A multicenter, open-label, single-arm phase 1/2 study to evaluate the safety and efficacy of FCN-159 in pediatric participants with neurofibromatosis type 1

10023 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by multiple progressive tumor and non-tumor manifestations, with abnormal activating MAPK pathway. Plexiform neurofibromas (PN) presents in 20-50% of NF1 patients (pts) and may cause serious complications. Selumetinib was approved for pediatric pts with NF1-related PN in US and EU, but therapeutic options remain limited in China. FCN-159 is a highly potent selective anti-tumorigenic inhibitor of MEK1/2, potentially effective in NF1-related PN. Methods: This multi-center, open-label phase1/2 clinical trial is the first-in human study to assess safety and efficacy in pediatric pts with NF1-related PN. The primary objective was to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) in the dose escalation, followed by a dose expansion phase 2 to evaluate safety and efficacy. The starting dose in pediatric pts was determined according to the adults in the dose-escalation phase (previously published in ASCO 2022, abstract no. 3011). Here, we first present the safety and efficacy results in pediatric participants. Results: As of data cut-off (November 21, 2022), 65 pts were enrolled, 19 pts in phase 1 and 45 pts in phase 2. A dose of 4 mg/m 2 (10 pts) and 5 mg/m 2 (9 pts) were evaluated in phase 1 and no DLT was observed. Pediatric pts in the 5 mg/m 2 cohort achieved similar exposure to the 8 mg adult cohort. AUC simulation from population PK model at different BSA ranges were also similar to the adults of 8 mg. Therefore, the RP2D was determined to be 5 mg/m 2 .Treatment-emergent adverse events (TEAEs) were reported in 62 pts (95.4%). Common TEAEs (≥ 20%) were mouth ulcer (43.1%), sinus arrhythmia (36.9%), upper respiratory tract infection (35.4%), folliculitis (21.5%), paronychia (21.5%), and increased blood creatine phosphokinase (20%). 5 pts (7.7%) experienced grade ≥3 treatment-related AEs (TRAEs), including 2 pts (2/10, 10%) in the 4 mg/m 2 group and 3 pts (3/55, 5.5%) in the 5 mg/m 2 group. Grade 3 TRAEs were increased aspartate aminotransferase (1.5%), electrocardiogram QT prolongation (1.5%), folliculitis (3.1%), and dermatitis acneiform (1.5%). No grade ≥ 4 TRAEs were observed. 2 pts (3.1%) reported treatment-related serious adverse events (one case of rhabdomyolysis and dermatitis acneiform each). TEAEs led to dose interruption (26.2%), and discontinuation (1.5%). No reported TEAE led to dose reduction or death. Of the 19 pts with at least one tumor assessment data after baseline, 8 (42%) pts had partial response, 11 (57.8%) with stable disease and none with disease progression. The median DOR could not be evaluated. Conclusions: Overall, FCN-159 was well-tolerated and demonstrated promising anti-tumor activity in pediatric participants with NF1-related PN. Long-term efficacy and safety follow-up are ongoing. Clinical trial information: NCT04954001 .