Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma

Abstract

Purpose: BRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600-mutant LGG; other cohorts will be reported elsewhere.

Methods: This is a four-part, phase I/II study (ClinicalTrials.gov identifier: NCT02124772) in patients age < 18 years with relapsed/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives.

Results: Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2). There were no dose-limiting toxicities with combination therapy (part C). The recommended phase II dose of trametinib, with or without dabrafenib, was 0.032 mg/kg once daily for patients age < 6 years and 0.025 mg/kg once daily for patients age ≥ 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600-mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event-related treatment discontinuations were more common with monotherapy (54% v 22%).

Conclusion: The trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600-mutant LGG.

Conflict of interest statement

Eric Bouffet

Consulting or Advisory Role: Novartis

Research Funding: Roche (Inst)

Birgit Geoerger

Consulting or Advisory Role: Boehringer Ingelheim, AZD, Novartis

Christopher Moertel

Stock and Other Ownership Interests: OX2 Therapeutics

Patents, Royalties, Other Intellectual Property: Patents related to intellectual property held by OX2 Therapeutics and the University of Minnesota

James A. Whitlock

Consulting or Advisory Role: Jazz Pharmaceuticals

Research Funding: Novartis (Inst), Daiichi Sankyo (Inst), Syndax (Inst)

Isabelle Aerts

Consulting or Advisory Role: AstraZeneca

Travel, Accommodations, Expenses: Jazz Pharmaceuticals

Darren Hargrave

Honoraria: AstraZeneca/MedImmune, Bayer, Alexion Pharmaceuticals

Consulting or Advisory Role: AstraZeneca, Roche/Genentech, Novartis, Bayer, Boehringer Ingelheim

Speakers' Bureau: Alexion Pharmaceuticals

Research Funding: AstraZeneca

Expert Testimony: AstraZeneca

Travel, Accommodations, Expenses: Boehringer Ingelheim, Novartis, Roche/Genentech, Alexion Pharmaceuticals

Other Relationship: Celgene, Novartis, Bristol Myers Squibb, Epizyme, AbbVie, AstraZeneca/MedImmune, Day One Therapeutics

Lisa Osterloh

Employment: Novartis

Eugene Tan

Employment: Novartis

Stock and Other Ownership Interests: Novartis

Jeea Choi

Employment: Novartis

Mark Russo

Employment: Novartis

Stock and Other Ownership Interests: Novartis

No other potential conflicts of interest were reported.

Figures

FIG 1.

Study design. aCohort not restricted to patients with BRAF V600–mutant disease. bIntermediate dose added on the basis of steady state pharmacokinetics and the tolerability of 0.025 mg/kg and 0.04 mg/kg once-daily doses. cPreviously determined RP2D for dabrafenib monotherapy: age < 12 years, 5.25 mg/kg; age ≥ 12 years, 4.5 mg/kg, divided into two equal doses daily. dTwo patients with BRAF V600–mutant HGG were enrolled in part C and are included in this predominantly LGG cohort as a diagnosis of HGG did not define any other disease-specific cohort in the trial. dab, dabrafenib; HGG, high-grade glioma; LCH, Langerhans cell histiocytosis; LGG, low-grade glioma; NF-1, neurofibromatosis type 1; PN, plexiform neurofibroma; RP2D, recommended phase II dose; tram, trametinib.

FIG 2.

Duration of exposure to study treatment and best percentage change from baseline in measurable lesions by independent review in patients with BRAF V600–mutant LGGa. (A) Duration of exposure to trametinib monotherapy (n = 13; one best overall response missing) or (B) dabrafenib + trametinib combination therapy (n = 36) in patients with BRAF V600–mutant LGG; best overall response assessed by independent review (RANO 2017) is shown. Best percentage change from baseline in the sum of the products of biperpendicular diameters in measurable lesions assessed by independent review (RANO 2017) in patients with BRAF V600–mutant LGG receiving (C) trametinib monotherapy (n = 13; one best overall response missing) or (D) dabrafenib + trametinib combination therapy (n = 36). aTwo patients with BRAF V600–mutant HGG were enrolled in part C and are included in this predominantly LGG cohort as a diagnosis of HGG did not define any other disease-specific cohort in the trial. HGG, high-grade glioma; LGG, low-grade glioma; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; RP2D, recommended phase III dose; SD, stable disease; UNK, unknown.

FIG 3.

PFS by independent review in patients with BRAF V600–mutant LGGa. Kaplan-Meier plots showing PFS in patients with BRAF V600–mutant LGG treated with (A) trametinib monotherapy (n = 13) or (B) dabrafenib + trametinib combination therapy (n = 36), assessed by independent review (RANO 2017). aTwo patients with BRAF V600–mutant HGG were enrolled in part C and are included in this predominantly LGG cohort as a diagnosis of HGG did not define any other disease-specific cohort in the trial. HGG, high-grade glioma; LGG, low-grade glioma; PFS, progression-free survival; RANO, Response Assessment in Neuro-Oncology.