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

Novartis

Status and phase: Completed; Phase 2

Conditions: Glioblastoma; Chordoid Glioma of Third Ventricle; Papillary Glioneuronal Tumor; Ganglioglioma; Pilocytic Astrocytoma; Extraventricular Neurocytoma; Gangliocytoma; Anaplastic Astrocytoma; Giant Cell Astrocytoma; Rosette-forming Glioneurona Tumor; Angiocentric Glioma; Anaplastic Ganglioglioma; Astrocytoma; Desmoplastic Infantile Astrocytoma and Ganglioglioma; Cerebellar Iponeurocytoma; Central Neurocytoma; Dysplastic Gangliocytoma of Cerebrellum; Oligodendroglioma, Childhood; Pleomorphic Xanthoastrocytoma; Diffuse Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Pleomorphic Xanthoastrocytoma

Treatments: Drug: Carboplatin; Drug: Vincristine; Drug: Dabrafenib; Drug: trametinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02684058

2015-004015-20 (EudraCT Number)

CDRB436G2201

Details and patient eligibility

About

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)

Full 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)

Enrollment: 151 patients

Sex: All

Ages: 12 months to 17 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

151 participants in 3 patient groups

LGG cohort: dabrafenib and trametinib

Experimental group

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)

Treatment:

Drug: Dabrafenib

Drug: trametinib

LGG cohort: carboplatin and vincristine

Active Comparator group

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.

Treatment:

Drug: Vincristine

Drug: Carboplatin

HGG cohort: dabrafenib and trametinib

Experimental group

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)

Treatment:

Drug: Dabrafenib

Drug: trametinib