Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors
Condition: Diffuse Astrocytoma; Anaplastic Astrocytoma; Astrocytoma; Oligodendroglioma, Childhood; Anaplastic Oligodendroglioma; Glioblastoma; Pilocytic Astrocytoma; Giant Cell Astrocytoma; Pleomorphic Xanthoastrocytoma; Anaplastic Pleomorphic Xanthoastrocytoma; Angiocentric Glioma; Chordoid Glioma of Third Ventricle; Gangliocytoma; Ganglioglioma; Anaplastic Ganglioglioma; Dysplastic Gangliocytoma of Cerebrellum; Desmoplastic Infantile Astrocytoma and Ganglioglioma; Papillary Glioneuronal Tumor; Rosette-forming Glioneurona Tumor; Central Neurocytoma; Extraventricular Neurocytoma; Cerebellar Iponeurocytoma
MeSH terms: Neoplasms; Glioblastoma; Glioma; Astrocytoma; Oligodendroglioma; Ganglioglioma; Neurocytoma; Ganglioneuroma
Intervention: Dabrafenib; trametinib; Carboplatin; Vincristine
Intervention description: Dabrafenib was available as 50 mg and 75 mg hard capsules and as 10 mg dispersible tablets for oral suspension. Dabrafenib was administered orally, twice daily, and was dosed based on age and weight Patients < 12 years old and ≥ 16 kg were to be administered either the dabrafenib capsules or dabrafenib dispersible tablets for oral suspension (dose: 5.25 mg/kg/day) Patients ≥ 12 years old and ≥ 19 kg were to be administered either the dabrafenib capsules or dabrafenib dispersible tablets for oral suspension (dose: 4.5 mg/kg/day) Patients < 12 years old and < 16 kg were to be administered dabrafenib dispersible tablets for oral suspension (dose: 5.25 mg/kg/day) Patients ≥12 years old and <19 kg were to be administered dabrafenib dispersible tablets for oral suspension (dose: 4.5 mg/kg/day); Trametinib was available as 0.5 mg and 2 mg film-coated tablets and as 5.0 mg powder in bottle for oral solution (0.05 mg/ml after reconstitution with 90 ml water).Trametinib was administered orally, once daily in combination with the first daily dose of dabrafenib and was dosed based on age and weight.
Patients <6 years old and <26 kg were to be administered the trametinib oral solution (dose: 0.032 mg/kg/day) Patients <6 years old and ≥26 kg were to be administered either the trametinib oral solution or trametinib tablets (dose: 0.032 mg/kg/day) Patients ≥6 years old and ≥10 kg < 33 kg were to be administered the trametinib oral solution (dose: 0.025 mg/kg/day) Patients ≥6 years old and ≥33 kg were to be administered either the trametinib oral solution or the trametinib tablets (dose: 0.025 mg/kg/day); Carboplatin was supplied locally as commercially available and labelled accordingly to comply with legal requirements of each country. Carboplatin was administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy. Each maintenance cycle was 6 weeks, and consisted of 4 weeks of chemotherapy with 2 weeks of rest.
Induction: 175 mg/m^2 as weekly intravenous (IV) infusion on weeks 1 to 4, and on weeks 7 to 10, on the same day as vincristine dosing Maintenance: 175 mg/m^2 as weekly IV infusion over 60 minutes on weeks 1 to 4 of each cycle.; Vincristine was supplied locally as commercially available and labelled accordingly to comply with legal requirements of each country. Vincristine was administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy.
Induction: 1.5 mg/m^2 as weekly IV bolus infusion (0.05 mg/kg if child is <12 kg) (maximum dose of 2.0 mg) for 10 weeks.
Maintenance: 1.5 mg/m^2 as weekly IV bolus infusion (0.05 mg/kg if child is <12 kg) (maximum dose of 2.0 mg) on weeks 1 to 3 of each cycle, on the same day as carboplatin dosing.
Intervention MeSH terms: Carboplatin; Vincristine; Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 151.0
Sex: All
Minimum age: 12 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Malignant glioma; BRAF mutant positive; High grade glioma; Low grade glioma; Dabrafenib; Trametinib; Pediatrics; Brain neoplasma

Summary:

      The purpose of this study was to investigate the activity of dabrafenib in combination with
      trametinib in children and adolescent patients with BRAF V600 mutation positive low grade
      glioma (LGG) or relapsed or refractory high grade glioma (HGG)
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Diagnosis of BRAF V600 mutant High Grade glioma that had 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

        Key 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