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Clinical Trial Results:
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)

Summary
EudraCT number	2015-004015-20
Trial protocol	GB SE CZ DE ES IT FI DK FR NL BE
Global end of trial date	28 Apr 2023

Results information
Results version number	v2(current)
This version publication date	13 Mar 2024
First version publication date	11 Nov 2023
Other versions	v1
Version creation reason	Correction of full data set Updated to align with CT.gov results disclosure form

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CDRB436G2201

ISRCTN number

US NCT number

NCT02684058

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

28 Apr 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Apr 2023

Was the trial ended prematurely?

Main objective of the trial

LGG cohort: Compare the anti-tumor activity of dabrafenib in combination with trametinib versus carboplatin with vincristine, as measured by Overall Response Rate (ORR) by central independent assessment using the Response Assessment in Neuro-Oncology (RANO) criteria. HGG cohort: Evaluate the anti-tumor activity of dabrafenib in combination with trametinib, as measured by ORR by central independent assessment using the RANO criteria.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Dec 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 3

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Czechia: 3

Country: Number of subjects enrolled

Denmark: 5

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Israel: 2

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Japan: 17

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Russian Federation: 5

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

United States: 21

Worldwide total number of subjects

151

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 58 centers across 20 countries

Screening details

Pediatric patients for both cohorts were screened for eligibility during the 28 days immediately prior to starting study treatment on Day 1. In the HGG cohort, 46 patients were screened of whom 41 patients entered the HGG cohort

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

LGG cohort: dabrafenib and trametinib

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

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)

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

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.

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet, Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

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)

LGG cohort: carboplatin and vincristine

Arm description

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.

Arm type

Active comparator

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

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.

HGG cohort: dabrafenib and trametinib

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet, Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine	HGG cohort: dabrafenib and trametinib
Started	73	37	41
Treated	73	33	41
Completed	56	14	17
Not completed	17	23	24
Adverse event, serious fatal	-	-	2
Physician decision	5	1	2
Adverse event, non-fatal	3	8	1
Protocol deviation	-	1	-
Progressive disease	4	10	19
New therapy for study indication	1	-	-
Subject/guardian decision	4	3	-

Baseline characteristics

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Reporting group title

LGG cohort: dabrafenib and trametinib

Reporting group description

Reporting group title

LGG cohort: carboplatin and vincristine

Reporting group description

Reporting group title

HGG cohort: dabrafenib and trametinib

Reporting group description

Reporting group values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine	HGG cohort: dabrafenib and trametinib	Total
Number of subjects	73	37	41	151
Age Categorical
Units: Participants
<=18 years	73	37	41	151
Between 18 and 65 years	0	0	0	0
>=65 years	0	0	0	0
Sex: Female, Male
Units: Participants
Female	44	22	23	89
Male	29	15	18	62
Race/Ethnicity, Customized
Units: Subjects
White	55	25	25	105
Asian	5	3	11	19
Black Or African American	2	3	1	6
Not Reported	2	1	1	4
Unknown	6	4	3	13
Other	3	1	0	4

End points

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Reporting group title

LGG cohort: dabrafenib and trametinib

Reporting group description

Reporting group title

LGG cohort: carboplatin and vincristine

Reporting group description

Reporting group title

HGG cohort: dabrafenib and trametinib

Reporting group description

Primary: LGG cohort: Overall response rate (ORR) by central independent assessment using Response Assessment in Neuro-Oncology (RANO) criteria

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End point title

LGG cohort: Overall response rate (ORR) by central independent assessment using Response Assessment in Neuro-Oncology (RANO) criteria ^[1]

End point description

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.

End point type

Primary

End point timeframe

Up to approximately (approx.) 3 years

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)	46.6 (34.8 to 58.6)	10.8 (3.0 to 25.4)

LGG cohort: ORR analysis

Comparison groups

LGG cohort: dabrafenib and trametinib v LGG cohort: carboplatin and vincristine

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

< 0.001

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

7.19

Confidence interval

level

95%

sides

2-sided

lower limit

2.3

upper limit

22.4

Notes
[2] - one-sided p-value at 2.5% level of significance

Primary: HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria

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End point title

HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria ^[3] ^[4]

End point description

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.

End point type

Primary

End point timeframe

Up to approx. 3.2 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is reporting results for the HGG cohort arm
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Percentage of participants
number (confidence interval 95%)	56.1 (39.7 to 71.5)

No statistical analyses for this end point

Secondary: LGG cohort: ORR by investigator assessment using RANO criteria

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End point title

LGG cohort: ORR by investigator assessment using RANO criteria ^[5]

End point description

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.

End point type

Secondary

End point timeframe

Up to approx. 3 years and up to approx 4.2 years

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)
Up to approx. 3 years	54.8 (42.7 to 66.5)	13.5 (4.5 to 28.8)
Up to approx. 4.2 years	58.9 (46.8 to 70.3)	18.9 (8.0 to 35.2)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria ^[6]

End point description

Time from first documented response (PR or CR) until disease progression or death as per 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. 9999= value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 3 years and up to approx 4.2 years

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	40	6
Units: Months
median (confidence interval 95%)
Up to approx. 3 years	20.3 (12.0 to 9999)	9999 (6.6 to 9999)
Up to approx 4.2 years	30.0 (16.6 to 9999)	19.4 (6.6 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria ^[7]

End point description

End point type

Secondary

End point timeframe

Up to approx. 3 years and up to approx 4.2 years

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	43	7
Units: Months
median (confidence interval 95%)
Up to approx. 3 years	9999 (25.5 to 9999)	9999 (5.3 to 9999)
Up to approx 4.2 years	44.4 (33.1 to 9999)	22.5 (5.3 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Central Independent Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Central Independent Assessment using RANO Criteria ^[8]

End point description

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. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 3 years and up to approx 4.2 years

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Months
median (confidence interval 95%)
Up to approx. 3 years	20.1 (12.8 to 9999)	7.4 (3.6 to 11.8)
Up to approx 4.2 years	24.9 (12.9 to 31.6)	7.2 (2.8 to 11.2)

LGG cohort: PFS analysis

Statistical analysis description

Up to approx. 3 years

Comparison groups

LGG cohort: dabrafenib and trametinib v LGG cohort: carboplatin and vincristine

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.55

Notes
[9] - Log-rank test at an overall one-sided 2.5% level of significance

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Investigator Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Investigator Assessment using RANO Criteria ^[10]

End point description

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. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 3 years and up to approx 4.2 years

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Months
median (confidence interval 95%)
Up to approx. 3 years	9999 (-9999 to 9999)	9999 (12.6 to 9999)
Up to approx 4.2 years	46.0 (38.6 to 9999)	30.8 (7.0 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Central Independent Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Central Independent Assessment using RANO Criteria ^[11]

End point description

Time from randomization to first documented response (CR or PR) as per central independent assessment using RANO criteria. 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. 9999 = value was not estimable

End point type

Secondary

End point timeframe

Up to approx. 4.2 years

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Months
median (confidence interval 95%)	11.0 (6.0 to 9999)	9999 (-9999 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Investigator Assessment using RANO Criteria

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End point title

LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Investigator Assessment using RANO Criteria ^[12]

End point description

End point type

Secondary

End point timeframe

Up to approx. 4.2 years

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Months
median (confidence interval 95%)	7.4 (5.3 to 9999)	9999 (-9999 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by investigator assessment using RANO criteria

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End point title

LGG cohort: Clinical Benefit Rate (CBR) by investigator assessment using RANO criteria ^[13]

End point description

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.

End point type

Secondary

End point timeframe

Up to approx. 4.2 years

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)	91.8 (83.0 to 96.9)	56.8 (39.5 to 72.9)

No statistical analyses for this end point

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by central independent assessment using RANO criteria

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End point title

LGG cohort: Clinical Benefit Rate (CBR) by central independent assessment using RANO criteria ^[14]

End point description

End point type

Secondary

End point timeframe

Up to approx. 4.2 years

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)	86.3 (76.2 to 93.2)	43.2 (27.1 to 60.5)

No statistical analyses for this end point

Secondary: LGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

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End point title

LGG cohort: Kaplan-Meier Estimates of Overall survival (OS) ^[15]

End point description

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. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Up to 4.6 years

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Months
median (confidence interval 95%)	9999 (-9999 to 9999)	9999 (-9999 to 9999)

No statistical analyses for this end point

Secondary: LGG cohort: 2-year OS estimate

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End point title

LGG cohort: 2-year OS estimate ^[16]

End point description

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

End point type

Secondary

End point timeframe

2 years from first dose

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)	100.0 (100.0 to 100.0)	96.9 (79.8 to 99.6)

No statistical analyses for this end point

Secondary: HGG cohort: ORR by investigator assessment using RANO criteria

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End point title

HGG cohort: ORR by investigator assessment using RANO criteria ^[17]

End point description

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.

End point type

Secondary

End point timeframe

Up to approx. 3.2 years and up to approx. 4.8 years

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Percentage of participants
number (confidence interval 95%)
Up to approx. 3.2 years	58.5 (42.1 to 73.7)
Up to approx. 4.8 years	61.0 (44.5 to 75.8)

No statistical analyses for this end point

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

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End point title

HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria ^[18]

End point description

Time from first documented response (PR or CR) until disease progression or death as per central independent assessment using RANO criteria. 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. 9999=value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 3.2 years and up to approx. 4.8 years

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	23
Units: Months
median (confidence interval 95%)
Up to approx. 3.2 years	22.2 (7.6 to 9999)
Up to approx. 4.8 years	27.4 (9.2 to 9999)

No statistical analyses for this end point

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

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End point title

HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria ^[19]

End point description

Time from first documented response (PR or CR) until disease progression or death as per investigator assessment using RANO criteria. 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. 9999= value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 3.2 years and up to approx. 4.8 years

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	25
Units: Months
median (confidence interval 95%)
Up to approx. 3.2 years	26.6 (14.9 to 9999)
Up to approx. 4.8 years	32.7 (14.9 to 9999)

No statistical analyses for this end point

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Investigatort Assessment using RANO Criteria

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End point title

HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Investigatort Assessment using RANO Criteria ^[20]

End point description

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. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Months
median (confidence interval 95%)	24.0 (12.5 to 9999)

No statistical analyses for this end point

Secondary: HGG cohort: Time to response (TTR) as per Central Independent Assessment using RANO Criteria

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End point title

HGG cohort: Time to response (TTR) as per Central Independent Assessment using RANO Criteria ^[21]

End point description

Time from start of treatment to first documented response of CR or PR as per independent assessment using RANO criteria. 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. 9999= value was not estimable.

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Months
median (confidence interval 95%)	8.5 (2.0 to 9999)

No statistical analyses for this end point

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Central Independent Assessment using RANO Criteria

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End point title

HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Central Independent Assessment using RANO Criteria ^[22]

End point description

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.

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Months
median (confidence interval 95%)	9.0 (5.3 to 20.1)

No statistical analyses for this end point

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Investigator Assessment using RANO Criteria

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End point title

HGG Cohort: Clinical benefit rate (CBR) as per Investigator Assessment using RANO Criteria ^[23]

End point description

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Percentage of participants
number (confidence interval 95%)	75.6 (59.7 to 87.6)

No statistical analyses for this end point

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Central Independent Assessment using RANO Criteria

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End point title

HGG Cohort: Clinical benefit rate (CBR) as per Central Independent Assessment using RANO Criteria ^[24]

End point description

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Percentage of participants
number (confidence interval 95%)	65.9 (49.4 to 79.9)

No statistical analyses for this end point

Secondary: HGG cohort: Time to response (TTR) as per Investigator Assessment using RANO Criteria

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End point title

HGG cohort: Time to response (TTR) as per Investigator Assessment using RANO Criteria ^[25]

End point description

Time from start of treatment to first documented response of CR or PR as per investigator assessment using RANO criteria. 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. 9999 = value was not estimable

End point type

Secondary

End point timeframe

Up to approx. 4.8 years

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Months
median (confidence interval 95%)	3.4 (1.8 to 9999)

No statistical analyses for this end point

Secondary: Cmax for trametinib

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End point title

Cmax for trametinib ^[26]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	55	36
Units: ng/mL
geometric mean (geometric coefficient of variation)	22.7 ± 41.1	21.3 ± 36.3

No statistical analyses for this end point

Secondary: AUClast for trametinib

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End point title

AUClast for trametinib ^[27]

End point description

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).

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	55	36
Units: hour (hr) * nanogram (ng)/mililiter (mL)
geometric mean (geometric coefficient of variation)	328 ± 33.4	282 ± 53.7

No statistical analyses for this end point

Secondary: HGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

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End point title

HGG cohort: Kaplan-Meier Estimates of Overall survival (OS) ^[28]

End point description

End point type

Secondary

End point timeframe

Up to 5.1 years

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Months
median (confidence interval 95%)	9999 (19.8 to 9999)

No statistical analyses for this end point

Secondary: T1/2 for trametinib

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End point title

T1/2 for trametinib ^[29]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	14	24
Units: hour
geometric mean (geometric coefficient of variation)	25.7 ± 37.9	26.7 ± 62.6

No statistical analyses for this end point

Secondary: AUCtau for trametinib

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End point title

AUCtau for trametinib ^[30]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	44	33
Units: hr * ng/mL
geometric mean (geometric coefficient of variation)	339 ± 22.2	307 ± 22.8

No statistical analyses for this end point

Secondary: Tmax for trametinib

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End point title

Tmax for trametinib ^[31]

End point description

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.

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	55	36
Units: hour
geometric mean (geometric coefficient of variation)	1.53 ± 54.6	1.67 ± 58.1

No statistical analyses for this end point

Secondary: Ctrough for trametinib

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End point title

Ctrough for trametinib ^[32]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	55	36
Units: ng/ml
geometric mean (geometric coefficient of variation)	9.82 ± 30.1	8.73 ± 72.7

No statistical analyses for this end point

Secondary: AUClast for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

AUClast for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[33]

End point description

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).

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	54	34
Units: hr * ng/ml
geometric mean (geometric coefficient of variation)
Dabrafenib	4870 ± 60.3	4330 ± 44.7
Carboxy-dabrafenib	64200 ± 46.9	73400 ± 31.5
Desmethyl-dabrafenib	3870 ± 68.2	3520 ± 60.2
Hydroxy-dabrafenib	2980 ± 50.1	2810 ± 36.5

No statistical analyses for this end point

Secondary: Cmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

Cmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[34]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	54	34
Units: ng/ml
geometric mean (geometric coefficient of variation)
Dabrafenib	1330 ± 93.5	1520 ± 65.9
Carboxy-dabrafenib	7210 ± 51.6	9050 ± 31.4
Desmethyl-dabrafenib	377 ± 67.2	388 ± 67.2
Hydroxy-dabrafenib	687 ± 82.6	801 ± 58.8

No statistical analyses for this end point

Secondary: AUCtau for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

AUCtau for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[35]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	47	34
Units: hr * ng/ml
geometric mean (geometric coefficient of variation)
Dabrafenib (n= 34 / 47)	4910 ± 54.0	4300 ± 44.7
Carboxy-dabrafenib (n= 29 / 47)	60700 ± 45.7	71200 ± 34.0
Desmethyl-dabrafenib (n= 27 / 44)	3660 ± 66.9	3360 ± 57.7
Hydroxy-dabrafenib (n= 33 / 47)	2960 ± 47.4	2840 ± 35.7

No statistical analyses for this end point

Secondary: Tmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

Tmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[36]

End point description

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.

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	54	34
Units: hr
geometric mean (geometric coefficient of variation)
Dabrafenib	1.47 ± 52.9	1.47 ± 54.2
Carboxy-dabrafenib	3.66 ± 51.4	3.37 ± 35.4
Desmethyl-dabrafenib	2.29 ± 82.0	2.21 ± 76.7
Hydroxy-dabrafenib	1.68 ± 57.8	1.97 ± 45.9

No statistical analyses for this end point

Secondary: T1/2 for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

T1/2 for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[37]

End point description

PK parameters were calculated by standard non-compartmental analysis. T1/2 is the elimination half-life. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	18	33
Units: hr
geometric mean (geometric coefficient of variation)
Dabrafenib (n= 33 / 18)	3.09 ± 36.4	2.48 ± 36.6
Carboxy-dabrafenib (n= 20 / 8)	6.59 ± 43.9	7.12 ± 32.3
Desmethyl-dabrafenib (n= 3 / 1)	16.1 ± 9999	7.06 ± 392.5
Hydroxy-dabrafenib (n= 20 / 10)	3.52 ± 71.7	2.66 ± 47.8

No statistical analyses for this end point

Secondary: Ctrough for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

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End point title

Ctrough for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib) ^[38]

End point description

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

End point type

Secondary

End point timeframe

Week 3 Day 1 pre-dose

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	54	34
Units: ng/ml
geometric mean (geometric coefficient of variation)
Dabrafenib	46.0 ± 125.1	38.0 ± 162.0
Carboxy-dabrafenib	3190 ± 54.4	3980 ± 46.1
Desmethyl-dabrafenib	310 ± 70.1	275 ± 116.5
Hydroxy-dabrafenib	44.3 ± 99.7	41.8 ± 123.8

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability questionnaire item: taste of the medication before rinsing the mouth

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End point title

HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability questionnaire item: taste of the medication before rinsing the mouth ^[39]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	32	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	18	5
Week 5\|Very good, good, and neither good nor bad	20	6
Week 1\|Bad	4	2
Week 5\|Bad	1	0
Week 1\|Very bad	0	0
Week 5\|Very bad	1	0
Week 1\|Unable to answer question	5	0
Week 5\|Unable to answer question	2	0
Week 1\|Missing	5	1
Week 5\|Missing	8	2

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability questionnaire item: taste of the medication before rinsing the mouth

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End point title

HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability questionnaire item: taste of the medication before rinsing the mouth ^[40]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	35	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	15	2
Week 5\|Very good, good, and neither good nor bad	12	5
Week 1\|Bad	5	3
Week 5\|Bad	6	0
Week 1\|Very bad	2	0
Week 5\|Very bad	2	0
Week 1\|Unable to answer question	4	1
Week 5\|Unable to answer question	1	0
Week 1\|Missing	9	2
Week 5\|Missing	14	3

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability assessment: after- taste once the medication was swallowed

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End point title

HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability assessment: after- taste once the medication was swallowed ^[41]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	32	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	13	4
Week 5\|Very good, good, and neither good nor bad	16	5
Week 1\|Bad	6	1
Week 5\|Bad	2	0
Week 1\|Very bad	0	0
Week 5\|Very bad	0	0
Week 1\|Unable to answer question	3	0
Week 5\|Unable to answer question	3	0
Week 1\|Missing	10	3
Week 5\|Missing	11	3

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: after- taste once the medication was swallowed

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End point title

HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: after- taste once the medication was swallowed ^[42]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	35	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	15	3
Week 5\|Very good, good, and neither good nor bad	16	5
Week 1\|Bad	5	3
Week 5\|Bad	3	0
Week 1\|Very bad	2	0
Week 5\|Very bad	1	0
Week 1\|Unable to answer question	2	0
Week 5\|Unable to answer question	2	0
Week 1\|Missing	11	2
Week 5\|Missing	13	3

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[43]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	32	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	13	4
Week 5\|Very good, good, and neither good nor bad	18	5
Week 1\|Bad	5	1
Week 5\|Bad	1	0
Week 1\|Very bad	1	0
Week 5\|Very bad	0	0
Week 1\|Unable to answer question	3	0
Week 5\|Unable to answer question	2	0
Week 1\|Missing	10	3
Week 5\|Missing	11	3

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: immediate reaction once the medication was placed into the mouth

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End point title

HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: immediate reaction once the medication was placed into the mouth ^[44]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	35	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	15	3
Week 5\|Very good, good, and neither good nor bad	15	5
Week 1\|Bad	4	3
Week 5\|Bad	4	0
Week 1\|Very Bad	3	0
Week 5\|Very Bad	2	0
Week 1\|Unable to answer question	2	0
Week 5\|Unable to answer question	1	0
Week 1\|Missing	11	2
Week 5\|Missing	13	3

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability questionnaire item: remaining after-taste once rinsing the mouth with water

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End point title

HGG and LGG cohort: Palatability of dabrafenib oral suspension based on the palatability questionnaire item: remaining after-taste once rinsing the mouth with water ^[45]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving dabrafenib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	32	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	15	4
Week 5\|Very good, good, and neither good nor bad	17	6
Week 1\|Bad	5	2
Week 5\|Bad	2	0
Week 1\|Very bad	0	0
Week 5\|Very bad	1	0
Week 1\|Unable to answer question	7	1
Week 5\|Unable to answer question	4	0
Week 1\|Missing	5	1
Week 5\|Missing	8	2

No statistical analyses for this end point

Secondary: HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: remaining after-taste once rinsing the mouth with water

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End point title

HGG and LGG cohort: Palatability of trametinib oral solution based on the palatability assessment: remaining after-taste once rinsing the mouth with water ^[46]

End point description

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.

End point type

Secondary

End point timeframe

Week 1 and Week 5

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for all arms receiving trametinib

End point values	LGG cohort: dabrafenib and trametinib	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	35	8
Units: Participants
Week 1\|Very good, good, and neither good nor bad	15	2
Week 5\|Very good, good, and neither good nor bad	14	4
Week 1\|Bad	3	2
Week 5\|Bad	2	0
Week 1\|Very Bad	2	0
Week 5\|Very Bad	2	0
Week 1\|Unable to answer question	6	2
Week 5\|Unable to answer question	3	1
Week 1\|Missing	9	2
Week 5\|Missing	14	3

No statistical analyses for this end point

Secondary: LGG cohort: PROMIS Parent Proxy Global Health 7+2 scores- Global health score

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End point title

LGG cohort: PROMIS Parent Proxy Global Health 7+2 scores- Global health score ^[47]

End point description

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. 9999 indicates that the value was not estimable

End point type

Secondary

End point timeframe

Baseline, and Day 1 of Week 5, 8, 16, 24, 32, 49, 48 and 56, and thereafter every 16 weeks until end of treatment (EOT), EOT, and every 16 weeks in the post-treatment efficacy follow-up phase until disease progression (assessed up to 4.6 years)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	61	23
Units: Score on a Scale
arithmetic mean (standard deviation)
Baseline (n= 61 / 23)	42.67 ± 10.068	42.89 ± 10.502
Week 5 Day 1 (n= 50 / 18)	42.14 ± 9.439	39.06 ± 10.109
Week 8 Day 1 (n= 53 / 18)	43.83 ± 9.461	38.36 ± 7.759
Week 16 Day 1 (n= 48 / 10)	44.68 ± 9.159	41.11 ± 10.798
Week 24 Day 1 (n= 46 / 10)	45.27 ± 9.168	36.57 ± 6.241
Week 32 Day 1 (n= 47 / 11)	45.46 ± 8.887	40.96 ± 7.159
Week 40 Day 1 (n= 40 / 7)	45.37 ± 9.687	38.84 ± 4.960
Week 48 Day 1 (n= 43 / 10)	44.83 ± 9.421	41.56 ± 6.953
Week 56 Day 1 (n= 46 /7)	44.54 ± 8.876	38.66 ± 8.851
Week 72 Day 1 (n= 40 / 0)	44.21 ± 8.967	9999 ± 9999
Week 88 Day 1 (n= 38 / 0)	44.91 ± 8.847	9999 ± 9999
Week 104 Day 1 (n= 39 / 0)	45.60 ± 8.231	9999 ± 9999
Week 120 Day 1 (n= 33 / 0)	44.41 ± 7.317	9999 ± 9999
Week 136 Day 1 (n= 24 / 0)	44.45 ± 8.074	9999 ± 9999
Week 152 Day 1 (n= 17 / 0)	47.88 ± 10.534	9999 ± 9999
Week 168 Day 1 (n= 13 / 0)	46.48 ± 9.888	9999 ± 9999
EOT (n= 50 / 14)	44.98 ± 10.274	39.69 ± 10.536
Post Treatment Follow-Up 1 (n= 1 / 4)	45.40 ± 9999	45.53 ± 6.288
Post Treatment Follow-Up 2 (n= 1 / 1)	27.70 ± 9999	39.70 ± 9999
Post Treatment Follow-Up 3 (n= 1 / 1)	43.60 ± 9999	34.60 ± 9999
Post Treatment Follow-Up 4 (n= 1 / 2)	31.20 ± 9999	43.60 ± 8.061
Post Treatment Follow-Up 5 (n= 1 / 1)	29.40 ± 9999	37.90 ± 9999
Post Treatment Follow-Up 6 (n= 0 / 2)	9999 ± 9999	36.45 ± 7.425
Post Treatment Follow-Up 7 (n= 0 / 0)	9999 ± 9999	9999 ± 9999
Post Treatment Follow-Up 8 (n= 0 / 1)	9999 ± 9999	37.90 ± 9999

No statistical analyses for this end point

Secondary: LGG cohort: PROMIS Parent Proxy Global Health 7+2 scores- Pain score

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End point title

LGG cohort: PROMIS Parent Proxy Global Health 7+2 scores- Pain score ^[48]

End point description

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. 9999 indicates that the value was not estimable.

End point type

Secondary

End point timeframe

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	61	23
Units: Score on a Scale
arithmetic mean (standard deviation)
Baseline (n=61 / 23)	52.14 ± 7.658	52.64 ± 7.054
Week 5 Day 1 (n=51 / 18)	50.11 ± 7.275	50.97 ± 6.263
Week 8 Day 1 (n=54 / 18)	49.93 ± 7.727	51.00 ± 6.037
Week 16 Day 1 (n=48 / 10)	49.72 ± 7.300	51.75 ± 6.330
Week 24 Day 1 (n=46 / 10)	50.65 ± 7.450	51.81 ± 7.937
Week 32 Day 1 (n=47 / 11)	48.77 ± 6.647	49.59 ± 6.387
Week 40 Day 1 (n=40 / 7)	49.87 ± 6.389	52.52 ± 7.402
Week 48 Day 1 (n=43 / 10)	49.89 ± 6.581	51.20 ± 5.903
Week 56 Day 1 (n=46 / 7)	48.14 ± 6.496	53.99 ± 5.466
Week 72 Day 1 (n=40 / 0)	49.46 ± 6.498	9999 ± 9999
Week 88 Day 1 (n=38 / 0)	47.82 ± 6.083	9999 ± 9999
Week 104 Day 1 (n=39 / 0)	48.74 ± 6.605	9999 ± 9999
Week 120 Day 1 (n=33 / 0)	48.56 ± 7.583	9999 ± 9999
Week 136 Day 1 (n=24 / 0)	46.16 ± 5.305	9999 ± 9999
Week 152 Day 1 (n=17 / 0)	47.42 ± 6.765	9999 ± 9999
Week 168 Day 1 (n=13 / 0)	48.61 ± 6.298	9999 ± 9999
EOT (n=50 / 14)	51.46 ± 6.830	52.87 ± 6.113
Post Treatment Follow-Up 1 (n=1 / 4)	53.05 ± 9999	50.60 ± 4.900
Post Treatment Follow-Up 2 (n=1 / 1)	58.51 ± 9999	43.25 ± 9999
Post Treatment Follow-Up 3 (n=1 / 1)	53.05 ± 9999	43.25 ± 9999
Post Treatment Follow-Up 4 (n=1 / 2)	58.51 ± 9999	43.25 ± 0.000
Post Treatment Follow-Up 5 (n=1 / 1)	58.51 ± 9999	43.25 ± 9999
Post Treatment Follow-Up 6 (n=0 / 2)	9999 ± 9999	50.88 ± 10.790
Post Treatment Follow-Up 7 (n=0 / 0)	9999 ± 9999	9999 ± 9999
Post Treatment Follow-Up 8 (n=0 / 1)	9999 ± 9999	43.25 ± 9999

No statistical analyses for this end point

Secondary: LGG cohort: Parent Proxy Global Health 7+2 scores- Fatigue score

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End point title

LGG cohort: Parent Proxy Global Health 7+2 scores- Fatigue score ^[49]

End point description

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. 9999 indicates that the value was not estimable

End point type

Secondary

End point timeframe

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	61	23
Units: Score on a Scale
arithmetic mean (standard deviation)
Baseline (n= 61 / 23)	53.30 ± 6.731	54.37 ± 7.981
Week 5 Day 1 (n= 51 / 18)	53.96 ± 7.588	56.88 ± 6.430
Week 8 Day 1 (n= 54 / 18)	52.68 ± 6.967	58.10 ± 4.823
Week 16 Day 1 (n= 48 / 10)	51.22 ± 6.983	57.81 ± 6.193
Week 24 Day 1 (n=46 / 10)	51.04 ± 8.005	55.02 ± 7.248
Week 32 Day 1 (n= 47 / 11)	52.49 ± 7.219	57.66 ± 5.899
Week 40 Day 1 (n= 40 / 7)	52.27 ± 7.450	58.49 ± 7.072
Week 48 Day 1 (n= 43 / 10)	51.65 ± 7.362	53.48 ± 8.004
Week 56 Day 1 (n= 46 / 7)	50.51 ± 7.150	57.63 ± 7.254
Week 72 Day 1 (n= 40 / 0)	49.93 ± 6.910	9999 ± 9999
Week 88 Day 1 (n= 38 / 0)	50.52 ± 7.358	9999 ± 9999
Week 104 Day 1 (n= 39 / 0)	51.11 ± 6.899	9999 ± 9999
Week 120 Day 1 (n= 33 / 0)	50.40 ± 7.317	9999 ± 9999
Week 136 Day 1 (n= 24 / 0)	50.97 ± 8.667	9999 ± 9999
Week 152 Day 1 (n= 17 / 0)	47.71 ± 8.037	9999 ± 9999
Week 168 Day 1 (n= 13 / 0)	48.21 ± 8.188	9999 ± 9999
EOT (n= 50 / 14)	52.35 ± 7.565	56.88 ± 5.246
Post Treatment Follow-Up 1 (n= 1 / 4)	48.94 ± 9999	52.36 ± 6.840
Post Treatment Follow-Up 2 (n= 1 / 1)	62.62 ± 9999	62.62 ± 9999
Post Treatment Follow-Up 3 (n= 1 / 1)	48.94 ± 9999	48.94 ± 9999
Post Treatment Follow-Up 4 (n= 1 / 2)	56.07 ± 9999	48.94 ± 0.000
Post Treatment Follow-Up 5 (n= 1 / 1)	62.62 ± 9999	48.94 ± 9999
Post Treatment Follow-Up 6 (n= 0 / 2)	9999 ± 9999	55.78 ± 9.673
Post Treatment Follow-Up 7 (n= 0 / 0)	9999 ± 9999	9999 ± 9999
Post Treatment Follow-Up 8 (n= 0 / 1)	9999 ± 9999	48.94 ± 9999

No statistical analyses for this end point

Other pre-specified: LGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria (longer follow-up time)

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End point title

LGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria (longer follow-up time) ^[50]

End point description

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

End point type

Other pre-specified

End point timeframe

Up to approx 4.2 years

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for LGG cohort arms

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine
Number of subjects analysed	73	37
Units: Percentage of participants
number (confidence interval 95%)	54.8 (42.7 to 66.5)	16.2 (6.2 to 32.0)

No statistical analyses for this end point

Other pre-specified: HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria (longer follow-up time)

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End point title

HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria (longer follow-up time) ^[51]

End point description

End point type

Other pre-specified

End point timeframe

Up to approx 4.8 years

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting results for the HGG cohort arm

End point values	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	41
Units: Percentage of participants
number (confidence interval 95%)	56.1 (39.7 to 71.5)

No statistical analyses for this end point

Post-hoc: All-collected deaths

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End point title

All-collected deaths

End point description

On-treatment deaths were collected from 1st dose to 30 days after last dose of treatment (or start of crossover treatment), up to 4.2 years (LGG) and 4.1 years (HGG). Post- treatment efficacy/survival follow-up deaths were collected from 31 days post-treatment to end of study (or start of crossover treatment), up to 4.6 years (LGG) and 5.1 years (HGG). For participants in the LGG cohort who crossed over to dabrafenib and trametinib, on-treatment deaths were collected from 1st dose to 30 days after last dose of crossover treatment, up to 4.2 years. None of the patients who crossed-over were included in the crossover post-treatment efficacy/survival follow-up (FU)

End point type

Post-hoc

End point timeframe

On-treatment: Up to 4.2 years (LGG) and 4.1 years (HGG). Post- treatment: Up to 4.6 years (LGG) and 5.1 years (HGG).Crossover arm: on-treatment: up to 4.2 years

End point values	LGG cohort: dabrafenib and trametinib	LGG cohort: carboplatin and vincristine	HGG cohort: dabrafenib and trametinib
Number of subjects analysed	73	33	41
Units: Participants
On- treatment	0	0	6
Post-treatment efficacy/survival FU	0	0	11
Crossover on-treatment	0	1	0
Crossover post-treatment efficacy/survival FU	0	0	0
All deaths	0	1	17

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment AEs: from first dose to 30 days after last treatment (or start of crossover treatment), up to 4.2 years (LGG) and 4.1 years (HGG). Crossover on-treatment: AEs from first dose to 30 days after last dose of crossover treatment, up to 4.2 years

Adverse event reporting additional description

Consistent with EudraCTdisclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

HGG cohort: dabrafenib + trametinib (On-treatment)

Reporting group description

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

Reporting group title

LGG cohort: dabrafenib + trametinib (On-treatment)

Reporting group description

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

Reporting group title

LGG cohort: carboplatin + vincristine (On-treatment)

Reporting group description

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)

Reporting group title

LGG cohort: carboplatin+ vincristine (Crossover On-treatment)

Reporting group description

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)

Serious adverse events	HGG cohort: dabrafenib + trametinib (On-treatment)	LGG cohort: dabrafenib + trametinib (On-treatment)	LGG cohort: carboplatin + vincristine (On-treatment)	LGG cohort: carboplatin+ vincristine (Crossover On-treatment)
Total subjects affected by serious adverse events
subjects affected / exposed	28 / 41 (68.29%)	34 / 73 (46.58%)	14 / 33 (42.42%)	4 / 12 (33.33%)
number of deaths (all causes)	6	0	0	1
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 41 (7.32%)	12 / 73 (16.44%)	6 / 33 (18.18%)	2 / 12 (16.67%)
occurrences causally related to treatment / all	2 / 3	22 / 29	5 / 8	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine haemorrhage
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
C-reactive protein increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	0 / 41 (0.00%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shunt malfunction
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth avulsion
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ventricle dilatation
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fluid circulation disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	3 / 41 (7.32%)	1 / 73 (1.37%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 4	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine with aura
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	2 / 41 (4.88%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paresis
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system lesion
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Optic perineuritis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Detachment of retinal pigment epithelium
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Papilloedema
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 41 (2.44%)	3 / 73 (4.11%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema nodosum
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial sepsis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalomyelitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic shock syndrome
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 41 (0.00%)	3 / 73 (4.11%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 41 (0.00%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral myositis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematological infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	HGG cohort: dabrafenib + trametinib (On-treatment)	LGG cohort: dabrafenib + trametinib (On-treatment)	LGG cohort: carboplatin + vincristine (On-treatment)	LGG cohort: carboplatin+ vincristine (Crossover On-treatment)
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 41 (100.00%)	73 / 73 (100.00%)	33 / 33 (100.00%)	11 / 12 (91.67%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	4 / 41 (9.76%)	10 / 73 (13.70%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	6	18	0	1
Melanocytic naevus
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	0 / 33 (0.00%)	2 / 12 (16.67%)
occurrences all number	3	7	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	3 / 33 (9.09%)	1 / 12 (8.33%)
occurrences all number	3	4	5	1
Catheter site pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	0	3	0
Chills
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences all number	2	4	1	0
Facial pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	1	5	0
Influenza like illness
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	1	1	2	0
Fatigue
subjects affected / exposed	6 / 41 (14.63%)	25 / 73 (34.25%)	10 / 33 (30.30%)	1 / 12 (8.33%)
occurrences all number	7	38	16	2
Oedema peripheral
subjects affected / exposed	4 / 41 (9.76%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	7	2	0	0
Pyrexia
subjects affected / exposed	20 / 41 (48.78%)	51 / 73 (69.86%)	2 / 33 (6.06%)	7 / 12 (58.33%)
occurrences all number	81	239	4	50
Malaise
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	3	0	1
Cyst
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1
Hyperpyrexia
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Non-cardiac chest pain
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	2 / 33 (6.06%)	2 / 12 (16.67%)
occurrences all number	3	6	3	3
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	6 / 33 (18.18%)	0 / 12 (0.00%)
occurrences all number	1	1	8	0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Nasal congestion
subjects affected / exposed	4 / 41 (9.76%)	3 / 73 (4.11%)	2 / 33 (6.06%)	2 / 12 (16.67%)
occurrences all number	4	4	3	2
Cough
subjects affected / exposed	7 / 41 (17.07%)	11 / 73 (15.07%)	4 / 33 (12.12%)	3 / 12 (25.00%)
occurrences all number	9	18	7	6
Dysphonia
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	1	2	0
Epistaxis
subjects affected / exposed	6 / 41 (14.63%)	16 / 73 (21.92%)	1 / 33 (3.03%)	2 / 12 (16.67%)
occurrences all number	7	42	2	2
Oropharyngeal pain
subjects affected / exposed	6 / 41 (14.63%)	10 / 73 (13.70%)	7 / 33 (21.21%)	4 / 12 (33.33%)
occurrences all number	6	16	8	5
Rhinitis allergic
subjects affected / exposed	0 / 41 (0.00%)	3 / 73 (4.11%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	4	2	0
Rhinorrhoea
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	4 / 33 (12.12%)	2 / 12 (16.67%)
occurrences all number	1	2	4	3
Tonsillar hypertrophy
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1
Dyspnoea
subjects affected / exposed	2 / 41 (4.88%)	1 / 73 (1.37%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	3	1	2	1
Snoring
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 41 (4.88%)	1 / 73 (1.37%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	2	1	6	0
Intentional self-injury
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Insomnia
subjects affected / exposed	3 / 41 (7.32%)	2 / 73 (2.74%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences all number	4	4	1	0
Mental status changes
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Somatic symptom disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Product issues
Device malfunction
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	3 / 41 (7.32%)	9 / 73 (12.33%)	5 / 33 (15.15%)	3 / 12 (25.00%)
occurrences all number	3	11	15	4
Blood bicarbonate decreased
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	9	0
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 41 (7.32%)	7 / 73 (9.59%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences all number	4	8	1	0
Alanine aminotransferase increased
subjects affected / exposed	4 / 41 (9.76%)	10 / 73 (13.70%)	9 / 33 (27.27%)	2 / 12 (16.67%)
occurrences all number	5	12	18	3
Ejection fraction decreased
subjects affected / exposed	4 / 41 (9.76%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	4	2	0	0
Lymphocyte count decreased
subjects affected / exposed	3 / 41 (7.32%)	5 / 73 (6.85%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	4	7	16	0
Neutrophil count decreased
subjects affected / exposed	2 / 41 (4.88%)	11 / 73 (15.07%)	16 / 33 (48.48%)	2 / 12 (16.67%)
occurrences all number	13	22	43	2
Platelet count decreased
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	10 / 33 (30.30%)	0 / 12 (0.00%)
occurrences all number	1	6	29	0
SARS-CoV-2 test negative
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	1 / 33 (3.03%)	2 / 12 (16.67%)
occurrences all number	2	8	1	3
Weight increased
subjects affected / exposed	6 / 41 (14.63%)	12 / 73 (16.44%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	6	13	0	0
Weight decreased
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	4 / 33 (12.12%)	0 / 12 (0.00%)
occurrences all number	1	3	4	0
White blood cell count decreased
subjects affected / exposed	5 / 41 (12.20%)	9 / 73 (12.33%)	12 / 33 (36.36%)	1 / 12 (8.33%)
occurrences all number	8	17	43	1
Streptococcus test positive
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Blood pressure decreased
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
SARS-CoV-2 test positive
subjects affected / exposed	0 / 41 (0.00%)	6 / 73 (8.22%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences all number	0	8	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 41 (4.88%)	3 / 73 (4.11%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	3	3	3	0
Procedural pain
subjects affected / exposed	0 / 41 (0.00%)	2 / 73 (2.74%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	2	2	0
Infusion related reaction
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	0	0	8	0
Head injury
subjects affected / exposed	3 / 41 (7.32%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	1	0	0
Arthropod bite
subjects affected / exposed	3 / 41 (7.32%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	5	2	0	0
Ligament sprain
subjects affected / exposed	2 / 41 (4.88%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	0	1
Skin abrasion
subjects affected / exposed	0 / 41 (0.00%)	6 / 73 (8.22%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	0	6	1	3
Tibia fracture
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Cardiac disorders
Aortic valve incompetence
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	17 / 41 (41.46%)	39 / 73 (53.42%)	8 / 33 (24.24%)	7 / 12 (58.33%)
occurrences all number	62	84	14	10
Dizziness
subjects affected / exposed	4 / 41 (9.76%)	8 / 73 (10.96%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	4	11	0	1
Neuralgia
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	3	0
Paraesthesia
subjects affected / exposed	3 / 41 (7.32%)	5 / 73 (6.85%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	3	7	3	0
Peripheral motor neuropathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	0	0	5	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	0	0	5	0
Seizure
subjects affected / exposed	5 / 41 (12.20%)	4 / 73 (5.48%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	11	4	12	1
Neuropathy peripheral
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0
Presyncope
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	2 / 12 (16.67%)
occurrences all number	0	0	1	2
Ataxia
subjects affected / exposed	3 / 41 (7.32%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 41 (9.76%)	14 / 73 (19.18%)	20 / 33 (60.61%)	0 / 12 (0.00%)
occurrences all number	6	21	56	0
Lymphopenia
subjects affected / exposed	3 / 41 (7.32%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	0	0	0
Leukopenia
subjects affected / exposed	3 / 41 (7.32%)	3 / 73 (4.11%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	4	3	8	0
Neutropenia
subjects affected / exposed	7 / 41 (17.07%)	10 / 73 (13.70%)	10 / 33 (30.30%)	1 / 12 (8.33%)
occurrences all number	8	14	29	1
Thrombocytopenia
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	5 / 33 (15.15%)	0 / 12 (0.00%)
occurrences all number	1	1	17	0
Iron deficiency anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	1	4	2	0
Ear pain
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	1	4	1	1
Eye disorders
Eyelid ptosis
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0
Uveitis
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	7	0	0
Dry eye
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	1 / 33 (3.03%)	0 / 12 (0.00%)
occurrences all number	4	4	1	0
Eye pain
subjects affected / exposed	1 / 41 (2.44%)	3 / 73 (4.11%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	3	0	2
Vision blurred
subjects affected / exposed	1 / 41 (2.44%)	6 / 73 (8.22%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	1	7	1	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 41 (12.20%)	15 / 73 (20.55%)	7 / 33 (21.21%)	0 / 12 (0.00%)
occurrences all number	10	27	13	0
Abdominal pain upper
subjects affected / exposed	2 / 41 (4.88%)	13 / 73 (17.81%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	2	18	3	0
Angular cheilitis
subjects affected / exposed	3 / 41 (7.32%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	4	2	0	1
Aphthous ulcer
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	2	0	1
Dental caries
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	2	0	2
Diarrhoea
subjects affected / exposed	10 / 41 (24.39%)	27 / 73 (36.99%)	6 / 33 (18.18%)	2 / 12 (16.67%)
occurrences all number	12	43	7	2
Nausea
subjects affected / exposed	11 / 41 (26.83%)	21 / 73 (28.77%)	17 / 33 (51.52%)	3 / 12 (25.00%)
occurrences all number	17	32	33	3
Constipation
subjects affected / exposed	6 / 41 (14.63%)	10 / 73 (13.70%)	12 / 33 (36.36%)	1 / 12 (8.33%)
occurrences all number	9	21	14	1
Vomiting
subjects affected / exposed	12 / 41 (29.27%)	25 / 73 (34.25%)	17 / 33 (51.52%)	6 / 12 (50.00%)
occurrences all number	23	56	61	10
Stomatitis
subjects affected / exposed	3 / 41 (7.32%)	6 / 73 (8.22%)	5 / 33 (15.15%)	1 / 12 (8.33%)
occurrences all number	3	10	7	1
Dyspepsia
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0
Food poisoning
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Toothache
subjects affected / exposed	2 / 41 (4.88%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	0	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	4 / 41 (9.76%)	10 / 73 (13.70%)	0 / 33 (0.00%)	2 / 12 (16.67%)
occurrences all number	5	11	0	2
Alopecia
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	9 / 33 (27.27%)	1 / 12 (8.33%)
occurrences all number	1	2	9	1
Dermatitis
subjects affected / exposed	3 / 41 (7.32%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	8	0	0
Acne
subjects affected / exposed	6 / 41 (14.63%)	10 / 73 (13.70%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	9	11	0	1
Dry skin
subjects affected / exposed	14 / 41 (34.15%)	20 / 73 (27.40%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	17	28	1	1
Eczema
subjects affected / exposed	5 / 41 (12.20%)	13 / 73 (17.81%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	9	14	0	1
Erythema
subjects affected / exposed	5 / 41 (12.20%)	12 / 73 (16.44%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	6	19	0	2
Keratosis pilaris
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Hand dermatitis
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	2	0	2
Ingrowing nail
subjects affected / exposed	3 / 41 (7.32%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	3	2	0	1
Erythema nodosum
subjects affected / exposed	3 / 41 (7.32%)	5 / 73 (6.85%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	9	8	0	0
Panniculitis
subjects affected / exposed	0 / 41 (0.00%)	6 / 73 (8.22%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	13	0	0
Papule
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	1	0	2
Pruritus
subjects affected / exposed	4 / 41 (9.76%)	9 / 73 (12.33%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	5	10	2	1
Urticaria
subjects affected / exposed	5 / 41 (12.20%)	6 / 73 (8.22%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	5	9	2	0
Rash maculo-papular
subjects affected / exposed	6 / 41 (14.63%)	13 / 73 (17.81%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	11	16	0	2
Skin hyperpigmentation
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Skin striae
subjects affected / exposed	1 / 41 (2.44%)	5 / 73 (6.85%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	5	0	1
Rash
subjects affected / exposed	9 / 41 (21.95%)	14 / 73 (19.18%)	3 / 33 (9.09%)	1 / 12 (8.33%)
occurrences all number	21	29	4	1
Dermatitis contact
subjects affected / exposed	3 / 41 (7.32%)	2 / 73 (2.74%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	3	2	0	2
Dyshidrotic eczema
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Rash papular
subjects affected / exposed	0 / 41 (0.00%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	5	0	0
Hyperkeratosis
subjects affected / exposed	0 / 41 (0.00%)	3 / 73 (4.11%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	0	4	1	1
Rash erythematous
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	5	0	0
Erythema multiforme
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	2	2	2	0
Skin lesion
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	5	11	0	1
Renal and urinary disorders
Haematuria
subjects affected / exposed	3 / 41 (7.32%)	3 / 73 (4.11%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	3	3	5	2
Proteinuria
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	4	1	2	0
Endocrine disorders
Growth hormone deficiency
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	0	2
Thyroid disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 41 (7.32%)	9 / 73 (12.33%)	1 / 33 (3.03%)	2 / 12 (16.67%)
occurrences all number	3	9	1	2
Back pain
subjects affected / exposed	3 / 41 (7.32%)	7 / 73 (9.59%)	4 / 33 (12.12%)	0 / 12 (0.00%)
occurrences all number	5	11	4	0
Muscular weakness
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	0	1	3	0
Myalgia
subjects affected / exposed	3 / 41 (7.32%)	7 / 73 (9.59%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	5	7	4	0
Pain in extremity
subjects affected / exposed	4 / 41 (9.76%)	13 / 73 (17.81%)	4 / 33 (12.12%)	1 / 12 (8.33%)
occurrences all number	4	21	4	2
Pain in jaw
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	6 / 33 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	1	8	0
Immobilisation syndrome
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Infections and infestations
Conjunctivitis
subjects affected / exposed	4 / 41 (9.76%)	6 / 73 (8.22%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	4	8	2	0
Gingivitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1
Nasopharyngitis
subjects affected / exposed	2 / 41 (4.88%)	9 / 73 (12.33%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	2	18	2	1
COVID-19
subjects affected / exposed	6 / 41 (14.63%)	26 / 73 (35.62%)	0 / 33 (0.00%)	3 / 12 (25.00%)
occurrences all number	7	29	0	4
Urinary tract infection
subjects affected / exposed	3 / 41 (7.32%)	4 / 73 (5.48%)	2 / 33 (6.06%)	1 / 12 (8.33%)
occurrences all number	4	8	2	2
Upper respiratory tract infection
subjects affected / exposed	10 / 41 (24.39%)	16 / 73 (21.92%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	13	29	2	2
Rash pustular
subjects affected / exposed	1 / 41 (2.44%)	6 / 73 (8.22%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	8	0	1
Rhinitis
subjects affected / exposed	4 / 41 (9.76%)	7 / 73 (9.59%)	4 / 33 (12.12%)	2 / 12 (16.67%)
occurrences all number	5	14	4	3
Sinusitis
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	4	0	1
Paronychia
subjects affected / exposed	3 / 41 (7.32%)	17 / 73 (23.29%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	3	23	0	2
Otitis media
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	1	2	2	0
Bronchitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Ear infection
subjects affected / exposed	0 / 41 (0.00%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	6	0	0
Oral candidiasis
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	1
Fungal skin infection
subjects affected / exposed	0 / 41 (0.00%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	4	0	0
Gastroenteritis
subjects affected / exposed	2 / 41 (4.88%)	4 / 73 (5.48%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	5	0	1
Folliculitis
subjects affected / exposed	1 / 41 (2.44%)	3 / 73 (4.11%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	1	4	3	0
Pharyngitis
subjects affected / exposed	1 / 41 (2.44%)	6 / 73 (8.22%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	8	0	0
Pulpitis dental
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Respiratory tract infection
subjects affected / exposed	1 / 41 (2.44%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	2	0	1
Viral infection
subjects affected / exposed	1 / 41 (2.44%)	4 / 73 (5.48%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	4	0	0
Tinea manuum
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Tonsillitis
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	2	2	1	1
Vaginal infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	4 / 33 (12.12%)	0 / 12 (0.00%)
occurrences all number	1	3	5	0
Hypernatraemia
subjects affected / exposed	3 / 41 (7.32%)	3 / 73 (4.11%)	0 / 33 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	4	0	0
Cerebral salt-wasting syndrome
subjects affected / exposed	0 / 41 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Decreased appetite
subjects affected / exposed	3 / 41 (7.32%)	4 / 73 (5.48%)	8 / 33 (24.24%)	0 / 12 (0.00%)
occurrences all number	3	4	9	0
Hypokalaemia
subjects affected / exposed	1 / 41 (2.44%)	3 / 73 (4.11%)	4 / 33 (12.12%)	0 / 12 (0.00%)
occurrences all number	1	3	9	0
Hyperkalaemia
subjects affected / exposed	2 / 41 (4.88%)	2 / 73 (2.74%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	2	4	2	0
Hyperglycaemia
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	3 / 33 (9.09%)	0 / 12 (0.00%)
occurrences all number	2	2	3	0
Hypomagnesaemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	6 / 33 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	2	27	0
Hyponatraemia
subjects affected / exposed	1 / 41 (2.44%)	2 / 73 (2.74%)	2 / 33 (6.06%)	0 / 12 (0.00%)
occurrences all number	2	3	3	0
Hypophosphataemia
subjects affected / exposed	2 / 41 (4.88%)	1 / 73 (1.37%)	3 / 33 (9.09%)	1 / 12 (8.33%)
occurrences all number	2	2	6	3
Obesity
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	1 / 33 (3.03%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1
Vitamin D deficiency
subjects affected / exposed	0 / 41 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

07 Jun 2017

● Revised the investigational treatment regimen from dabrafenib monotherapy to include trametinib with dabrafenib for children and adolescents with BRAF V600 mutation-positive relapsed or refractory HGG. ● Guidance provided to the Sponsor by the FDA and CHMP, in addition to updated efficacy data from the ongoing dabrafenib monotherapy study (CDRB436A2102) supported the use of combination treatment in pediatric glioma clinical studies. ● Safety related changes were also implemented to include: ● Requirement to obtain informed consent/assent for patients who continued treatment beyond progression per RANO criteria. ● Added ophthalmic examinations to follow any visual changes in patients receiving trametinib and dabrafenib combination therapy. ● Updated dose modification guidance for combination treatment. ● Revised cardiac toxicity monitoring and the conditions for re-starting study treatment per FDA advice. ● Clarified that skeletal maturation monitoring of wrist or tibia could be assessed by Xray or MRIs. ● Added the collection of seizure AE on study treatment. ● Updated the AESIs pertaining to dabrafenib and trametinib.

23 Feb 2018

● Added a new cohort of BRAF V600 mutant LGG children and adolescent patients whose tumor was unresectable and required systemic treatment. Additionally, the amendment also added a pediatric formulation of dabrafenib as a dispersible tablet. ● The LGG cohort was added to enroll approximately 102 pediatric patients with BRAF V600 mutant LGG, randomized 2:1 dabrafenib with trametinib vs carboplatin plus vincristine, with overall response rate (PR+CR) as the primary endpoint. ● In addition, taste questionnaires for trametinib and dabrafenib pediatric formulations were implemented for all patients who received the trametinib oral solution and/or dabrafenib oral suspension. The PROMIS PRO questionnaire was added for the LGG cohort of patients. Sparse PK collection was included for a subset of LGG patients.

07 Aug 2018

● Changed the age range of patients eligible to enroll in the study from ≥ 6 to < 18 years of age to ≥ 12 months to < 18 years of age. This change was possible as the recommended dose for the combination of dabrafenib with trametinib for patients between 12 months and 6 years of age had been determined. ● The inclusion and exclusion criteria were updated to clarify the eligible population for the LGG cohort as patients with BRAF V600 mutant LGG, who either have 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. Further, the exclusion criteria specified that LGG patients who had any prior systemic anticancer therapy or antitumor radiotherapy were excluded. ● The primary endpoint for the HGG cohort was changed from investigator assessment of ORR to central independent review of ORR. This change could lessen the potential for bias that could be introduced due to investigator assessment in a single arm study. Investigator assessment of ORR was therefore added as a secondary endpoint.

11 Mar 2019

● Added an additional interim analysis of key safety and pharmacokinetics (PK) data of the adolescent patients (ages ≥ 12 to < 18 years) in the HGG cohort to support a health authority request in the first half of 2019 for data in adolescent patients. ● In addition, an exclusion criterion was added to exclude patients with history or current evidence of retinal vein occlusion and central serous retinopathy. This exclusion criteria is standard language for all studies with trametinib and was inadvertently omitted from previous versions of CDRB436G2201. ● Optional CSF collection was removed. CSF samples were expected to be very limited (1/30 patients provided a sample), hence, the value of the analyses was limited.

12 Dec 2019

● Added dose modification requirements for cases of severe cutaneous adverse reactions (SCARs) which had been reported during treatment with dabrafenib in combination with trametinib outside this clinical study. Changed the duration of male and female contraception following the last dose of dabrafenib from 4 weeks to 2 weeks and following the last dose of trametinib from 6 months to 16 weeks. ● Further, one of the inclusion criteria was clarified to indicate that local histological diagnosis of HGG was sufficient for study entry and also criteria for patients with Gilbert’s syndrome were established.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: LGG cohort: Overall response rate (ORR) by central independent assessment using Response Assessment in Neuro-Oncology (RANO) criteria

Primary: LGG cohort: Overall response rate (ORR) by central independent assessment using Response Assessment in Neuro-Oncology (RANO) criteria

Primary: HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria

Primary: HGG cohort: Overall response rate (ORR) by central independent assessment using RANO criteria

Secondary: LGG cohort: ORR by investigator assessment using RANO criteria

Secondary: LGG cohort: ORR by investigator assessment using RANO criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Progression-Free Survival (PFS) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Central Independent Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Time to Response (TTR) as per Investigator Assessment using RANO Criteria

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by investigator assessment using RANO criteria

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by investigator assessment using RANO criteria

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by central independent assessment using RANO criteria

Secondary: LGG cohort: Clinical Benefit Rate (CBR) by central independent assessment using RANO criteria

Secondary: LGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

Secondary: LGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

Secondary: LGG cohort: 2-year OS estimate

Secondary: LGG cohort: 2-year OS estimate

Secondary: HGG cohort: ORR by investigator assessment using RANO criteria

Secondary: HGG cohort: ORR by investigator assessment using RANO criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as per Investigator Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Investigatort Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Investigatort Assessment using RANO Criteria

Secondary: HGG cohort: Time to response (TTR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Time to response (TTR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Kaplan-Meier Estimates of Progression free survival (PFS) as per Central Independent Assessment using RANO Criteria

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Investigator Assessment using RANO Criteria

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Investigator Assessment using RANO Criteria

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG Cohort: Clinical benefit rate (CBR) as per Central Independent Assessment using RANO Criteria

Secondary: HGG cohort: Time to response (TTR) as per Investigator Assessment using RANO Criteria

Secondary: HGG cohort: Time to response (TTR) as per Investigator Assessment using RANO Criteria

Secondary: Cmax for trametinib

Secondary: Cmax for trametinib

Secondary: AUClast for trametinib

Secondary: AUClast for trametinib

Secondary: HGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

Secondary: HGG cohort: Kaplan-Meier Estimates of Overall survival (OS)

Secondary: T1/2 for trametinib

Secondary: T1/2 for trametinib

Secondary: AUCtau for trametinib

Secondary: AUCtau for trametinib

Secondary: Tmax for trametinib

Secondary: Tmax for trametinib

Secondary: Ctrough for trametinib

Secondary: Ctrough for trametinib

Secondary: AUClast for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: AUClast for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Cmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Cmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: AUCtau for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: AUCtau for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Tmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Tmax for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: T1/2 for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: T1/2 for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Ctrough for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Secondary: Ctrough for dabrafenib and its metabolites (carboxy-dabrafenib, desmethyl-dabrafenib amd hydroxy-dabrafenib)

Clinical Trial Results:
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)