E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paediatric patients with BRAF V600 mutation positive Low Grade Glioma (LGG) or relapsed or refractory High Grade Glioma (HGG)
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E.1.1.1 | Medical condition in easily understood language |
Children and adolescents with a form of brain tumor called either low-grade glioma or high-grade glioma, which are characterised by a mutation in the BRAF V600 gene |
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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 | 21.1 |
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) |
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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 |
- HGG cohort: evaluate the anti-tumor activity of dabrafenib in combination with trametinib, as measured by overall response rate (ORR) by central independent assessment using RANO criteria.
- LGG cohort: compare the anti-tumor activity of dabrafenib in combination with trametinib versus carboplatin with vincristine, as measured by overall response rate (ORR) by central independent review assessment using RANO criteria. |
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E.2.2 | Secondary objectives of the trial |
- HGG cohort: evaluate the overall response rate (ORR) by investigator assessment, duration of response (DOR), time to response (TTR), clinical benefit rate (CBR), progression-free survival (PFS) by both investigator review and central independent review, as well as overall survival (OS), and safety.
-LGG cohort: the secondary objectives related to efficacy in this study are to compare the two treatment groups with respect to the overall response rate (ORR) by investigator review, duration of response (DOR), time to response (TTR), clinical benefit rate (CBR),and progression-free survival (PFS) by both investigator review and central independent review as well as overall survival (OS), safety, and patient reported outcome (PRO).
Secondary objective for both HGG, and LGG cohort:
- evaluate the palatability of dabrafenib oral suspension and trametinib oral solution
- characterize the PK of dabrafenib and its metabolites and trametinib
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion criteria:
- Male or female between ≥ 12 months and <18 years of age at the time of signing the informed consent form
-Diagnosis of BRAF V600 mutant High Grade glioma that has relapsed, progressed or failed to respond to frontline therapy
-Diagnosis of BRAF V600 mutant Low Grade glioma with progressive disease following surgical excision, or non-surgical candidates with necessity to begin first systemic treatment because of a risk of neurological impairment with progression.
-Confirmed measurable disease
Additional protocol-related inclusion criteria may apply |
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E.4 | Principal exclusion criteria |
-Previous treatment with dabrafenib, trametinib, other RAF inhibitor, other MEK or ERK inhibitor
-HGG patient: Cancer treatment within the past 3 weeks. LGG patient: Any systemic therapy or radiotherapy prior to enrollment
-LGG patients: history of allergic reaction or contraindications to the use of carboplatin or vincristine
-Stem cell transplant within the past 3 months
-History of heart disease
-Pregnant or lactating females
Additional protocol-related exclusion criteria may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
- HGG cohort: Overall Response Rate (ORR) as determined by central independent assessment based on Magnetic resonance imaging MRI) or CT (CAT) scans using Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
- LGG cohort: ORR as determined by blinded central independent
assessment based on MRI or CT scans using RANO criteria. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within the first 32 weeks of treatment |
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E.5.2 | Secondary end point(s) |
HGG cohort:
- ORR as determined by investigator assessment based on Magnetic resonance imaging (MRI) or CT (CAT)scans using Response Assessment in Neuro-Oncology (RANO criteria)
-Incidence of Adverse events (AEs) and serious AE (SAEs) reported during treatment with dabrafenib and trametinib in this population.
- Assess the safety of dabrafenib and trametinib in this population through monitoring changes in vital signs.
-Abnormal lab values: Assess the safety of dabrafenib and trametinib in this
population through hematology, chemistry and urinalysis tests.
-Changes in Eelectrocardiodiagram (ECG) values: Assess the safety of dabrafenib and trametinib in this population through changes in ECG values.
- Assess the safety of dabrafenib and trametinib in this
patient population through changes in ECHO results.
HGG and LGG cohorts:
- Duration of Response (DOR) as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria
- Time to response (TTR) as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria
- Overall Survival (OS) as defined as the time from first dose to death due to any cause
- Progression-free survival PFS as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria
- Palatability questionnaire data for DRB suspension and TMT solution
-Evaluate clinical benefit rate (CBR) by investigator and central independent review
LGG cohort:
- overall response rate (ORR) as determined by investigator assessment based on MRI or CT scans using RANO criteria
- PROMIS parent proxy scale to estimate differences between treatment groups
- Incidence of AEs and SAEs reported during treatment with dabrafenib and trametinib as compared to chemotherapy
-OS as defined as the time from the first dose to death due to any cause
-Assess the safety of dabrafenib and trametinib in this population as compared to chemotherapy through
-- monitoring changes in vital signs.
-- hematology, chemistry and urinalysis tests (abnormal lab values)
-- changes in ECG values
-- changes in ECHO results
Patients on DRB+TMT:
- Area under the curve (AUClast) assessed from time zero to the last measurable sampling time
- Area under the curve (AUCtau) calculated to the end of a dosing interval at steady state (12 hours)
- Maximum plasma concentration (Cmax): the maximum (peak) observed plasma drug concentration after a single dose
- The time to reach maximum (peak) concentration (Tmax)of study drug after a single dose
- The elimination half-life (T1/2) associated with the terminal slope of a semi-log concentration-time curve
- Predose plasma concentration (Ctrough) measured at the end of a dosing interval at steady state, taken directly before next study drug administration. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR: Within the first 32 weeks of treatment
DOR: Within the first year of treatment
TTR: Within the first year of treatment
CBR: Within the first 24 weeks of treatment
OS: 2 years from last patient dosed
PFS: within 4 months of treatment
AUClast, AUCtau, Cmax, Tmax, Elimination half-life, Ctrough: Within the first month of treatment
AEs, SAEs, Vital signs:, Abnormal lab values, ECG and ECHO: From first dose to end of treatment (EOT)
ORR: Within the first 32 weeks of treatment
Palatability of pediatric formulations: Within the first 5 weeks of treatment
PROMIS Parent Proxy scale: Within the first 32 weeks of treatment
OS in LGG cohort: 2 years from first dose |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Australia |
Brazil |
Canada |
Japan |
Russian Federation |
United States |
Belgium |
Denmark |
Finland |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
Switzerland |
United Kingdom |
Czechia |
Argentina |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 22 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |