| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paediatric patients with BRAF V600 mutation positive relapsed or refractory High Grade Glioma (HGG) |
| Pacientes pediatricos con Glioma de Alto Grado (HGG) recidivante o refractario con mutación BRAF V600 positiva |
|
| E.1.1.1 | Medical condition in easily understood language |
| Children and adolescents with a form of brain tumor called high-grade glioma, which is characterised by a mutation in the BRAF V600 gene |
| Niños o adolescentes con un tipo de tumor cerebral llamado Glioma de Alto Grado, que se caracteriza por una mutación en gen BRAF V600. |
|
| 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 | 10065443 |
| E.1.2 | Term | Malignant glioma |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the anti-tumor activity of dabrafenib in combination with trametinib, as measured by overall response rate (ORR) to the combination therapy by investigator assessment using the RANO criteria. |
| El objetivo principal es evaluar la actividad antitumoral de dabrafenib en combinación con trametinib determinado mediante la tasa de respuesta global (ORR) de la terapia combinada mediante evaluación por el investigador utilizando los criterios RANO. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate ORR by central independent review
2. Evaluate duration of response (DOR) by investigator and central independent review
3. Evaluate time to response (TTR) by investigator and central independent review
4. Evaluate progression free survival (PFS) by investigator and central independent review
5. Evaluate overall survival (OS)
6. Evaluate the safety profile of dabrafenib in combination with trametinib in children and adolescents
7. Characterize the pharmacokinetics of dabrafenib, its metabolites and trametinib in the study population |
1. Evaluar ORR mediante revisión independiente central
2. Evaluar la duración de la respuesta (DOR) por el investigador y mediante revisión independiente central
3. Evaluar el tiempo hasta la respuesta (TTR) por el investigador y mediante revisión independiente centra
4. Evaluar la supervivencia libre de progresión (PFS) por el investigador y mediante revisión independiente central
5. Evaluar la supervivencia global (OS)
6. Evaluar el perfil de seguridad de dabrafenib en combinación con trametinib en la población del estudio
7. Caracterizar la farmacocinética de dabrafenib, sus metabolitos y trametinib en la población del estudio |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Key Inclusion criteria:
- Male or female between >/= 6 and <18 years of age at the time of signing the informed
consent form
- Relapsed, progressed, or failed to respond to frontline therapy. Frontline therapy is
presumed to be optimal surgical approach (biopsy or resection) with radiation and/or
chemotherapy.
- Histologically confirmed diagnosis of High Grade Glioma (Grade III or IV glioma as
defined by WHO histological classification system, revised 2016, see Appendix 4),
including anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic
gangliogliomas.
- Locally determined and centrally confirmed measurable disease with minimal biperpendicular diameter that must be at least twice the imaging slice thickness to be used for efficacy assessments. (Both local and centrally confirmed results must show
measurable disease to meet eligibility)
- BRAF V600 mutation-positive tumor as locally determined using molecular methods in a
CLIA-approved laboratory or equivalent, or at a Novartis designated central reference
laboratory upon request
- Tumor tissue (newly obtained or archival paraffin blocks/slides) must be available and
subsequently provided to Novartis for central confirmatory testing of HGG histopathology
and BRAF mutational status.
- Performance score of >/=50% according to the Karnofsky/Lansky performance status scale
- Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum
pregnancy test within 7 days prior to day 1
- Must have adequate bone marrow function in the absence of growth factor support and is defined as:
-Absolute neutrophil count (ANC) >/=1000/microL;
-Platelets >/=75,000/mmL and transfusion independent, defined as not receiving platelet
transfusions within a 7 day period prior to meeting this enrollment criteria
-Hemoglobin >/=8.0 g/dL (may receive red blood cell transfusions)
- Adequate renal function defined as:
-Calculated eGFR (Schwartz formula, http://www.medcalc /pedigfr.html), or
radioisotope GFR >/=90 mL/min/1.73 m2; or
-A serum creatinine within the testing lab reference range (for age/gender, if available)
- Adequate liver function defined as:
-Bilirubin (sum of conjugated + unconjugated) </=1.5 x upper limit of normal (ULN)
for age
-AST and ALT </=2.5 x ULN
- Adequate cardiac function defined as:
-LVEF greater than or equal to institutional LLN by ECHO (while not receiving
medications for cardiac function)
-Corrected QT (QTcF) interval </=480 msecs.
- Able to swallow capsules:
-If less than 12 years old, must be >/= 16kg body weight
-If ≥ 12 years old, must be >/= 19kg body weight
- If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to the first dose of study treatment.
- Written informed consent/assent must be obtained prior to any protocol specific screening procedures being performed. |
Criterios de inclusión clave:
- Ambos sexos >/=6 y < 18 años de edad.
- Diagnóstico histológicamente confirmado de Glioma de Alto Grado (glioma de Grado III o IV según la definición del sistema de clasificación histológica de la OMS, revisado 2016), incluyendo xantoastrocitoma pleomórfico anaplásico (aPXA) y ganglioglioma anaplásico.
- Enfermedad recidivante, que haya progresado, o sin respuesta a la terapia de primera línea.
- Tumor positivo a mutación BRAF V600, determinado localmente utilizando métodos moleculares en un laboratorio aprobado CLIA o equivalente, o en un laboratorio de referencia central designado por Novartis bajo solicitud.
- Enfermedad medible determinada localmente y confirmada centralmente.
- Debe proporcionarse tejido tumoral (de archivo o de nueva obtención) para análisis confirmatorio central de histopatología HGG y estadio de la mutación BRAF.
- Puntuación de estado funcional de Karnofsky/Lansky >/=50%.
- Función de la médula ósea adecuada en ausencia de soporte con factor de crecimiento.
- Función renal, función hepática, y función cardiaca adecuadas.
- Debe ser capaz de tragar cápsulas; debe tener un peso >/= 16 kg si tiene menos de 12 años, o >/=19 kg si tiene >/= 12 años.
- Si está recibiendo glucocorticosteroides, el paciente debe estar con una dosis estable o en proceso de disminución de dosis durante al menos 7 días antes de la primera dosis del tratamiento del studio. |
|
| E.4 | Principal exclusion criteria |
- Malignancy OTHER than BRAF V600 mutant HGG.
- Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
inhibitor, or ERK inhibitor.
- Cancer therapy (chemotherapy with delayed toxicity, immunotherapy, biologic therapy,
vaccine therapy) or investigational drugs within 3 weeks preceding the first dose of study
treatment.
- Radiotherapy to CNS glioma lesions within 3 months prior to first dose of study treatment, unless there is clear evidence of radiologic progression outside of the field of radiation.
- History of malignancy with confirmed activating RAS mutation or with BRAF fusion
such as BRF-KIAA1549. Note: Prospective RAS testing is not required. However, if the
results of previous RAS testing are known, they must be used in assessing eligibility.
- Current use of a prohibited medication or herbal preparation or requires any of these
medications during the study. See Section 6.4 for details.
- Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 from previous anti-cancer
therapy, including major surgery, except those that in the opinion of the investigator are
not clinically relevant given the known safety/toxicity profile of the study treatment (e.g.,
alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based
chemotherapy).
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib, trametinib and their excipients.
- Autologous or allogeneic stem cell transplant within 3 months prior to the first dose of
study treatment
- History or current diagnosis of cardiac disease indicating significant risk of safety for
patients participating in the study such as uncontrolled or significant cardiac disease,
including any of the following:
recent myocardial infarction (within last 6 months),
uncontrolled congestive heart failure,
unstable angina (within last 6 months),
clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g.,
sustained ventricular tachycardia, and clinically significant second or third degree AV
block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to
the first dose of study treatment
coronary angioplasty or stenting (within last 6 months)
intra-cardiac defibrillators
abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram
(patients with grade 1 abnormalities can be enrolled on study. Patients with moderate valvular thickening should NOT be enrolled)
- Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or
uncontrolled infection), psychological, familial, sociological, or geographical conditions
that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol
- Presence of active GI disease or other condition (e.g., small bowel or large bowel
resection) that will interfere significantly with the absorption of drugs.
- A history of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory
evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant (e.g. are menstruating), unless they are using highly effective methods of contraception during dosing of study treatment and for 4 months after stopping study medication. Effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or bilateral tubal ligation or tubal occlusion at least
six weeks before taking study treatment. In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.
Male sterilization (at least 6 months prior to screening). For female patients on the
study, the vasectomized male partner should be the sole partner for that patient.
Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS)
with a documented failure rate of less than 1% per year. Double-barrier contraception:
condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal
spermicidal agent (foam/gel/cream/suppository). |
Criterios de exclusión clave:
- Neoplasia DISTINTA de HGG BRAF V600 mutado.
- Tratamiento previo con dabrafenib u otro inhibidor RAF, trametinib u otro inhibidor MEK, o un inhibidor ERK.
- Terapia para el cáncer (quimioterapia con toxicidad retardada, inmunoterapia, terapia biológica, terapia con vacuna) o fármacos en investigación en las 3 semanas anteriores a la primera dosis del tratamiento del estudio.
- Radioterapia para lesiones de glioma del SNC en los 3 meses previos a la primera dosis del tratamiento del estudio, a menos que exista evidencia clara de progresión radiológica fuera del campo de radiación.
- Historia de neoplasia con mutación RAS activadora confirmada o con fusión BRAF como BRF-KIAA1549.
- Uso actual de una medicación prohibida o preparación a base de hierbas o precisa alguna de estas medicaciones durante el estudio. Ver el Apartado 6.4 para detalles.
- Toxicidad no resuelta superior al grado 2 del NCI CTCAE v 4.03 de una terapia anti-cáncer previa, incluyendo cirugía mayor, excepto los que en opinión del investigador no sean clínicamente relevantes dado el perfil conocido de seguridad/toxicidad del tratamiento del estudio (p.ej., alopecia y/o neuropatía periférica relacionada con quimioterapia basada en platino o alcaloides de la vinca).
- Antecedentes de reacciones alérgicas atribuidas a compuestos de composición química o biológica similar a dabrafenib, trametinib y sus excipientes.
- Trasplante autólogo o alogénico de células hematopoyéticas en los 3 meses previos a la primera dosis del tratamiento del estudio [NOTA: se excluyen los pacientes con evidencia de enfermedad de injerto contra huésped activa independientemente del tiempo transcurrido]
- Antecedentes o diagnóstico actual de enfermedad cardiaca que indique un riesgo significativo de seguridad para los pacientes que participan en el estudio como enfermedad cardiaca no controlada o significativa.
- Condiciones médicas no controladas (p.ej., diabetes mellitus, hipertensión, enfermedad hepática o infección no controlada), condiciones psicológicas, familiares, sociológicas, o geográficas que no permitan el cumplimiento con el protocolo; o que no quieran o sean incapaces de seguir los procedimientos exigidos en el protocolo.
- Presencia de enfermedad GI activa y otra condición (p.ej., resección del intestino delgado o intestino grueso) que interferirá significativamente con la absorción de los fármacos.
- Antecedentes de infección por Virus de la Hepatitis B o Virus de la Hepatitis C (los pacientes con evidencia analítica de Virus de la Hepatitis B y/o Virus de la Hepatitis C eliminado, pueden ser reclutados).
- Mujeres en edad fértil, definidas como toda mujer psicológicamente capaz de quedar embarazada (p.ej., que estén con la menstruación), a menos que estén utilizando métodos anticonceptivos de elevada eficacia durante la administración de la dosis del tratamiento del estudio y durante 4 meses después de suspender la medicación del estudio. Nota: métodos anticonceptivos hormonales no están permitidos debido a las posibles interacciones farmacológicas con dabrafenib.
- Mujeres que estén embarazadas o en periodo de lactancia activa.
- Hombres sexualmente activos a menos que utilicen un preservativo durante el coito mientras estén en el estudio y durante 12 semanas después de suspender el tratamiento del estudio, y acepten no engendrar un hijo durante este periodo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR, proportion of patients with a best overall confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria. |
| ORR, Respuesta Completa (CR) o Respuesta Parcial (PR) mediante evaluación por el investigador utilizando los criterios RANO. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will be assessed at screening (before initiation of study treatment) and every 8 weeks for the first year on treatment, and every 16 weeks thereafter for efficacy using RANO criteria. |
| Los pacientes sera evaluados en la visita de preselección (antes del inicio del tratamiento del studio) y cada 8 semanas durante el primer año de tratamiento y cada 16 semanas posteriormente para la eficacia usando los criterios de RANO. |
|
| E.5.2 | Secondary end point(s) |
1. ORR by central independent review assessment per RANO criteria
2. DOR, calculated as the time from the date of the first documented confirmed response (CR or PR) to the first documented progression or death due to any cause, as assessed separately by investigator and central independent reviewer per RANO criteria.
3. TTR, calculated as the time from the start date of study treatment to first documented confirmed response CR or PR (which must be confirmed subsequently) as assessed separately by investigator and independent central reviewer per RANO criteria
4. PFS, defined as time from first dose of study treatment to progression or death due to any cause, as assessed separately by central independent reviewer and investigator per RANO criteria
5. OS, defined as the time from first dose of study treatment to death due to any cause
6. Incidence of adverse events and serious adverse events, changes in laboratory results, vital signs, ECG and ECHO
7. Plasma concentration-time profiles of dabrafenib, its metabolites and trametinib and PK parameters |
1. Evaluar ORR mediante revisión independiente central
2. Evaluar la duración de la respuesta (DOR) por el investigador y mediante revisión independiente central
3. Evaluar el tiempo hasta la respuesta (TTR) por el investigador y mediante revisión independiente centra
4. Evaluar la supervivencia libre de progresión (PFS) por el investigador y mediante revisión independiente central
5. Evaluar la supervivencia global (OS)
6. Evaluar el perfil de seguridad de dabrafenib en combinación con trametinib en la población del estudio
7. Caracterizar la farmacocinética de dabrafenib, sus metabolitos y trametinib en la población del estudio |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be assessed at screening (before initiation of study treatment) and every 8 weeks for the first year on treatment, and every 16 weeks thereafter for efficacy using RANO criteria. |
| Los pacientes serán evaluados en la visita de preselección (antes del inicio del tratamiento del studio) y cada 8 semanas durante el primer año de tratamiento y cada 16 semanas después para la eficacia ultilizando los criterios RANO. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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