| 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)
|
| Pazienti pediatrici con glioma ad alto grado recidivante o refrattario positivo per mutazione di BRAF V600 |
|
| 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 |
| Bambini e adolescenti con glioma ad alto grado recidivante o refrattario positivo per mutazione di 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. |
| Valutare l’attività antitumorale di dabrafenib in combinazione con trametinib misurata tramite il tasso di risposta generale (Overall Response Rate – ORR) alla terapia in combinazione definita dallo sperimentatore utilizzando i criteri 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. Valutare la ORR tramite revisione indipendente centralizzata
2. Valutare la durata della risposta (Duration Of Response - DOR) tramite revisione da parte dello sperimentatore e revisione
indipendente centralizzata
3. Valutare il tempo alla risposta (Time To Response – TTR) tramite revisione da parte dello sperimentatore e revisione indipendente centralizzata
4. Valutare la sopravvivenza libera da progressione (Progression Free Survival – PFS) tramite revisione da parte dello sperimentatore e revisione indipendente centralizzata
5. Valutare la sopravvivenza globale (Overall Survival – OS)
6. Valutare il profilo di sicurezza di dabrafenib in combinazione con trametinib nella popolazione in studio
7. Caratterizzare la farmacocinetica di dabrafenib, i suoi metaboliti e di trametinib nella popolazione in studio |
|
| 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/μL;
-Platelets ≥75,000/μL 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. |
- Pazienti di sesso maschile o femminile di età compresa tra ≥ 6 e <18 anni.
- Diagnosi confermata istologicamente di glioma ad alto grado (HGG) (glioma di Grado III o IV in base al sistema di classificazione istologica WHO, revisione 2016), compreso xantoastrocitoma pleomorfo anaplastico (anaplastic Pleomorphic Xanthoastrocytoma -
aPXA) e ganglioglioma anaplastico.
- Malattia recidivante, in progressione o che non ha risposto alla terapia di prima linea.
- Tumore positivo per mutazione di BRAF V600 come determinato a livello locale utilizzando metodi molecolari in un laboratorio approvato CLIA o equivalente, o presso un laboratorio centralizzato di riferimento designato da Novartis su richiesta.
- Malattia misurabile determinata a livello locale e confermata a livello centralizzato.
- Disponibilità di tessuto tumorale (di archivio o fresco) da fornire per il test confermatorio centralizzato dell’istopatologia dell’HGG e dello stato mutazionale BRAF.
- Punteggio Karnofsky/Lansky di performance ≥50%.
- Adeguata funzionalità del midollo osseo in assenza di supporto del fattore di crescita.
- Adeguata funzionalità renale, funzionalità epatica e funzionalità cardiaca.
- Pazienti in grado di deglutire le capsule; i pazienti devono avere un peso corporeo ≥16 kg se di età inferiore ai 12 anni, oppure ≥19 kg se di età ≥12 anni.
- Se in trattamento con glucocorticoidi, i pazienti devono essere in trattamento a dose stabile o nella fase di riduzione del dosaggio da almeno 7 giorni prima della prima somministrazione del trattamento in 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). |
- Patologia maligna DIVERSA da HGG con mutazione BRAF V600.
- Pregresso trattamento con dabrafenib o altro inibitore RAF, trametinib o altro inibitore MEK o un inibitore ERK.
- Terapia antitumorale (chemioterapia con tossicità ritardata, immunoterapia, terapia biologica, terapia vaccinale) o farmaci
sperimentali nelle 3 settimane precedenti la prima somministrazione di trattamento in studio.
- Radioterapia alle lesioni SNC del glioma nei 3 mesi precedenti la prima somministrazione del trattamento in studio, a meno che non vi sia chiara evidenza di progressione radiologica al di fuori del campo di radiazione.
- Anamnesi di patologia maligna con mutazione attivante RAS confermata o con fusione di BRAF quale BRF-KIAA1549.
- Attuale uso di un farmaco o di una preparazione erboristica proibiti oppure necessità di assumere tali trattamenti durante lo studio. Fare riferimento alla Sezione 6.4 del protocollo per i dettagli.
- Tossicità non risolta superiore a grado 2 in base alla classificazione NCI CTCAE v 4.03 da pregressa terapia antitumorale, compreso intervento chirurgico maggiore, ad eccezione di quelli che a giudizio dello sperimentatore non sono clinicamente rilevanti dati il profilo di sicurezza/tossicità noto del trattamento in studio (ad es. alopecia e/o neuropatia periferica correlata a chemioterapia a base di platino o alcaloidi della Vinca).
- Anamnesi di reazioni allergiche attribuite a composti di composizione chimica o biologica simile a dabrafenib, trametinib e loro eccipienti.
- Trapianto autologo o allogenico di cellule staminali nei 3 mesi precedenti la prima somministrazione di trattamento in studio
[NOTA: i pazienti con evidenza di malattia attiva da trapianto contro l’ospite sono esclusi indipendentemente dal tempo trascorso].
- Anamnesi o attuale diagnosi di patologia cardiaca che indica un rischio significativo di sicurezza per i pazienti partecipanti allo
studio, come patologia cardiaca non controllata o significativa.
- Condizioni mediche non controllate (ad es. diabete mellito, ipertensione, patologia epatica o infezione non controllata),
condizioni psicologiche, familiari, sociologiche o geografiche che non consentono l’aderenza al protocollo; oppure indisponibilità o
incapacità di seguire le procedure richieste nel protocollo.
- Presenza di patologia gastrointestinale attiva o altra condizione (ad es. resezione dell’intestino tenue o dell’intestino crasso) che
interferiscono in modo significativo con l’assorbimento dei farmaci.
- Anamnesi di infezione da virus dell’epatite B o virus dell’epatite C (i pazienti con evidenza di laboratorio dell’eliminazione del virus dell’epatite B/virus dell’epatite C possono essere arruolati nello studio).
- Donne potenzialmente fertili, definite come tutte le donne fisiologicamente in grado di iniziare una gravidanza (ad es. che hanno
il ciclo mestruale), a meno che non utilizzino metodi contraccettivi di efficacia elevata durante la somministrazione del trattamento
in studio e per 4 mesi dopo l’interruzione del farmaco in studio. Nota: i metodi contraccettivi ormonali non sono consentiti a causa
delle potenziali interazioni farmaco-farmaco con dabrafenib.
- Donne in gravidanza o allattamento.
- Uomini sessualmente attivi a meno che non utilizzino il preservativo durante lo studio e per 12 settimane dopo l’interruzione del trattamento in studio e che acconsentano a non concepire un figlio durante questo 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, proporzione di pazienti con la best overall confirmed Complete Response (CR) o la Partial Response (PR) sulla base del parere dello sperimentatore mediante criteri valutati con Response Assessment in Neuro-Oncology (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. |
I pazienti verranno esaminati allo screening (prima dell’inizio del trattamento in studio) ed ogni 8 settimane per il primo anno di trattamento, ed ogni 16 settimane successivamente per valutare
l’efficacia di trattamento mediante i criteri 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. ORR mediante valutazione indipendente centralizzata secondo i criteri RANO
2.DOR, calcolato come il tempo dalla data del primo confirmed Complete Response (CR) o Partial Response (PR) o dalla morte dovuta a qualunque causa, valutata separatamente dagli sperimentatori e dal revisore indipendente centrale secondo i criteri RANO.
3. TTR, calcolato come il tempo dalla data di inizio del trattamento di studio al primo CR o PR (che deve essere confermato successivamente) come valutato separatamente dallo sperimentatore e dal revisore indipendente centrale secondo i criteri RANO.
4. PFS, definito come il tempo dalla prima dose di trattamento allo studio fino alla progressione o la morte per qualsiasi causa, valutata separatamente dallo sperimentatore e dal revisore indipendente centrale secondo i criteri RANO.
5. OS, definito come il tempo dalla prima dose di trattamento di studio a morte per qualsiasi causa
6. Incidenza di AE e SAE, variazioni in risultati del laboratorio, segni vitali, ECG e ECHO
7. Profili di concentrazione nel tempo di dabrafenib nel plasma, dei suoi metaboliti e di trametinib e PK |
|
| 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. |
I pazienti verranno esaminati allo screening (prima dell’inizio del
trattamento in studio) ed ogni 8 settimane per il primo anno di trattamento, ed ogni 16 settimane successivamente per valutare
l’efficacia di trattamento mediante i criteri 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
| No |
| 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 | 3 |
| 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 | 0 |
| 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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