Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors

NCT02684058 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CDRB436G22012015-004015-20
• Study Type: interventional
• Target: 151
• Locations: 20 countries
• Sites: 57

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)

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

Outcome Measures

Primary Outcomes (2)

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

  Percentage of participants in the LGG cohort with a best overall confirmed Complete Response (CR) or Partial Response (PR) as assessed per RANO criteria by central independent assessment. The 95% 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.

  Up to approximately (approx.) 3 years

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

  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.

  Up to approx. 3.2 years

Secondary Outcomes (44)

• LGG Cohort: ORR by Investigator Assessment Using RANO Criteria

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

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

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

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

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

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

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

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

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

Other Outcomes (2)

• LGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria (Longer Follow-up Time)

  Up to approx 4.2 years

• HGG Cohort: Overall Response Rate (ORR) by Central Independent Assessment Using RANO Criteria (Longer Follow-up Time)

  Up to approx 4.8 years

Study Arms (3)

LGG cohort: dabrafenib and trametinib

EXPERIMENTAL

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)

Drug: Dabrafenib; Drug: trametinib

LGG cohort: carboplatin and vincristine

ACTIVE COMPARATOR

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.

Drug: Carboplatin; Drug: Vincristine

HGG cohort: dabrafenib and trametinib

EXPERIMENTAL

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)

Drug: Dabrafenib; Drug: trametinib

Interventions

Dabrafenib DRUG

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)

Also known as: DRB436

HGG cohort: dabrafenib and trametinib; LGG cohort: dabrafenib and trametinib

trametinib DRUG

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)

Also known as: TMT212

HGG cohort: dabrafenib and trametinib; LGG cohort: dabrafenib and trametinib

Carboplatin DRUG

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.

LGG cohort: carboplatin and vincristine

Vincristine DRUG

Vincristine was supplied locally as commercially available and labelled accordingly to comply with legal requirements of each country. Vincristine was administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy. Induction: 1.5 mg/m\^2 as weekly IV bolus infusion (0.05 mg/kg if child is \<12 kg) (maximum dose of 2.0 mg) for 10 weeks. Maintenance: 1.5 mg/m\^2 as weekly IV bolus infusion (0.05 mg/kg if child is \<12 kg) (maximum dose of 2.0 mg) on weeks 1 to 3 of each cycle, on the same day as carboplatin dosing.

LGG cohort: carboplatin and vincristine

Eligibility Criteria

• Age: 12 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (57)

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

Childrens National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

Nicklaus Childrens Hospital

Miami, Florida, 33155, United States

Location

Ann and Robert H Lurie Childrens Hospital of Chicago .

Chicago, Illinois, 60611, United States

Location

Indiana University School of Medicine .

Indianapolis, Indiana, 46202-2810, United States

Location

Johns Hopkins University IDS Pharmacy John Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Washington University School of Medicine SC

St Louis, Missouri, 63110, United States

Location

Cincinnati Childrens Hospital Medical Center Cancer & Blood Disease Inst.

Cincinnati, Ohio, 45229-3039, United States

Location

St Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

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Texas Children s Hospital Baylor College of Medicine

Houston, Texas, 77030, United States

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Novartis Investigative Site

CABA, Buenos Aires, C1428AQK, Argentina

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Novartis Investigative Site

Randwick, New South Wales, 2130, Australia

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Novartis Investigative Site

Parkville, Victoria, 3052, Australia

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Novartis Investigative Site

Brussels, BE-B-1200, Belgium

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Novartis Investigative Site

Barretos, São Paulo, 14784 400, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 04829-310, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 08270-070, Brazil

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Novartis Investigative Site

Vancouver, British Columbia, V6H 3V4, Canada

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Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

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Novartis Investigative Site

Montreal, Quebec, H3T 1C5, Canada

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Novartis Investigative Site

Brno, 613 00, Czechia

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Novartis Investigative Site

Prague, 150 06, Czechia

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Novartis Investigative Site

Copenhagen, 2100 O, Denmark

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Novartis Investigative Site

Tampere, 33521, Finland

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Novartis Investigative Site

Lille, 59020, France

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Novartis Investigative Site

Lyon, 69373, France

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Novartis Investigative Site

Paris, 75231, France

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Novartis Investigative Site

Strasbourg, 67000, France

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Novartis Investigative Site

Toulouse, 31059, France

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Novartis Investigative Site

Villejuif, 94800, France

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Novartis Investigative Site

Augsburg, 86179, Germany

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Novartis Investigative Site

Berlin, 13353, Germany

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Novartis Investigative Site

Cologne, 50937, Germany

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Novartis Investigative Site

Essen, 45147, Germany

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Novartis Investigative Site

Göttingen, 37075, Germany

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Novartis Investigative Site

Hamburg, 20246, Germany

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Novartis Investigative Site

Heidelberg, 69120, Germany

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Novartis Investigative Site

Petah Tikva, 49202, Israel

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Novartis Investigative Site

Tel Litwinsky, 52621, Israel

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Novartis Investigative Site

Florence, FI, 50139, Italy

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Novartis Investigative Site

Genova, GE, 16147, Italy

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Novartis Investigative Site

Milan, MI, 20133, Italy

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Novartis Investigative Site

Roma, RM, 00165, Italy

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Novartis Investigative Site

Torino, TO, 10126, Italy

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Novartis Investigative Site

Fukuoka, Fukuoka, 812-8582, Japan

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Novartis Investigative Site

Setagaya-ku, Tokyo, 157-8535, Japan

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Novartis Investigative Site

Osaka, 534-0021, Japan

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Novartis Investigative Site

Utrecht, CS, 3584, Netherlands

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Novartis Investigative Site

Moscow, 117198, Russia

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Novartis Investigative Site

Madrid, 28009, Spain

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Novartis Investigative Site

Valencia, 46026, Spain

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Novartis Investigative Site

Stockholm, 17176, Sweden

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Novartis Investigative Site

Zurich, 8032, Switzerland

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Novartis Investigative Site

Leeds, LS1 3EX, United Kingdom

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Novartis Investigative Site

Liverpool, L12 2AP, United Kingdom

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Novartis Investigative Site

London, WC1N 3JH, United Kingdom

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Related Publications (4)

• Bouffet E, Hansford JR, Garre ML, Hara J, Plant-Fox A, Aerts I, Locatelli F, van der Lugt J, Papusha L, Sahm F, Tabori U, Cohen KJ, Packer RJ, Witt O, Sandalic L, Bento Pereira da Silva A, Russo M, Hargrave DR. Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. N Engl J Med. 2023 Sep 21;389(12):1108-1120. doi: 10.1056/NEJMoa2303815.

  PMID: 37733309 DERIVED

• Hargrave DR, Terashima K, Hara J, Kordes UR, Upadhyaya SA, Sahm F, Bouffet E, Packer RJ, Witt O, Sandalic L, Kieloch A, Russo M, Cohen KJ; Investigators involved in the high-grade glioma cohort. Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma. J Clin Oncol. 2023 Nov 20;41(33):5174-5183. doi: 10.1200/JCO.23.00558. Epub 2023 Aug 29.

  PMID: 37643378 DERIVED

• Barbato MI, Nashed J, Bradford D, Ren Y, Khasar S, Miller CP, Zolnik BS, Zhao H, Li Y, Bi Y, Shord SS, Amatya AK, Mishra-Kalyani PS, Scepura B, Al-Matari RA, Pazdur R, Kluetz PG, Donoghue M, Singh H, Drezner N. FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma. Clin Cancer Res. 2024 Jan 17;30(2):263-268. doi: 10.1158/1078-0432.CCR-23-1503.

  PMID: 37610803 DERIVED

• 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.

  PMID: 34331515 DERIVED

MeSH Terms

Conditions

Astrocytoma; Oligodendroglioma; Glioblastoma; Ganglioneuroma; Ganglioglioma; Neurocytoma; Glioma

Interventions

dabrafenib; trametinib; Carboplatin; Vincristine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Study director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: February 17, 2016
• Study Start: December 28, 2017
• Primary Completion: August 23, 2021
• Study Completion: April 28, 2023
• Last Updated: December 13, 2023
• Results First Posted: May 19, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share

Locations

IL (2); SE (1); CH (1); GB (3); CA (3); IT (5); JP (3); BE (1); BR (3); FI (1); AR (1); ES (3); US (10); DE (7); NL (1); FR (6); CZ (2); DK (1); RU (1); AU (2)