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

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)

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)

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 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)

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

Malignant glioma, BRAF mutant positive, High grade glioma, Low grade glioma, Dabrafenib, Trametinib, Pediatrics, Brain neoplasma

Participants in the LGG cohort randomized to receive dabrafenib (orally, twice daily and dosed based on weight and age) in combination with trametinib (orally, once daily in combination with the first daily dose of dabrafenib and was dosed based on weight)

Participants in the LGG cohort randomized to receive active comparator chemotherapy (carboplatin and vincristine). Participants received one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy.

Participants in the HGG cohort received dabrafenib (orally, twice daily and dosed based on weight and age) and trametinib (orally, once daily in combination with the first daily dose of dabrafenib and dosed based on weight)

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.

LGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using Response Assessment in Neuro-Oncology (RANO) Criteria

Percentage of participants in the LGG cohort with a best overall confirmed Complete Response (CR) or Partial Response (PR) as assessed per RANO criteria by central independent assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Percentage of participants in the HGG cohort with a best overall confirmed CR or PR as assessed per RANO criteria by central independent assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Percentage of participants in the LGG cohort with a best overall confirmed CR or PR as assessed per RANO criteria by investigator assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

LGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Central Independent Assessment Using RANO Criteria

Time from first documented response (PR or CR) until disease progression or death as per RANO criteria. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy, were censored at the date of the last adequate tumor evaluation. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

LGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Investigator Assessment Using RANO Criteria

Time from first documented response (PR or CR) until disease progression or death as per RANO criteria. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy, were censored at the date of the last adequate tumor evaluation. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

LGG Cohort: Kaplan-Meier Progression-Free Survival (PFS) as Per Central Independent Assessment Using RANO Criteria

Time from the date of randomization to the date of first documented disease progression as per central independent review assessment using RANO criteria or death due to any cause. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation.

LGG Cohort: Kaplan-Meier Progression-Free Survival (PFS) as Per Investigator Assessment Using RANO Criteria

Time from the date of randomization to the date of first documented disease progression as per investigator assessment using RANO criteria or death due to any cause. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation.

Time from date of randomization to first documented response of CR or PR as per central independent assessment using RANO criteria. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Time from date of randomization to first documented response of CR or PR as per investigator assessment using RANO criteria. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Percentage of participants with a best overall response of CR or PR, or stable disease (SD) which lasts for 24 weeks or longer. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically. SD: Partient did not qualify for CR, PR, or progressive disease and has stable nonenhancing (T2/FLAIR) lesions on same or lower doses of corticosteroids compared with baseline scan and clinically stable status.

Percentage of participants with a best overall response of CR or PR, or stable disease (SD) which lasts for 24 weeks or longer. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically. SD: Partient did not qualify for CR, PR, or progressive disease and has stable nonenhancing (T2/FLAIR) lesions on same or lower doses of corticosteroids compared with baseline scan and clinically stable status.

OS defined as the time from the first dose to death due to any cause in the LGG cohort. 2-year OS estimate will be calculated

ORR in the HGG cohort defined as the percentage of participants in the HGG cohort with a best overall confirmed CR or PR as assessed per RANO criteria by investigator assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

HGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Central Independent Assessment Using RANO Criteria

Time from first documented response (PR or CR) until disease progression or death as per RANO criteria. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

HGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Investigator Assessment Using RANO Criteria

Time from first documented response (PR or CR) until disease progression or death as per RANO criteria. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

HGG Cohort: Kaplan-Meier Estimates of Progression Free Survival (PFS) as Per Central Independent Assessment Using RANO Criteria

Time from the date of first dose of study treatment to the date of first documented disease progression as per central independent review assessment using RANO criteria or death due to any cause. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation.

HGG Cohort: Kaplan-Meier Estimates of Progression Free Survival (PFS) as Per Investigatort Assessment Using RANO Criteria

Time from the date of first dose of study treatment to the date of first documented disease progression as per investigator assessment using RANO criteria or death due to any cause. Confidence Intervals were estimated using the Brookmeyer Crowley method. Patients who had not progressed or died or had received further anticancer therapy were censored at the date of the last adequate tumor evaluation.

Time from start date of treatment to first documented response of CR or PR as per central independent assessment using RANO criteria. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Time from start date of treatment to first documented response of CR or PR as per investigator assessment using RANO criteria. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.

Percentage of participants with a best overall response of CR or PR, or stable disease (SD) which lasts for 24 weeks or longer. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically. SD: Partient did not qualify for CR, PR, or progressive disease and has stable nonenhancing (T2/FLAIR) lesions on same or lower doses of corticosteroids compared with baseline scan and clinically stable status.

Percentage of participants with a best overall response of CR or PR, or stable disease (SD) which lasts for 24 weeks or longer. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically. SD: Partient did not qualify for CR, PR, or progressive disease and has stable nonenhancing (T2/FLAIR) lesions on same or lower doses of corticosteroids compared with baseline scan and clinically stable status.

PK parameters will be calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast).

PK parameters will be calculated by standard non-compartmental analysis. Cmax is the maximum plasma drug concentration after single dose administration

PK parameters will be calculated by standard non-compartmental analysis. AUCtau is the AUC calculated to the end of a dosing interval (tau) at steady-state

PK parameters will be calculated by standard non-compartmental analysis. Tmax is the time to reach maximum plasma concentration

PK parameters will be calculated by standard non-compartmental analysis. T1/2 is the elimination half-life

PK parameters will be calculated by standard non-compartmental analysis. Ctrough is the pre-dose plasma concentration

AUClast for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast).

Cmax for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. Cmax is the maximum plasma drug concentration after single dose administration

AUCtau for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. AUCtau is the AUC calculated to the end of a dosing interval (tau) at steady-state

Tmax for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. Tmax is the time to reach maximum plasma concentration

T1/2 for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. T1/2 is the elimination half-life

Ctrough for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)

PK parameters will be calculated by standard non-compartmental analysis. Ctrough is the pre-dose plasma concentration

HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension and Trametinib Oral Solution Based on the Palatability Questionnaire Item: Taste of the Medication Before Rinsing the Mouth

Participants who received the dabrafenib oral suspension and/or trametinib oral solution completed the respective questionnaire to evaluate the palatability of the pediatric formulations. For each study medication (dabrafenib and trametinib), the number of participants indicating 1) very good, 2) good, 3) neither good nor bad, or 4) bad for the item in the palatability questionnaire assessing the taste of the medication before rinsing the mouth with water will be provided.

HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension and Trametinib Oral Solution Based on the Palatability Assessment: After- Taste Once the Medication Was Swallowed

Participants who received the dabrafenib oral suspension and/or trametinib oral solution completed the respective questionnaire to evaluate the palatability of the pediatric formulations. For each study medication (dabrafenib and trametinib), the number of participants indicating 1) very good, 2) good, 3) neither good nor bad, or 4) bad for the item in the palatability questionnaire assessing the after-tase once the medication was swallowed will be provided

HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension and Trametinib Oral Solution Based on the Palatability Questionnaire Item: Reaction Once the Medication Was Immediately Placed Into the Mouth

Participants who received the dabrafenib oral suspension and/or trametinib oral solution completed the respective questionnaire to evaluate the palatability of the pediatric formulations. For each study medication (dabrafenib and trametinib), the number of participants indicating 1) very good, 2) good, 3) neither good nor bad, or 4) bad for the item in the palatability questionnaire assessing the reaction once the medication was immediately placed into the mouth will be provided

HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension and Trametinib Oral Solution Based on the Palatability Questionnaire Item: After Taste Once Rinsing the Mouth With Water Remained

Participants who received the dabrafenib oral suspension and/or trametinib oral solution completed the respective questionnaire to evaluate the palatability of the pediatric formulations. For each study medication (dabrafenib and trametinib), the number of participants indicating 1) very good, 2) good, 3) neither good nor bad, or 4) bad for the item in the palatability questionnaire assessing the remaining after taste once rinsing the mouth with water will be provided

The PROMIS Parent Proxy Global Health 7+2 was used to evaluate the quality of life of participants. The questionnaire included 7 items measuring the global health of the patient. 4 of the 7 items used a 5-level Likert scale with 1=poor and 5=excellent; 1 of the 7 items used a 5-level Likert scale with 1=never and 5=always; and 2 of the 7 items used a 5-level Likert scale with 1=never and 5=almost always. Global health scores ranged from 7 to 35, higher scores indicate better overall wellbeing (i.e physical, mental, and social health)

The PROMIS Parent Proxy Global Health 7+2 was used to evaluate the quality of life of participants. The questionnaire included 1 item measuring the pain of the participants. Pain item used a 5-level Likert scale with 1= never and 5= almost always, higher scores indicate worsening pain

The PROMIS Parent Proxy Global Health 7+2 was used to evaluate the quality of life of participants. The questionnaire included 1 item measuring the fatigue interference of the participants. Fatigue item used a 5-level Likert scale with 1= never and 5= almost always, higher scores indicate worsening fatigue

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Shahid S, Kushner BH, Modak S, Basu EM, Rubin EM, Gundem G, Papaemmanuil E, Roberts SS. Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma. Pediatr Blood Cancer. 2021 Oct;68(10):e29265. doi: 10.1002/pbc.29265. Epub 2021 Jul 31.