NCT02684058

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

Phase II Open-label Global Study to Evaluate the Effect 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)

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 151 (actual)
• Sponsor: Novartis Pharmaceuticals · Industry
• Sex: All
• Age: 12 Months – 17 Years
• Healthy volunteers: Not accepted

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)

Conditions

• 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

Interventions

Type	Name	Description
DRUG	Dabrafenib	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)
DRUG	trametinib	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)
DRUG	Carboplatin	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.
DRUG	Vincristine	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.

Timeline

• Start date: 2017-12-28
• Primary completion: 2021-08-23
• Completion: 2023-04-28
• First posted: 2016-02-17
• Last updated: 2023-12-13
• Results posted: 2023-05-19

Locations

57 sites across 20 countries: United States, Argentina, Australia, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Russia, Spain, Sweden, Switzerland, United Kingdom

Regulatory

• FDA-regulated drug study