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BRAF V600 mutations are common in a variety of childhood cancers, including about 20% of low-grade gliomas (LGGs).
BRAF V600 mutations are associated with
poor response to standard chemotherapy and risk of transformation into secondary high-grade gliomas in children with LGG.
Molecular therapies targeting BRAF V600 mutations may provide a better clinical prognosis
than current options.
The study is a phase I/II clinical trial exploring the dose and pharmacokinetics of trametinib with or without dabrafenib in pediatric patients with malignancy, enrolling patients under 18 years of age with relapsed/refractory malignancy: Cohort A: trimetinib monotherapy dose exploration; Cohort B: disease-specific extended cohort; Cohort C: trametinib + dabrafenib dose exploration; Cohort D: disease-specific extended cohort
.
The main objective is to clarify the dose
that is appropriate for pediatric patients.
Secondary objectives are disease-specific efficacy and safety
.
Response to treatment in the trametinib monotherapy group (C) and combination group (D).
Overall, a total of 139 patients were treated
with trametinib (n=91) or dabrafenib + trametinib (n=48).
The dose-limiting toxicities of trametinib that occurred in > patients were mucositis (n=3) and hyponatremia (n=2).
Dose-limiting toxicity
was not observed in patients treated with the combination regimen.
The recommended phase II dose of trametinib, with or without dabrafenib, is 0.
032 mg/kg/day (< 6 years of age) or 0.
025 mg/kg/day (≥ 6 years of age); The dose of dabrafenib in the combination regimen is the dose
previously used for monotherapy.
Progression-free survival in patients with BRAF V600-mutant LGG in the trametinib monotherapy group (A) and combination group (B).
In 49 patients with glioma with BRAF V600 mutation, the objective response rate of trametinib monotherapy was 15% and that of combination therapy was 25%.
Treatment interruptions associated with adverse effects were more common in the monotherapy group (54 versus 22 percent).
In conclusion, the study showed that trametinib ±dabrafenib based on age and weight achieved safe and controllable target concentrations in children with low-grade gliomas with BRAF V600 mutations, and had certain clinical efficacy and tolerability
.
Original source:
Eric Bouffet, et al.
Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600–Mutant Low-Grade Glioma.
J Clin Oncol.
November, 2022.
https://ascopubs.
org/doi/full/10.
1200/JCO.
22.
01000
