Clinical Trials Register

Summary
EudraCT Number:	2016-001860-12
Sponsor's Protocol Code Number:	CMAK683X2101
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:	2017-05-08
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

2016-001860-12

A.3

Full title of the trial

A phase I/II, multicenter, open-label study of MAK683 in adult patients with advanced malignancies

Estudio de fase I/II, multicéntrico, abierto de MAK683 en pacientes adultos con tumores malignos avanzados

A.3.1

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

A safety and efficacy study of MAK683 in adults patients with advanced solid tumors

Estudio de seguridad y eficacia de MAK683 en pacientes adultos con tumores malignos avanzados

A.4.1

Sponsor's protocol code number

CMAK683X2101

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 Farmacéutica, S.A.
B.4.2	Country	Spain
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	Departamento Médico Oncología (GMO)
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	+34 90 0353036
B.5.5	Fax number	34 93 2479903
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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	2.5
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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: 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	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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.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

Advanced malignancies

tumores malignos avanzados

E.1.1.1

Medical condition in easily understood language

advanced malignancies

tumores malignos avanzados

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	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10066481
E.1.2	Term	Hematological malignancy
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

Phase I: To characterize safety and tolerability and determine the MTD and/or RP2D of MAK683
Phase II: To assess the anti-tumor activity of MAK683

Fase I: Caracterizar la seguridad y tolerabilidad y determinar la MTD y/o RP2D de MAK683
Fase II: Evaluar la actividad anti-tumoral de MAK683

E.2.2

Secondary objectives of the trial

Phase I:
•To characterize the anti-tumor activity of MAK683
•To characterize the PK profile of MAK683
•To characterize the pharmacodynamics effect of MAK683
Phase II:
•To characterize the anti-tumor activity of MAK683
•To characterize the safety and tolerability of MAK683
•To characterize the PK profile of MAK683
•To characterize the pharmacodynamics effect of MAK683

Fase I:
•Caracterizar la actividad anti-tumoral de MAK683
•Caracterizar el perfil de PK de MAK683
•Caracterizar el efecto farmacodinámico de MAK683
Fase II:
•Caracterizar la actividad anti-tumoral de MAK683
•Caracterizar la seguridad y tolerabilidad de MAK683
•Caracterizar el perfil de PK de MAK683
•Caracterizar el efecto farmacodinámico de MAK683

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients Age > = 18 years
[For Japan only: written consent is necessary from both the patient and his /her legal representative if he/she is under the age of 20 years.]
2.ECOG performance status 0 to 2
3.Patients with relapsed or refractory diffuse large B cell lymphoma, follicular lymphoma, other B cell lymphoma with measurable disease as determined by Non-Hodgkin’s Lymphoma Cheson response criteria (2014)
4.Patients with advanced solid tumor, including Nasopharyngeal carcinoma (Phase II part- Nasopharyngeal carcinoma patients without homozygous p16-deletion and other indications supported by emerging data, with measurable disease as determined by RECIST 1.1.
Other protocol-defined inclusion criteria may apply

1.Edad > = 18 años
2.Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) 0 a 2
3.Pacientes con linfoma difuso de células B grandes, linfoma folicular, otro linfoma de células B recidivantes o refractarios con enfermedad medible determinado mediante los criterios de respuesta de Cheson de Linfoma No-Hodgkin (2014).
4.Pacientes con tumor sólido avanzado o recidivante/metastásico, incluyendo carcinoma nasofaríngeo (parte Fase II – pacientes con carcinoma nasofaríngeo sin deleción p16 en homocigosis), cáncer de próstata (resistente a la castración), cáncer gástrico, cáncer de ovario y otras indicaciones si lo apoyan los datos recientes, con enfermedad medible determinado mediante RECIST 1.1.

E.4

Principal exclusion criteria

1.Other malignant disease than the one being treated in this study
2.Severe and/or uncontrolled medical conditions that in the investigator’s opinion could affect the safety of individual or impair the assessment of study result.
3.B-cell lymphoma patients who have received prior allogeneic stem cell transplant
4.Patient have received anti-cancer therapies within defined time frames prior to the first dose of study treatment
5.Symptomatic CNS involvement which are neurologically unstable or requiring increasing doses of steroids to control.
6.Patient having out of range laboratory values defined as:
1)Insufficient bone marrow function at screening:
•Platelets < = 50 x 109/L (50,000/mm3)
•Hemoglobin (Hgb) < = 90 g/L (9 g/dL)
•Absolute neutrophil count (ANC) < = 1.0 x 109/L (1000/mm3)
2)Insufficient hepatic and renal function at screening:
•ALP, ALT, and AST > 3 x ULN (>5 x ULN if subject has liver metastases)
•Total bilirubin > =2 x ULN
•Serum creatinine > 1.5 x ULN and/or creatinine clearance < = 50 mL/min
7.Unable to stop any prohibited medications, including strong CYP3A4 inhibitors or inducers, CYP3A4 or CYP2C8 substrates with a narrow therapeutic index, long acting proton pump inhibitors.
Other protocol-defined exclusion criteria may apply.

1.Otra enfermedad tumoral aparte de la que se está tratando en este estudio.
2.Condiciones médicas severas y/o no controladas que a criterio del investigador podría afectar la seguridad del individuo o alterar la evaluación del resultado del estudio.
3.Pacientes con linfoma de células B que han recibido trasplante alogénico de células progenitoras hematopoyéticas. madre previo
4.Pacientes que han recibido terapias anti-cáncer en plazos definidos antes de la primera dosis del tratamiento del estudio.
5.Afectación asintomática del SNC que es neurológicamente inestable o precisan aumento de dosis de esteroides para controlarlo.
6.Pacientes con valores de laboratorio fuera de rango definido como:
1)Función insuficiente de la médula ósea en la selección:
•Plaquetas < = 50 x 109/l (50,000/mm3)
•Hemoglobina (Hgb) < = 80 g/l (8 g/dl)
•Recuento absoluto de neutrófilos (ANC) < = 1,0 x 109/l (1000/mm3)
2)Función hepática y renal insuficiente en la selección:
•Fosfatasa alcalina (en ausencia de enfermedad ósea), alanino aminotransferasa (ALT), y aspartato aminotransferasa (AST) más de o igual a 3 x LSN (más de o igual a 5 x LSN si el sujeto tiene metástasis de hígado)
•Bilirrubina total > 1,5 x LSN
•Creatinina en suero > 1,5 x LSN y/o aclaramiento de creatinina < = 50 mL/min (calculado utilizando la fórmula de Cockcroft-Gault)
7.Incapaz de suspender ninguna de las medicaciones prohibidas, incluyendo inhibidores o inductores fuertes del citocromo P450 (CYP), inhibidores de la bomba de protones de larga duración y fármacos con riesgo conocido de causar Torsades de pointes (TdP).

E.5 End points

E.5.1

Primary end point(s)

Phase I:
Safety:
1.Incidence of dose limiting toxicities (DLTs) in the first 28 days of treatment
2.Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability:
Dose interruptions, reductions and dose intensity
Phase II:
Overall response rate (ORR), based on local assessment per Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Cheson, 2014), Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and PCWG2

Fase I:
Seguridad:
•Incidencia de las toxicidades limitantes de dosis (DLTs) en los primeros 28 dias de tratamiento
•Incidencia y severidad de acontecimientos adversos (AAs) y acontecimientos adversos graves (AAGs), incluyendo cambios en los valores de laboratorio, constantes vitales y electrocardiogramas (ECGs)
Tolerabilidad
•Interrupciones de dosis, reducciones e intensidad de la dosis
Fase II:
Tasa global de respuesta (ORR) basada en la evaluación de Linfoma de Hodgkin y No-Hodgkin (Cheson et al 2014), criterios de evaluación de Respuesta en Tumores Sólidos (RECIST) v1.1 y PCWG2

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
Safety:
1. Day 28
2. End of study
Phase II: End of study

Fase I:
Seguridad
1 Dia 28
2 Final del estudio
Fase II: Final del estudio

E.5.2

Secondary end point(s)

Phase I part:
ORR, Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Plasma concentrations and derived PK parameters of MAK683
Pre-and post-treatment expression of H3K27 tri methylation in PBMC
Phase II part:
Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability: Dose interruptions, reductions and dose intensity.
Plasma concentrations and PK profiles of MAK683
Pre-and post-treatment level of H3K27 tri methylation in PBMC

Fase I:
•ORR, DOR, PFS y BOR
•Concentraciones plasmáticas y parámetros obtenidos de PK de MAK683
•Expresión del nivel pre- y post-tratamiento de tri-metilación con H3K27 en células mononucleares de sangre periférica (PBMC)
Fase II:
•DOR, PFS y BOR
Seguridad: Incidencia y severidad de acontecimientos adversos (AAs) y acontecimientos adversos graves (AAGs), incluyendo cambios en los valores de laboratorio, constantes vitales y electrocardiogramas (ECGs)
Tolerabilidad: Interrupciones de dosis, reducciones e intensidad de la dosis
Concentraciones plasmáticas y perfiles de PK de MAK683
Nivel pre- y post-tratamiento de tri-metilación con H3K27 en células mononucleares de sangre periférica (PBMC)

E.5.2.1

Timepoint(s) of evaluation of this end point

End of study

Fin 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

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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

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)

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

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

Canada

China

France

Germany

Hong Kong

Italy

Japan

Korea, Republic of

Netherlands

Singapore

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

The study will end when the treatment period, 30-day safety follow-up and progression disease follow up (if applicable) have completed for all patients or if the study is terminated early.

El estudio finalizará cuando el periodo de tratamiento, periodo de seguimiento de seguridad de 30 dias y el seguimiento de la progresion de la enfermedad (si aplica) se hayan completado para todos los pacientes o si el studio finalizara anticipadamente

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:

100

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

148

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

2017-07-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-06-14

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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