Clinical Trials Register

Summary
EudraCT Number:	2011-000874-67
Sponsor's Protocol Code Number:	NO25390
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-13
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

2011-000874-67

A.3

Full title of the trial

An open-label, multicenter, single-arm, Phase I dose-escalation with efficacy tail extension study of vemurafenib (RO5185426) in pediatric patients with surgically incurable and unresectable Stage IIIC or Stage IV melanoma harboring BRAFV600 mutations

ESTUDIO EN FASE I, ABIERTO, MULTICÉNTRICO, CON INCREMENTO DE DOSIS, DE UN SOLO GRUPO Y CON SEGUIMIENTO DE LA EFICACIA QUE EVALUARÁ EL VEMURAFENIB (RO5185426) EN NIÑOS Y ADOLESCENTES CON MELANOMA EN ESTADIO IIIC O IV QUIRÚRGICAMENTE INCURABLE E IRRESECABLE QUE PRESENTA MUTACIONES BRAFV600

A.3.1

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

Clinical Study To Evaluate the Recommended Dose, Safety, Pharmacokinetics and Efficacy of vemurafenib (RO5185426) in Paediatric Patients 12 to 17 Years Old With BRAFV600 Mutation Positive

ESTUDIO PARA EVALUAR LA DOSIS RECOMENDADA Y CON SEGUIMIENTO DE LA EFICACIA, SEGURIDAD Y FARMACOCINÉTICA DE VEMURAFENIB (RO5185426) EN NIÑOS PACIENTE PEDIATRICOS DE 12 A 17 AÑOS CON MUTACIONES BRAFV600

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

NO25390

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/91/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F. Hoffman-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	CH-4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	NANANANA
B.5.5	Fax number	NANANANA
B.5.6	E-mail	global.rochegenentechtrials@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	Yes
D.2.1.1.1	Trade name	Zelboraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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	Zelboraf
D.3.2	Product code	RO5185426/F20
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	Vemurafenib
D.3.9.1	CAS number	918504-65-1
D.3.9.2	Current sponsor code	RO5185426-006
D.3.9.3	Other descriptive name	RG7204, PLX4032
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	240
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	Yes
D.2.1.1.1	Trade name	Zelboraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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	Zelboraf
D.3.2	Product code	RO5185426/F22
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Yes
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	Vemurafenib
D.3.9.1	CAS number	918504-65-1
D.3.9.2	Current sponsor code	RO5185426-006
D.3.9.3	Other descriptive name	RG7204, PLX4032
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	120
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

Metastatic Melanoma

Melanoma Metastásico

E.1.1.1

Medical condition in easily understood language

Metastatic Melanoma

Melanoma Metastásico

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
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

Dose-escalation phase: To estimate the MTD and to identify the recommended dose of vemurafenib in pediatric patients aged 12 through 17 years with newly diagnosed or recurrent unresectable Stage IIIC or Stage IV BRAF mutation?positive melanoma

Fase de incremento escalonado de la dosis:
Objetivos secundarios determinar la DMT e identificar la dosis recomendada de vemurafenib en niños y adolescentes de 12 a 17 años con melanoma en estadio IIIC o IV recién diagnosticado o recidivante con mutación de BRAF

E.2.2

Secondary objectives of the trial

Dose-escalation and extension phases: To describe the pharmacokinetics of vemurafenib in pediatric patients aged 12 through 17 years with BRAF mutation?positive newly diagnosed unresectable Stage IIIC or Stage IV or recurrent melanoma

Dose-escalation and extension phases: To evaluate the safety and tolerability of vemurafenib using NCI CTCAE v4.0 in pediatric patients aged 12 through 17 years with newly diagnosed or recurrent BRAF
mutation?positive unresectable Stage IIIC or Stage IV melanoma

Dose-escalation and extension phases: To evaluate the efficacy of vemurafenib in patients treated at the recommended dose using investigator-assessed BORR, based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v.1.1), PFS, OS, and clinical benefit
rate (CBR)

Fases de incremento escalonado de la dosis y de extensión: describir la farmacocinética de vemurafenib en niños y adolescentes de 12 a 17 años con melanoma en estadio IIIC o IV recién diagnosticado o recidivante e irresecable con mutación de BRAF

Fases de incremento escalonado de la dosis y de extensión: evaluar la seguridad y tolerabilidad de vemurafenib aplicando los CTCAE del NCI v4.0 en niños y adolescentes de 12 a 17 años con melanoma en estadio IIIC o IV recién diagnosticado o recidivante e irresecable con mutación de BRAF
Fases de incremento escalonado de la dosis y de extensión: evaluar la eficacia de vemurafenib en pacientes tratados con la dosis recomendada empleando la TMRG determinada por el investigador, basándose en los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST v.1.1), la SSP, la SG y la tasa de beneficio clínico (TBC)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with histologically confirmed surgically incurable and unresectable stage IIIC or stage IV (AJCC) melanoma. Unresectable stage IIIC disease must have confirmation from a surgical oncologist.
2.Patients must have a positive BRAF mutation result determined by a Roche-designated central reference laboratory using the cobas® 4800 BRAF V600 Mutation Test prior to administration of vemurafenib.
3.Patients may have newly diagnosed melanoma or have completed and failed prior standard of care regimen (e.g., DTIC, temozolomide, etc.).
4.Measurable disease according to RECIST criteria Version 1.1
5. Must have a head CT/MRI to evaluate for CNS metastasis within 28 days prior to treatment. Patients with radiographically stable, asymptomatic previously treated lesions are eligible provided:
-Patient has received prior treatment [including radiation therapy (whole brain radiotherapy is not allowed with the exception of patients who have also had definitive resection or stereotactic therapy of all radiologically detectable parenchymal lesions), stereotactic radiosurgery, surgical resection] to the site(s) of CNS metastatic disease ? 3 months prior to starting study treatment
-Patient has no requirement for glucocorticoids, and discontinued ? 21 days prior to starting study treatment
- Patient is not taking anticonvulsants (discontinued at least 3 weeks prior to treatment)
6.Patients aged ? 12 to ? 17 years
7.Performance Status: Karnofsky performance score of 50-100 (for patients ?16 years of age) or Lansky score of ? 60 (for patients < 16 years of age)
8.Patients must have recovered from effects of any major surgery or significant traumatic injury at least 14 days prior to administration of the first dose of study treatment.
9.Life expectancy > 3 months.
10. Adequate hematologic, renal and liver function as defined by laboratory values performed within 28 days prior to initiation of dosing.
11.Completed baseline skin exam by a dermatologist for cutaneous squamous cell carcinoma. Exam must be negative or if, suspected cutaneous SCC lesions are identified they must be excised, and there must be adequate wound healing prior to study treatment.

1. Pacientes con melanoma en estadio IIIC o estadio IV (AJCC) confirmado mediante examen histológico y quirúrgicamente incurable e irresecable; un cirujano oncológico debe confirmar el tumor en estadio IIIC no resecable.
2. Los pacientes deben tener un resultado positivo de mutación de BRAF determinado por un laboratorio central designado por Genentech/Roche, empleando el análisis de mutaciones Cobas® 4800 BRAF V600 antes de administrar vemurafenib.
3. Los pacientes pueden presentar un melanoma recién diagnosticado o haber finalizado un tratamiento habitual previo (p. ej., DTIC, temozolomida, etc.) sin respuesta.
4. Pacientes de ?12 a ?17 años de edad.
5. Enfermedad mensurable según los criterios RECIST v1.1
6. Esperanza de vida >3 meses.
7. Los pacientes deben someterse a una TC/RM craneal para detectar metástasis en el sistema nervioso central [SNC] en los 28 días previos al tratamiento. Podrán participar pacientes con lesiones asintomáticas y estables en el estudio radiológico que se hayan tratado anteriormente siempre que:
? Hayan recibido tratamiento (como radioterapia [no se permite la radioterapia de todo el encéfalo, con la excepción de los pacientes que se hayan sometido también a resección definitiva o tratamiento estereotáctico de todas las lesiones del parénquima radiológicamente detectables], radiocirugía estereotáctica y resección quirúrgica) en las zonas de metástasis en el SNC ? 3 meses antes de iniciar el tratamiento del estudio.
? El paciente no necesite glucocorticoides, y estos medicamentos se han suspendido ?21 días antes del comienzo del tratamiento del estudio.
? El paciente no esté tomando antiepilépticos (se han suspendido al menos 3 semanas antes del tratamiento).
8. Estado funcional: puntuación del estado funcional de Karnofsky de 50?100 (en los pacientes ?16 años) o puntuación de Lansky ?60 (en los pacientes <16 años).
9. Los pacientes deben haberse recuperado de los efectos de cualquier intervención quirúrgica mayor o traumatismo importante al menos 14 días antes de la administración de la primera dosis del medicamento del estudio.
10. Los pacientes deben tener una función adecuada de los órganos y la médula ósea, según lo indicado por los valores analíticos obtenidos en los 28 días previos al comienzo de la administración del medicamento
11. Examen inicial de la piel por un dermatólogo en busca de CECcu; el examen debe ser negativo o, si se detectan lesiones sospechosas de CECcu, hay que extirparlas, y la herida debe cicatrizar adecuadamente antes del tratamiento del ensayo.

E.4

Principal exclusion criteria

1.Patients with active or untreated CNS lesions
2.History of or known spinal cord compression, or carcinomatous meningitis.
3.Negative result for BRAF mutation as determined using the cobas® 4800 BRAF V600 Mutation Test
4.Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study.
5.Patients with a previous malignancy within the past 5 years are excluded except for patients with basal or squamous cell carcinoma (SCC) of the skin, melanoma in-situ, and carcinoma in-situ of the cervix.
6.Patients who have been previously treated with a selective/specific BRAF or MEK inhibitor (previous treatment with sorafenib is allowed).
7.Patients who have had any previous treatment with study drug (vemurafenib) or participated in a clinical trial that includes vemurafenib.
8.QTc >450 msec on screening ECG or history of congential long QT syndrome.
9.NCI-CTCAE Version 4.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
10.Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension, cerebrovascular accident or transient ischemic attack, or
symptomatic pulmonary embolism.
11.Known clinically significant active infection at the time of study treatment start, at the time of screening or within 14 days of study drug start.
12.History of allogeneic bone marrow transplantation or organ transplantation.
of the investigator would make the patient inappropriate for entry into this study.
13.Known HIV positivity or AIDS-related illness, or active HBV, and
active HCV.

1. Pacientes con lesiones activas o no tratadas en el SNC.
2. Antecedente o existencia de compresión de la médula espinal o meningitis carcinomatosa.
3. Ausencia de mutación de BRAF en el análisis de mutaciones Cobas® 4800 BRAF V600.
4. Administración prevista o en curso de tratamientos antineoplásicos distintos de los fármacos del estudio
5. No podrán participar pacientes con una neoplasia maligna previa durante los 5 años anteriores, salvo aquellos que presenten carcinoma basocelular o espinocelular de la piel, melanoma in situ y carcinoma in situ del cuello uterino.
6. Pacientes tratados anteriormente con un inhibidor selectivo/específico de BRAF o MEK (se permite el tratamiento previo con sorafenib).
7. Pacientes que hayan recibido anteriormente el medicamento del estudio (vemurafenib) o que hayan participado en un ensayo clínico con vemurafenib.
8. QTc ?450 ms en el ECG de la selección, antecedente de síndrome congénito de QT largo o alteraciones electrolíticas que no se corrijan.
9. Hemorragia de grado 3 según los CTCAE del NCI v4.0 en las 4 semanas previas al comienzo del tratamiento del estudio.
10. Cualquiera de lo siguiente en los 6 meses previos a la administración del medicamento del estudio: infarto de miocardio, angina grave/inestable, injerto de derivación arterial coronaria/periférica, insuficiencia cardíaca congestiva sintomática, arritmia cardíaca grave con necesidad de medicación, hipertensión no controlada, accidente cerebrovascular o accidente isquémico transitorio, o embolia pulmonar sintomática.
11. Infección activa y clínicamente importante conocida en el momento del inicio del tratamiento con el medicamento del estudio, en el momento de la selección o en los 14 días siguientes al comienzo de la medicación.
12. Antecedente de alotrasplante de médula ósea o de trasplante de órganos.
13. Existencia de positividad del VIH o de enfermedad relacionada con el SIDA, hepatitis B activa o hepatitis C activa.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable for this study is the rate of best overall response (BORR) assessed by the investigators according to the RECIST criteria (Version. 1.1). The BORR is defined as the number of patients whose best objective response is complete response (CR) or partial response (PR) divided by the total number of intent-to-treat patients. intent-to-treat patients are defined in 8.2.1. Patients with no post baseline tumor assessments and have not died will be considered as non-responders.

La variable de eficacia primaria para este estudio es la tasa de mejor respuesta global (TMRG) evaluado por los investigadores de acuerdo con los criterios de RECIST (VERSION. 1,1). La TMRG se define como el número de pacientes cuya mejor respuesta objetiva es la respuesta completa (CR) o respuesta parcial (PR), dividido por el número total de intención de tratar a los pacientes. pacientes por intención de tratar, se definen en 8.2.1. Los pacientes sin evaluaciones del tumor después de línea de base y que no hayan muerto serán considerados como no respondedores.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline total tumor burden must be assessed within a maximum of 4 weeks before first dose of study drug treatment. The first post start of treatment tumor assessment is scheduled at week 4. Subsequent tumor assessments will be performed every 8 weeks for the first 12 cycles and every 12 weeks, thereafter until disease progression, death due to any cause, unacceptable toxicity, discontinuation from the study. If at anytime during treatment phase there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled assessment, an unscheduled tumor assessment should be performed

El volumen tumoral total inicial se determinará en las 4 semanas (como máximo) anteriores a la administración de la primera dosis del tratamiento del estudio. la primera valoración del tumor una vez iniciado el tratamiento se realizará a las 4 semanas.Las valoraciones posteriores del tumor se llevarán a cabo cada 8 semanas durante los 12 primeros ciclos y luego cada 12 semanas, hasta progresión de la enfermedad, muerte o toxicidad inaceptable o discontinuación del tratamiento.Si en cualquier momento durante la fase de tratamiento hay sospecha de progresión de la enfermedad basada en los hallazgos clínicos o de laboratorio antes de la próxima evaluación programada, se debe realizar una evaluación del tumor no programada

E.5.2

Secondary end point(s)

Clinical benefit rate (CBR), PFS, OS, and duration of response.

Ratio del beneficio clínico (TBC), SLE, SG o duración de la respuesta

E.5.2.1

Timepoint(s) of evaluation of this end point

CBR and Duration of Response: Baseline total tumor burden must be assessed within a maximum of 4 weeks before first dose of study drug treatment. The first post start of treatment tumor assessment is scheduled at week 4. Subsequent tumor assessments will be performed every 8 weeks for the first 12 cycles and every 12 weeks, thereafter until disease progression, death due to any cause, unacceptable toxicity, discontinuation from the study.
PFS: Interval between the day of first treatment and the first documentation of progressive disease or death.
OS: Time from the date of first treatment to the date of death

CBR y Duración de la respuesta: la carga tumoral total de línea de base debe ser evaluada dentro de un máximo de 4 semanas antes de la primera dosis del tratamiento del fármaco del estudio. La primera apertura después de la evaluación de tumor el tratamiento está previsto en la semana 4. Evaluaciones tumorales siguientes se llevaron a cabo cada 8 semanas durante los primeros 12 ciclos y cada 12 semanas, a partir de entonces hasta la progresión de la enfermedad, la muerte por cualquier causa, toxicidad inaceptable, la interrupción del estudio.
PFS: Intervalo entre el día del primer tratamiento y la primera documentación de progresión de la enfermedad o la muerte.
OS: Tiempo desde la fecha del primer tratamiento a la fecha de la muerte

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

Yes

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

tolerability, exploratory - biomarkers

Tolerabilidad y biomarcadores exploratorios

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

Phase I dose-escalation with an efficacy tail extension trial of vemurafenib in pediatric patients

Fase I escalada de dosis con estudio de extensión de eficacia de vemurafenib en pacientes pediátrico

E.7.2

Therapeutic exploratory (Phase II)

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