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
Study type: Interventional
Phase: Phase 2

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)
    

Detailed description: 
      This study combines two pediatric glioma cohorts (LGG and HGG cohorts) into a multi-center,
      open-label, Phase II study:

        -  The LGG cohort is a multi-center, randomized, open-label part of this Phase II study
           conducted in children and adolescent patients with BRAF V600 mutation-positive LGG whose
           tumor was unresectable and who required first systemic treatment. Participants in the
           LGG cohort were randomized in a 2:1 ratio to either dabrafenib plus trametinib or
           carboplatin with vincristine.

        -  The HGG cohort is a multi-center, single-arm, open-label part of this Phase II study
           conducted in children and adolescent patients with BRAF V600 mutation-positive,
           refractory or relapsed HGG tumors after having received at least one previous standard
           therapy.

      The duration of treatment for participants on dabrafenib plus trametinib in LGG and for all
      patients in the HGG cohort was continued until the loss of clinical benefit in the opinion of
      the Investigator, unacceptable toxicity, start of a new anti-neoplastic therapy,
      discontinuation at the discretion of the investigator or patient/legal guardian, lost to
      follow-up, death, study termination by the sponsor, or until disease progression. The
      duration of treatment for patients in the carboplatin with vincristine arm in LGG cohort was
      continued for the prescribed number of cycles, as tolerated or until unacceptable toxicity,
      start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator
      or patient/legal guardian, lost to follow-up, death, study is terminated by the sponsor or
      until disease progression. Participants randomized to the carboplatin with vincristine
      treatment arm were allowed to cross over to receive dabrafenib in combination with trametinib
      after centrally confirmed RANO-defined disease progression. Crossover was allowed during the
      treatment period or the post-treatment period.

      After discontinuation of study treatment, all participants (LGG and HGG cohorts) were
      followed for safety for at least 30 days after the last dose of study treatment. All
      participants who discontinued study treatment for reasons other than disease progression,
      death, loss to follow up, or withdrawal of consent moved into the post-treatment efficacy
      follow-up phase. Finally, all participants were followed for survival once they discontinued
      study treatment for at least 2 years after the last patient first study treatment (except if
      consent was withdrawn, death, or the patient was lost to follow-up or discontinued study)
    

Intervention name(s): Dabrafenib; trametinib; Carboplatin; Vincristine
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.
Other intervention name(s): DRB436; TMT212
Intervention MeSH terms: Carboplatin; Vincristine; Trametinib; Dabrafenib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malignant glioma; BRAF mutant positive; High grade glioma; Low grade glioma; Dabrafenib; Trametinib; Pediatrics; Brain neoplasma