Work

Epct-01. Phase I Study of Day101 (tak580) in Children and Young Adults With Radiographically Recurrent or Progressive Low-grade Glioma (lgg)

Year: 2020

Type: conference-abstract

Abstract: BACKGROUND We report a phase I study examining pharmacokinetics, safety and recommended dosage of the type 2 RAF inhibitor DAY101 in children/young adults with radiographically recurrent/progressive LGGs harboring MAPK pathway alterations. METHODS Applying a 3 + 3 design, patients < 18 years of age with radiographically recurrent/progressive LGG received oral DAY101 weekly for 4-week cycles up to a maximum of 2 years, if deriving clinical benefit. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Eight patients had KIAA1549:BRAF fusions. One patient with NF1 did not have a biopsy. There were no DLTs. Weekly administration of DAY101 in children resulted in dose-proportional increases in Cmax and AUC similar to that described in adults. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease (independently-reviewed). Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSION The phase 1A data provide initial pharmacokinetic parameters to describe oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent/progressive LGG. Plasma exposures of DAY101 achieved in adults can be reached in pediatric patients. Oral weekly DAY101 is well-tolerated and possesses anti-tumor activity. The amended protocol will explore additional dose levels and the potential for differential dosing to achieve similar responses across a variety of BSAs.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noaa222.126