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Trametinib

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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)

trametinib

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.

Novartis Pharmaceuticals

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 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)

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)

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

Percentage of participants 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. This analysis was conducted at the end of the trial (after the primary endpoint analysis cut-off date) and includes a longer follow-up time

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% confidence intervals (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.

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.

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.

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 randomization to first documented response of CR or PR as per central independent assessment using RANO criteria. CIs were estimated using the Brookmeyer Crowley method. Patients without an event were censored either at the maximum follow-up time (if they experienced disease progression or death), or at their last tumor assessment date.

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 randomization to first documented response of CR or PR as per investigator assessment using RANO criteria. CIs were estimated using the Brookmeyer Crowley method. Patients without an event were censored either at the maximum follow-up time (if they experienced disease progression or death), or at their last tumor assessment date.

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.

Time from first dose to death due to any cause in the LGG cohort. Confidence Intervals were estimated using the Brookmeyer Crowley method. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact.

OS was defined as the time from the first dose to death due to any cause in the LGG cohort. The 2-year Kaplan-Meier OS estimate represented the estimated percentage of participants remaining free from OS events for up to 2 years. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact

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.

Time from first documented response (PR or CR) until disease progression or death as per central independent assessment using RANO criteria. CIs 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.

Time from first documented response (PR or CR) until disease progression or death as per investigator assessment using RANO criteria. CIs 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.

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.

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 of treatment to first documented response of CR or PR as per independent assessment using RANO criteria. CIs were estimated using the Brookmeyer Crowley method. Patients without an event were censored either at the maximum follow-up time (if they experienced disease progression or death), or at their last tumor assessment date.

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 of treatment to first documented response of CR or PR as per investigator assessment using RANO criteria. CIs were estimated using the Brookmeyer Crowley method. Patients without an event were censored either at the maximum follow-up time (if they experienced disease progression or death), or at their last tumor assessment date.

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.

Pharmacokinetic (PK) parameters were 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 were calculated by standard non-compartmental analysis. Cmax is the maximum plasma drug concentration after single dose administration

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

PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum plasma concentration. Actual recorded sampling times were considered for the calculations.

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

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

PK parameters were 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).

Participants who received the dabrafenib dispersible tablets for oral suspension completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on how it tasted before rinsing with water, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the trametinib oral solution completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on how it tasted before rinsing with water, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the dabrafenib dispersible tablets for oral suspension completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the after-taste of the medication after the medication was swallowed, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the trametinib oral solution completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the after-taste of the medication after the medication was swallowed, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the dabrafenib dispersible tablets for oral suspension completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the immediate reaction once the medication was placed into their mouth, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the trametinib oral solution completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the immediate reaction once the medication was placed into their mouth, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the dabrafenib dispersible tablets for oral suspension completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the after-taste of the medication after rinsing with water, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

Participants who received the trametinib oral solution completed a questionnaire to evaluate the palatability of the pediatric formulation. After taking the medication, participants provided feedback on the after-taste of the medication after rinsing with water, rating their experience as very good, good, neither good nor bad, bad or very bad. The ratings of very good, good, and neither good nor bad were grouped together for reporting purposes.

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 items used a 5-level Likert scale with 1=poor and 5=excellent; 1 item used a 5-level Likert scale with 1=never and 5=always; and 2 items used a 5-level Likert scale with 1=never and 5=almost always. The total raw global health score, ranging from 7 to 35, was computed by summing item values, with higher scores indicating better overall well-being. Raw scores were then transformed into T-scores, standardized with a mean of 50 and a standard deviation of 10. Higher T-scores reflected better global health status.

Participants who discontinued treatment for reasons other than disease progression entered the post-treatment efficacy follow-up phase, where the questionnaire was performed every 16 weeks until disease progression, withdrawal of consent by patient or a parental/legal guardian, or lost to follow-up.

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. Raw scores were then converted into T-scores, standardized with a mean of 50 and a standard deviation of 10. Higher T-scores indicated more severe pain experiences.

Participants who discontinued treatment for reasons other than disease progression entered the post-treatment efficacy follow-up phase, where the PROMIS Parent Proxy Global 7+2 Health questionnaire was performed every 16 weeks until disease progression, withdrawal of consent by patient or a parental/legal guardian, or lost to follow-up.

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. Raw scores were then converted into T-scores, standardized with a mean of 50 and a standard deviation of 10. Higher T-scores indicated a greater level of reported fatigue.

Participants who discontinued treatment for reasons other than disease progression entered the post-treatment efficacy follow-up phase, where the PROMIS Parent Proxy Global 7+2 Health questionnaire was performed every 16 weeks until disease progression, withdrawal of consent by patient or a parental/legal guardian, or lost to follow-up.

Deaths in the post treatment follow-up period are not considered Adverse Events. The total number at risk in the post treatment includes patients that entered the post treatment follow-up period (post-treatment efficacy and/or survival follow-up). Analysis performed in the safety set including participants who received at least one dose of study treatment. None of the patients who crossed-over were included in the crossover post-treatment efficacy/survival follow-up.

AEs collected during on-treatment period with dabrafenib and trametinib in the HGG cohort (up to 30 days post- treatment)

HGG Cohort: Dabrafenib and Trametinib (On-treatment)

Deaths collected in the post- treatment follow-up period for participants in the HGG cohort treated with dabrafenib and trametinib (starting from day 31 post- treatment). No AEs were collected during this period

HGG Cohort: Dabrafenib and Trametinib (Post-treatment Follow-up)

AEs collected during on-treatment period with dabrafenib and trametinib in the LGG cohort (up to 30 days post- treatment)

LGG Cohort: Dabrafenib and Trametinib (On-treatment)

Deaths collected in the post- treatment follow-up period for participants in the LGG cohort treated with dabrafenib and trametinib (starting from day 31 post- treatment). No AEs were collected during this period

LGG Cohort: Dabrafenib and Trametinib (Post-treatment Follow-up)

AEs collected during on-treatment period with carboplatin and vincristine in the LGG cohort (up to 30 days post- treatment or start date of crossover treatment, whichever was earlier)

LGG Cohort: Carboplatin and Vincristine (On-treatment)

Deaths collected in the post- treatment follow-up period (starting from day 31 post- treatment) for participants in the LGG cohort treated with carboplatin and vincristine. No AEs were collected during this period

LGG Cohort: Carboplatin and Vincristine (Post-treatment Follow-up)

AEs collected during crossover on-treatment period with dabrafenib and trametinib for participants in the LGG cohort randomized to carboplatin and vincristine who crossedover to dabrafenib and trametinib after disease progression (up to 30 days post- crossover treatment)

LGG Cohort: Carboplatin and Vincristine (Crossover On-treatment)

Deaths collected in the crossover post- treatment follow-up period (starting from day 31 post- crossover treatment) for participants in the LGG cohort treated with carboplatin and vincristine who crossed over to dabrafenib and trametinib. No AEs were collected during this period

LGG Cohort: Carboplatin and Vincristine (Crossover Post-treatment Follow-up)

LGG Cohort: Dabrafenib and Trametinib

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 were allowed to crossover to dabrafenib and trametinib after centrally confirmed and RANO-defined disease progression.

LGG Cohort: Carboplatin and Vincristine

HGG Cohort: Dabrafenib and Trametinib

Total

Age, Categorical

Sex: Female, Male

Race/Ethnicity, Customized

Study director

All participants on the LGG cohort to whom study treatment had been assigned by randomization regardless of whether or not treatment was administered. According to the intent to treat principle, patients were analyzed according to the treatment they had been assigned to during the randomization procedure.

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

All participants on the HGG cohort to whom study treatment had been assigned and who received at least one dose of study treatment.

HGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria

Up to approx. 3 years

Up to approx. 4.2 years

LGG Cohort: ORR by Investigator Assessment Using RANO Criteria

Up to approx 4.2 years

Participants on the LGG cohort to whom study treatment had been assigned by randomization regardless of whether or not treatment was administered with a confirmed CR or PR as per central independent review assessment using RANO criteria. According to the intent to treat principle, patients were analyzed according to the treatment they had been assigned to during the randomization procedure.

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

Participants on the LGG cohort to whom study treatment had been assigned by randomization regardless of whether or not treatment was administered with a confirmed CR or PR as per investigator review assessment using RANO criteria. According to the intent to treat principle, patients were analyzed according to the treatment they had been assigned to during the randomization procedure.

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

Participants on the LGG cohort to whom study treatment had been assigned by randomization regardless of whether or not treatment was administered. According to the intent to treat principle, patients were analyzed according to the treatment they had been assigned to during the randomization procedure.

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

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

LGG Cohort: Kaplan-Meier Estimates of Time to Response (TTR) as Per Central Independent Assessment Using RANO Criteria

LGG Cohort: Kaplan-Meier Estimates of Time to Response (TTR) as Per Investigator Assessment Using RANO Criteria

LGG Cohort: Clinical Benefit Rate (CBR) by Central Independent Assessment Using RANO Criteria

LGG Cohort: Clinical Benefit Rate (CBR) by Investigator Assessment Using RANO Criteria

LGG Cohort: Kaplan-Meier Estimates of Overall Survival (OS)

LGG Cohort: 2-year OS Estimate

Up to approx. 3.2 years

Up to approx. 4.8 years

HGG Cohort: ORR by Investigator Assessment Using RANO Criteria

Participants on the HGG cohort to whom study treatment had been assigned and who received at least one dose of study treatment with a confirmed CR or PR as per central independent assessment using RANO criteria

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

Participants on the HGG cohort to whom study treatment had been assigned and who received at least one dose of study treatment with a confirmed CR or PR as per investigator assessment using RANO criteria

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

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

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

HGG Cohort: Time to Response (TTR) as Per Central Independent Assessment Using RANO Criteria

HGG Cohort: Time to Response (TTR) as Per Investigator Assessment Using RANO Criteria

HGG Cohort: Clinical Benefit Rate (CBR) as Per Central Independent Assessment Using RANO Criteria

HGG Cohort: Clinical Benefit Rate (CBR) as Per Investigator Assessment Using RANO Criteria

HGG Cohort: Kaplan-Meier Estimates of Overall Survival (OS)

Participants who received at least one dose of trametinib with an evaluable AUClast PK parameter

AUClast for Trametinib

Participants who received at least one dose of trametinib with an evaluable Cmax PK parameter

Cmax for Trametinib

Participants who received at least one dose of trametinib with an evaluable AUCtau PK parameter

AUCtau for Trametinib

Participants who received at least one dose of trametinib with an evaluable Tmax PK parameter

Tmax for Trametinib

Participants who received at least one dose of trametinib with an evaluable T1/2 PK parameter

T1/2 for Trametinib

Participants who received at least one dose of trametinib with an evaluable Ctrough PK parameter

Ctrough for Trametinib

Carboxy-dabrafenib

Desmethyl-dabrafenib

Hydroxy-dabrafenib

Participants who received at least one dose of dabrafenib with an evaluable AUClast PK parameter

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

Participants who received at least one dose of dabrafenib with an evaluable Cmax PK parameter

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

Participants who received at least one dose of dabrafenib with an evaluable AUCtau PK parameter

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

Participants who received at least one dose of dabrafenib with an evaluable Tmax PK parameter

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

Participants who received at least one dose of dabrafenib with an evaluable T1/2 PK parameter

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

Participants who received at least one dose of dabrafenib with an evaluable Ctrough PK parameter

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

Week 1

Week 5

Participants who received at least one dose of dabrafenib as dispersible tablet for oral suspension and completed the palatability questionnaire for dabrafenib at week 1 or 5.

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

Participants who received at least one dose of trametinib oral solution and completed the palatability questionnaire for trametinib at week 1 or 5.

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

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

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

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

HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Assessment: Immediate Reaction Once the Medication Was Placed Into the Mouth

HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension Based on the Palatability Questionnaire Item: Remaining After-taste Once Rinsing the Mouth With Water

HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Assessment: Remaining After-taste Once Rinsing the Mouth With Water

Baseline

Week 5 Day 1

Week 8 Day 1

All participants on the LGG cohort to whom study treatment had been assigned by randomization (regardless of whether or not treatment was administered) and contributed to this analysis. According to the intent to treat principle, patients were analyzed according to the treatment they had been assigned to during the randomization procedure.

Number analyzed indicated number of participants with available data for this outcome measure at the specified timepoints.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT02684058	Diffuse Astrocy... Anaplastic Astr... Astrocytoma Oligodendroglio... Anaplastic Olig... Glioblastoma Pilocytic Astro... Giant Cell Astr... Pleomorphic Xan... Anaplastic Pleo... Angiocentric Gl... Chordoid Glioma... Gangliocytoma Ganglioglioma Anaplastic Gang... Dysplastic Gang... Desmoplastic In... Papillary Glion... Rosette-forming... Central Neurocy... Extraventricula... Cerebellar Ipon...	Dabrafenib trametinib Carboplatin Vincristine	12 Months - 17 Years	Novartis
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	NCT02684058	Diffuse Astrocy... Anaplastic Astr... Astrocytoma Oligodendroglio... Anaplastic Olig... Glioblastoma Pilocytic Astro... Giant Cell Astr... Pleomorphic Xan... Anaplastic Pleo... Angiocentric Gl... Chordoid Glioma... Gangliocytoma Ganglioglioma Anaplastic Gang... Dysplastic Gang... Desmoplastic In... Papillary Glion... Rosette-forming... Central Neurocy... Extraventricula... Cerebellar Ipon...	Dabrafenib trametinib Carboplatin Vincristine	12 Months - 17 Years	Novartis

Spots Global Cancer Trial Database for cerebellar iponeurocytoma