Clinical trial NCT02684058: Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Astrocytoma
Anaplastic Astrocytoma
Astrocytoma
Oligodendroglioma, Childhood
Anaplastic Oligodendroglioma
Glioblastoma
Pilocytic Astrocytoma
Giant Cell Astrocytoma
Pleomorphic Xanthoastrocytoma
Anaplastic Pleomorphic Xanthoastrocytoma
Angiocentric Glioma
Chordoid Glioma of Third Ventricle
Gangliocytoma
Ganglioglioma
Anaplastic Ganglioglioma
Dysplastic Gangliocytoma of Cerebrellum
Desmoplastic Infantile Astrocytoma and Ganglioglioma
Papillary Glioneuronal Tumor
Rosette-forming Glioneurona Tumor
Central Neurocytoma
Extraventricular Neurocytoma
Cerebellar Iponeurocytoma
Keywords: Malignant glioma
BRAF mutant positive
High grade glioma
Low grade glioma
Dabrafenib
Trametinib
Pediatrics
Brain neoplasma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-02-17
Enrollment: 151
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to investigate the activity of dabrafenib in combination with trametinib in children and adolescent patients with BRAF V600 mutation positive low grade glioma (LGG) or relapsed or refractory high grade glioma (HGG)

Detailed description: This study combines two pediatric glioma cohorts (LGG and HGG cohorts) into a multi-center, open-label, Phase II study:

* The LGG cohort is a multi-center, randomized, open-label part of this Phase II study conducted in children and adolescent patients with BRAF V600 mutation-positive LGG whose tumor was unresectable and who required first systemic treatment. Participants in the LGG cohort were randomized in a 2:1 ratio to either dabrafenib plus trametinib or carboplatin with vincristine.
* The HGG cohort is a multi-center, single-arm, open-label part of this Phase II study conducted in children and adolescent patients with BRAF V600 mutation-positive, refractory or relapsed HGG tumors after having received at least one previous standard therapy.

The duration of treatment for participants on dabrafenib plus trametinib in LGG and for all patients in the HGG cohort was continued until the loss of clinical benefit in the opinion of the Investigator, unacceptable toxicity, start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator or patient/legal guardian, lost to follow-up, death, study termination by the sponsor, or until disease progression. The duration of treatment for patients in the carboplatin with vincristine arm in LGG cohort was continued for the prescribed number of cycles, as tolerated or until unacceptable toxicity, start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator or patient/legal guardian, lost to follow-up, death, study is terminated by the sponsor or until disease progression. Participants randomized to the carboplatin with vincristine treatment arm were allowed to cross over to receive dabrafenib in combination with trametinib after centrally confirmed RANO-defined disease progression. Crossover was allowed during the treatment period or the post-treatment period.

After discontinuation of study treatment, all participants (LGG and HGG cohorts) were followed for safety for at least 30 days after the last dose of study treatment. All participants who discontinued study treatment for reasons other than disease progression, death, loss to follow up, or withdrawal of consent moved into the post-treatment efficacy follow-up phase. Finally, all participants were followed for survival once they discontinued study treatment for at least 2 years after the last patient first study treatment (except if consent was withdrawn, death, or the patient was lost to follow-up or discontinued study)

Eligibility criteria: Key Inclusion Criteria:

* Diagnosis of BRAF V600 mutant High Grade glioma that had relapsed, progressed or failed to respond to frontline therapy
* Diagnosis of BRAF V600 mutant Low Grade glioma with progressive disease following surgical excision, or non-surgical candidates with necessity to begin first systemic treatment because of a risk of neurological impairment with progression.
* Confirmed measurable disease

Key Exclusion Criteria:

* Previous treatment with dabrafenib, trametinib, other RAF inhibitor, other MEK or ERK inhibitor
* HGG patient: Cancer treatment within the past 3 weeks. LGG patient: Any systemic therapy or radiotherapy prior to enrollment
* LGG patients: history of allergic reaction or contraindications to the use of carboplatin or vincristine
* Stem cell transplant within the past 3 months
* History of heart disease
* Pregnant or lactating females

Primary outcomes:
measure: LGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using Response Assessment in Neuro-Oncology (RANO) Criteria
timeFrame: Up to approximately (approx.) 3 years
measure: HGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 3.2 years
Secondary outcomes:
measure: LGG Cohort: ORR by Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 3 years and up to approx 4.2 years
measure: LGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 3 years and up to approx 4.2 years
measure: LGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 3 years and up to approx 4.2 years
measure: LGG Cohort: Kaplan-Meier Progression-Free Survival (PFS) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 3 years and up to approx 4.2 years
measure: LGG Cohort: Kaplan-Meier Progression-Free Survival (PFS) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 3 years and up to approx 4.2 years
measure: LGG Cohort: Kaplan-Meier Estimates of Time to Response (TTR) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 4.2 years
measure: LGG Cohort: Kaplan-Meier Estimates of Time to Response (TTR) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 4.2 years
measure: LGG Cohort: Clinical Benefit Rate (CBR) by Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 4.2 years
measure: LGG Cohort: Clinical Benefit Rate (CBR) by Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 4.2 years
measure: LGG Cohort: Kaplan-Meier Estimates of Overall Survival (OS)
timeFrame: Up to 4.6 years
measure: LGG Cohort: 2-year OS Estimate
timeFrame: 2 years from first dose
measure: HGG Cohort: ORR by Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 3.2 years and up to approx. 4.8 years
measure: HGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 3.2 years and up to approx. 4.8 years
measure: HGG Cohort: Kaplan-Meier Estimates of Duration of Response (DOR) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 3.2 years and up to approx. 4.8 years
measure: HGG Cohort: Kaplan-Meier Estimates of Progression Free Survival (PFS) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Kaplan-Meier Estimates of Progression Free Survival (PFS) as Per Investigatort Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Time to Response (TTR) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Time to Response (TTR) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Clinical Benefit Rate (CBR) as Per Central Independent Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Clinical Benefit Rate (CBR) as Per Investigator Assessment Using RANO Criteria
timeFrame: Up to approx. 4.8 years
measure: HGG Cohort: Kaplan-Meier Estimates of Overall Survival (OS)
timeFrame: Up to 5.1 years
measure: AUClast for Trametinib
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Cmax for Trametinib
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: AUCtau for Trametinib
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Tmax for Trametinib
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: T1/2 for Trametinib
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Ctrough for Trametinib
timeFrame: Week 3 Day 1 pre-dose
measure: AUClast for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Cmax for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: AUCtau for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Tmax for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: T1/2 for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
measure: Ctrough for Dabrafenib and Its Metabolites (Carboxy-dabrafenib, Desmethyl-dabrafenib Amd Hydroxy-dabrafenib)
timeFrame: Week 3 Day 1 pre-dose
measure: HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension Based on the Palatability Questionnaire Item: Taste of the Medication Before Rinsing the Mouth
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Questionnaire Item: Taste of the Medication Before Rinsing the Mouth
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension Based on the Palatability Assessment: After- Taste Once the Medication Was Swallowed
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Assessment: After- Taste Once the Medication Was Swallowed
timeFrame: Week 1 and Week 5
measure: 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
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Assessment: Immediate Reaction Once the Medication Was Placed Into the Mouth
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Dabrafenib Oral Suspension Based on the Palatability Questionnaire Item: Remaining After-taste Once Rinsing the Mouth With Water
timeFrame: Week 1 and Week 5
measure: HGG and LGG Cohort: Palatability of Trametinib Oral Solution Based on the Palatability Assessment: Remaining After-taste Once Rinsing the Mouth With Water
timeFrame: Week 1 and Week 5
measure: LGG Cohort: PROMIS Parent Proxy Global Health 7+2 Scores- Global Health Score
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)
measure: LGG Cohort: PROMIS Parent Proxy Global Health 7+2 Scores- Pain Score
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)
measure: LGG Cohort: PROMIS Parent Proxy Global Health 7+2 Scores- Fatigue Score
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)
Other outcomes:
measure: LGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria (Longer Follow-up Time)
timeFrame: Up to approx 4.2 years
measure: HGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria (Longer Follow-up Time)
timeFrame: Up to approx 4.8 years
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Washington
country: United States
facility: Childrens National Hospital
state: District of Columbia
city: Miami
country: United States
facility: Nicklaus Childrens Hospital
state: Florida
city: Chicago
country: United States
facility: Ann and Robert H Lurie Childrens Hospital of Chicago .
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine .
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University IDS Pharmacy John Hopkins Hospital
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine SC
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital Medical Center Cancer & Blood Disease Inst.
state: Ohio
city: Memphis
country: United States
facility: St Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children s Hospital Baylor College of Medicine
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Brussels
country: Belgium
facility: Novartis Investigative Site
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Brno
country: Czechia
facility: Novartis Investigative Site
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Gottingen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Petach-Tikva
country: Israel
facility: Novartis Investigative Site
city: Tel-Hashomer
country: Israel
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Setagaya-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
state: CS
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Shahid S, Kushner BH, Modak S, Basu EM, Rubin EM, Gundem G, Papaemmanuil E, Roberts SS. Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma. Pediatr Blood Cancer. 2021 Oct;68(10):e29265. doi: 10.1002/pbc.29265. Epub 2021 Jul 31.