Clinical Trials Register

Summary
EudraCT Number:	2012-002250-23
Sponsor's Protocol Code Number:	CBEZ235D2101
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:	2012-07-26
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

2012-002250-23

A.3

Full title of the trial

Phase Ib dose finding study of abiraterone acetate plus BEZ235 or BKM120 in patients with castration-resistant prostate cancer

Estudio de fase Ib de búsqueda de dosis de acetato de abiraterona más BEZ235 o BKM120 en pacientes con cáncer de próstata resistente a la castración

A.3.1

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

Phase Ib dose finding study of abiraterone acetate plus BEZ235 or BKM120 in patients with castration-resistant prostate cancer

Estudio de fase Ib de búsqueda de dosis de acetato de abiraterona más BEZ235 o BKM120 en pacientes con cáncer de próstata resistente a la castración

A.4.1

Sponsor's protocol code number

CBEZ235D2101

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 Farmaceutica 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 Services 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 Farmaceutica S.A.
B.5.2	Functional name of contact point	Javier Malpesa Barcones
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les Corts Catalanes 761
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	+34933061111
B.5.5	Fax number	+34933064290
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.3.1	Product name	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
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	BEZ235
D.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEZ235
D.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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: 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.3.1	Product name	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
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	BEZ235
D.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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	400
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	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	BKM120
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	BKM120
D.3.9.1	CAS number	not known
D.3.9.2	Current sponsor code	BKM120
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.3.2	Product code	BKM120
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	BKM120
D.3.9.1	CAS number	not known
D.3.9.2	Current sponsor code	BKM120
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: 6
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	Zytiga
D.2.1.1.2	Name of the Marketing Authorisation holder	Jansen-Cilag International NV
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	Zytiga
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	ABIRATERONE
D.3.9.1	CAS number	154229-19-3
D.3.9.4	EV Substance Code	SUB07361MIG
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	250
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: 7
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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	prednisone
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	PREDNISONE
D.3.9.1	CAS number	53-03-2
D.3.9.4	EV Substance Code	SUB10020MIG
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.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

patients with castration-resistant prostate cancer

hombres adultos con cáncer de prostata en los que el acetato de abiraterona ha fracasado.

E.1.1.1

Medical condition in easily understood language

Adult patients with castration-resistant prostate cancer

Pacientes adultos en los que el tratamiento on acetato de abiraterona ha fracasado y son resistente a la castración

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10062904
E.1.2	Term	Hormone-refractory prostate cancer
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

Dose escalation part:
Define maximum tolerated dose (MTD) and /or recommended dose for expansion (RDE) of the combinations abiraterone acetate + BEZ235 and abiraterone acetate + BKM120 by assessing the incidence of dose limiting toxicities (DLTs) in cycle 1.
Dose expansion part:
Assess anti-tumor activity of the combinations (abiraterone acetate + BEZ235 and abiraterone acetate + BKM120) in castration-resistant prostate cancer patients with abiraterone acetate failure as on treatment
Prostate specific antigen (PSA) progression according to prostate cancer working group 2 criteria (PCWG2) by assessing PSA decline ? 30% at Week 12 or later.

fase de escalado:
? Determinar la DMT y/o DRE de acetato de abiraterona + BEZ235 (b.i.d.) y acetato de abiraterona + BKM120 (QD) en pacientes con CPRC en los que el acetato de abiraterona no ha tenido efecto
Fase de expansión:
Evaluar la actividad antitumoral de las combinaciones (acetato de abiraterona + BEZ235 y acetato de abiraterona + BKM120) en pacientes con CPRC en los que el acetato de abiraterona ha fracasado, definida como progresión del PSA en tratamiento según los criterios PCWG2

E.2.2

Secondary objectives of the trial

Dose escalation part:
? Assess safety and tolerability of the combinations
? Assess preliminary anti-tumor activity of the combinations by measuring PSA decline, time to PSA progression, radiological
progression-free survival and radiological response rate
? Characterize PK of BEZ235, BKM120 and abiraterone acetate
? Investigate potential drug-drug interaction between BEZ235 and abiraterone acetate
Dose expansion part:
? Assess safety and tolerability of the combinations
? Evaluate additional anti-tumor parameters such as time to PSA progression, radiological progression-free survival, radiological response rate and overall survival
? Characterize PK of BEZ235, BKM120 and abiraterone acetate

Fase de escalado:
? Evaluar la seguridad y tolerabilidad de las combinaciones.
? Evaluar la actividad antitumoral preliminar de las combinaciones.
? Caracterizar la PK de BEZ235, BKM120 y acetato de abiraterona ; investigar la posible interacción fármaco-fármaco entre BEZ235 y acetato de abiraterona
Fase de expansión:
Evaluar la seguridad y tolerabilidad
? Evaluar los parámetros antitumorales adicionales
? Caracterizar la PK de BEZ235, BKM120 y acetato de abiraterona

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Histologically or cytologically confirmed diagnosis of advanced or metastatic castration resistant prostate cancer.
Advanced or metastatic castration-resistant prostate cancer progression after abiraterone acetate failure
Patients should have no more than 2 lines of prior chemotherapies including cytotoxic agents (i.e. docetaxel)
Other protocol defined criteria may apply

? Hombres adultos ? 18 años de edad
? Estado funcional del Grupo Cooperativo de Oncología del Este ? 2
? Los pacientes deben tener un nivel de testosterona tras la castración (<= 50 ng/dL o 1.7 nmol/L). (El estado de castración debe mantenerse mediante análogos de GnRH administrados de forma continua, salvo que el paciente se haya sometido a una orquiectomía quirúrgica).
? Diagnóstico confirmado mediante histología o citología de cáncer de próstata resistente a la castración avanzado o metastásico.
? Progresión del cáncer de próstata resistente a la castración avanzado o metastásico después de que el acetato de abiraterona haya fracasado.
? Los pacientes no deberán haber recibido más de 2 líneas de quimioterapia previa incluidos los fármacos citotóxicos (es decir, docetaxel).
? Interrupción de todos los tratamientos anti-andrógenos, anti-neoplásicos o en investigación >= 4 semanas (6 semanas para bicalutamida). Pacientes con una función adecuada de los órganos y médula ósea,
Solo parte de escalada de la dosis:
? El paciente debe tener documentada una progresión de la enfermedad con la línea de tratamiento anterior conforme a los criterios PCWG2:
a. Un paciente con una progresión únicamente basada en el incremento del PSA debe haber tenido una secuencia de valores incrementado 3 veces consecutivas en intervalos de al menos 1 semana y debe tener un nivel mínimo de 5,0 ng/ml para su participación.
b. Los pacientes que manifestaron una progresión de la enfermedad según RECIST son elegibles independientemente del PSA.
c. Pacientes con progresión ósea únicamente conforme a los criterios PCWG2.
Solo parte de expansión de dosis:
? El paciente debe haber tenido una respuesta del PSA anterior, seguida de una progresión del PSA documentada con tratamiento de acetato de abiraterona.
? El acetato de abiraterona debe ser el último tratamiento antes de su participación en la parte de expansión de dosis del estudio y no se permite ningún otro tratamiento contra el cáncer entre el acetato de abiraterona y la participación en el estudio.

E.4

Principal exclusion criteria

Previous treatment with PI3K pathway inhibitors (e.g. PI3K, AKT,mTOR inhibitor), ketoconazole, AA or other CYP17 inhibitors (exception of AA), or MDV3100.
Patient has active uncontrolled or symptomatic CNS metastases
Patients who experienced dose reductions and/or treatment interruptions due to abiraterone acetate related toxicities (i.e. serious AEs, AEs, liver toxicities during abiraterone acetate treatment

? Tratamiento anterior con inhibidores de la vía PI3K (p. ej., inhibidor PI3K, AKT, mTOR), ketoconazol, acetato de abiraterona u otros inhibidores CYP17 (a excepción de acetato de abiraterona) o MDV3100.
? Pacientes con metástasis activas en el SNC sintomáticas y no controladas.
? Hipertensión inadecuadamente controlada (es decir, presión arterial sistólica >=160 mmHg o presión arterial diastólica >=95 mmHg).
? Pacientes con QTcF > 480 ms en el ECG de la visita de selección (utilizando la fórmula QTcF), síndrome QT corto/largo o antecedentes de prolongación QT/Torsades de Pointes.
? Pacientes con alteración de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de los fármacos del estudio.
? Pacientes con antecedentes médicos documentados o episodios de depresión mayor activa, trastorno bipolar (I o II), trastorno obsesivo compulsivo, esquizofrenia, antecedentes de intentos de suicidio, pensamientos suicidas u homicidas (p. ej., riesgo de autolesionarse o hacer daño a los demás) y/o:
a. Pacientes con CTCAE ? grado 3 de ansiedad
b. Pacientes con una puntuación de ? 15 en la escala sobre el estado de ánimo GAD-7
c. Pacientes con una puntuación ? 12 en el cuestionario PHQ-9
? Pacientes que hayan experimentado reducciones de dosis y/o interrupciones del tratamiento debido a toxicidades relacionadas con el acetato de abiraterona (es decir, AA graves, AA, toxicidades hepáticas durante el tratamiento con acetato de abiraterona).
Criterios de exclusión (solo parte de expansión de dosis)
? Pacientes que hayan recibido un tratamiento sistémico contra el cáncer entre el acetato de abiraterona y su participación en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Dose escalation part
Incidence of DLTs in cycle 1
Dose expansion part
PSA decline ? 30% at Week 12 or later

Fase de escalado de dosis:
Inicidencia de DLT in ciclo 1
Fase de Exapansión de dosis:
Disminución PSA? 30% a partir de la semana 12.

E.5.1.1

Timepoint(s) of evaluation of this end point

PSA decline ? 30% at Week 12 or later.

Fase de escalado dosis: durante el ciclo 1
Fase de expansion de dosis: a partir de la semana 12.

E.5.2

Secondary end point(s)

Dose escalation part :
Frequency and severity of adverse events
Abnormal lab values
Other safety data as considered appropriate
Time to PSA progression (TTpP) according to Prostate Cancer Clinical Trials Working Group criteria (PCWG2)
Radiological PFS (rPFS) according to RECIST 1.1 and according to PCWG2.
rRR: Best overall response rate according to RECIST 1.1
OS
BEZ235, BKM120 and AA plasma concentrations
Dose expansion part
Frequency and severity of adverse events
Abnormal lab values
Other safety data as considered appropriate
TTpP as per PCWG2
rPFS according to RECIST 1.1 and according to PCWG2.
rRR according to RECIST 1.1
OS
BEZ235, BKM120 and AA plasma concentrations

Fase de escalado de dosis:
Frecuencia y gravedad de los acontecimientos adversos
Anomalías en los valores de laboratorio
Otros datos de seguridad según se consideren apropiados
? Disminución del PSA ? 30% en la semana 12 o posterior
? Tiempo hasta la progresión del PSA (TTpP) según los criterios del Grupo de trabajo de ensayos clínicos sobre el cáncer de próstata (PCWG2)
? SLP radiológica (SLPr) según RECIST 1.1 y PCWG2
? TRr: mejor tasa de respuesta global según RECIST 1.1
Concentraciones plasmáticas de BEZ235, BKM120 y acetato de abiraterona

Fase de expansion de dosis:
Frecuencia y gravedad de los acontecimientos adversos
Anomalías en los valores de laboratorio
Otros datos de seguridad según se consideren apropiados
? TTpP según PCWG2
? SLPr según RECIST 1.1 y PCWG2
? TRr según RECIST 1.1
? SG
Fase de expasnión de dosis:

E.5.2.1

Timepoint(s) of evaluation of this end point

Time to PSA progression, radiologic progression free survival, best overall response rate and overall survival when 75% of death occur.

Tiempo de progresión por PSA, supervivencia libre de progresion, mejor tasa de respuesta global y la supervivencia general cuando el 75% de las muertes se producen.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

acetato de abiraterona

abiraterone and prednisone

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

Canada

Switzerland

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

end of study will be upon of the Follow up period of the last patient on treatment as described in the protocol

el studio finalizará cuando una vez el ultimo paciente haya completado el follow up como describe el protocolo

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

120

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)

Mentioned in the protocol. Patients will receive study medication till intolerable toxicity, withdraw of consent, lost to follow up or death. After discontinuation from study drug, further treatment is left to the investigator?s discretion. No cross over from BEZ235 to BKM120 or vis versa is allowed.

Mencionado en el protocolo. Los pacientes recibirán la medicación del estudio hasta la toxicidad intolerable, retirar el consentimiento, perdieron durante el seguimiento o la muerte. Después de la interrupción del fármaco del estudio, el tratamiento adicional se deja a discreción del investigador. No cruzar la frontera desde BEZ235 de BKM120 oa la relación está permitido.

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

2012-10-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-05

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

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