Irradiación esplénica durante los 6 meses anteriores a la primera dosis del fármaco del estudio.
-Recepción de una transfusión de plaquetas dentro de los 28 días anteriores a la primera dosis del tratamiento del estudio.
-Sujetos con mutación o deleción de TP53.

Para más criterios de exclusión ver protocolo

E.5 End points

E.5.1

Primary end point(s)

• Incidence and severity of dose limiting toxicity (DLTs) within the first 2 treatment cycles in Part 1 of the study
• Response rate (RR) for the composite endpoint (anemia improvement of ≥ 1.5 g/dL and no spleen volume progression and no symptom worsening) at the end of Cycle 6

-incidencia y la gravedad de la toxicidad limitante de dosis (DLT) en los 2 primeros ciclos de tratamiento de la parte 1 del estudio.
-La Tasa de Respuesta (TR) se compone de una mejora de la anemia >/= 1,5 g/dl, ninguna progresión del volumen del bazo y ningún empeoramiento de los síntomas al final del Ciclo 6

E.5.1.1

Timepoint(s) of evaluation of this end point

• within the first 2 treatment cycles
• End of cycle 6

-En los primeros ciclos de tratamiento
-Al final del ciclo 6

E.5.2

Secondary end point(s)

• PK parameters (e.g., AUC, Cmax, Tmax) and concentration vs. time profiles of each investigational drug within combination regimens
• Presence and/or concentration of anti-crizanlizumab or anti-MBG453 antibodies
• Change in spleen length (by palpation) from baseline
• Change in spleen volume (by MRI/CT) from baseline
• Estimate of progression free survival (PFS) where events are defined as follows:
• Progressive splenomegaly as assessed by increasing spleen volume (by MRI/CT) of ≥ 25% from baseline. The progression date will be the date of MRI/CT assessment confirming spleen volume increase of ≥ 25% from baseline
• Accelerated phase defined by a circulating peripheral blood blast content of > 10% but < 20% confirmed after 2 weeks. The progression date will be the date of first increase in peripheral blood blast content of > 10%
• Deteriorating cytopenia (dCP) independent from treatment defined for all patients by platelet count < 35 x10^9/L or neutrophil count < 0.75 x 10^9/L that lasts for at least 4 weeks. The progression date will be the date of first decrease of platelets < 35 x10^9/L or neutrophils < 0.75 x 10^9/L confirmed after 4 weeks
• Leukemic transformation defined by a peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x10^9/L that lasts for at least 2 weeks or a bone marrow blast count of ≥ 20%. The progression date will be the date of first increase in peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x10^9/L OR the date of the bone marrow blast count of ≥ 20%
• Death from any cause
• Proportion of subjects achieving improvement in bone marrow fibrosis of ≥ 1 grade from baseline
• Frequency, duration and severity of adverse events, abnormalities in vital signs and laboratory test values, including ECG data

• Parámetros de Pks (ejemplo: AUC, Cmax, Tmax) y concentración versus perfiles de tiempo de cada medicación de estudio en
los regímenes de combinación.
• Presencia y /o concentración de anticuerpos de anti-crizanlizumab o anti-MBG453.
• Cambio en la longitud de bazo (por palpación) desde visita basal.
• Cambio en el volumen del bazo (por Resonancia magnética o TAC) desde visita basal.
• Estimar la supervivencia libre de progresión donde los eventos son definidos como sigue:
- Esplenomegalia progresiva evaluada por el incremento del volumen del bazo (por resonancia magnética/TAC) de >/=25%
desde la visita basal.
- Fase acelerada definida por el contenido en blastos circulantes en sangre periférica >10% pero <20% confirmada después de dos
semanas. La fecha de progresión será la fecha del primer aumento en el contenido
de blastos en sangre periférica >10%.
- Citopenia deteriorante independiente de tratamiento definida para todos los pacientes por el recuento de plaquetas
<35x10^9/L o recuento de neutrófilos< 0.75 x10^9/L que dure al menos 4 semanas.La fecha de progresión será la fecha de la primera disminución de plaquetas < 35 x10^9/L o neutrófilos < 0.75 x 10^9/L confirmada después de 4 semanas.
- Transformación leucémica definida por el contenido de blastos en sangre periférica >/= 20% asociado con un recuento de blastos absoluto >/= 1x 10^9/L o la fecha de recuento de blastos en médula ósea >/= 20%.
- Muerte por cualquier causa.
- Proporción de sujetos que alcancen mejoria en la fibrosis de médula ósea >/= grado 1 desde visita basal.
- Frecuencia, duración y gravedad de los eventos adversos, anormalidades en signos vitales y valores de pruebas, incluyendo datos
de electrocardiograma.

E.5.2.1

Timepoint(s) of evaluation of this end point

• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12.
• first 6 cycles
• first 6 cycles
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12.
• From date of informed consent until end of safety follow up (30 days after last dose of ruxolitinib 30 days after last dose of siremadlin, 90 days after last dose of MBG453, 105 days after last dose of crizanlizumab)

• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6.
• Fin de ciclo 6.
• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6 y fin de ciclo 12
• Fin de ciclo 6 y fin de ciclo 12
• Desde la fecha de consentimiento informado hasta el final de seguimiento de seguridad (30 dias después de la última dosis de ruxolitinib, 30 dias después de la última dosis de siremadlin, 90 dias después de última dosis de MBG453, 105 dias después de última dosis de crizanlizumab)

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

quality of life and patient reported outcomes

calidad de vida y resultados informados por los pacientes

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

safety, tolerability, and the recommended Phase 2 dose (RP2D) of each combination partner used with

seguridad, tolerabilidad y dosis recomendada de Fase2 (RP2D) de cada pareja de combinación utilizada

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

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

Yes

E.8.1.7.1

Other trial design description

escalado de dosis para el brazo con HDM201 in la parte 1

dose escalation for arm with HDM201 in part 1

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

Canada

Denmark

France

Germany

Hungary

Italy

Lebanon

Netherlands

Russian Federation

Spain

Sweden

Switzerland

Turkey

United Kingdom

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

LPLV

Ultima visita del ultimo paciente

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:

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

130

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)

For subjects who in the opinion of the investigator are still deriving clinical benefit from ruxolitinib combination treatment after discontinuation, every effort will be made to continue provision of study treatment outside this study through an alternative setting as part of the Novartis post-trial access program, as permitted by and in accordance with local laws and regulations.

Para sujetos que en la opinión del investigador aun obtengan beneficios clínicos del tratamiento en combinación con ruxolitinib después de la discontinuación, todos los
esfuerzos serán realizados para continuar con la provisión del tratamiento del estudio fuera del estudio a través de una configuración alternativa como parte del acceso post ensayo de Novartis, como está permitido por y de acuerdo con las leyes y regulaciones locales.

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

2019-09-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-05

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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