Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer and NF1 PN. Dabrafenib, a BRAF inhibitor, is active in children with BRAF V600–mutant tumors; however, activation of MAPK signaling in BRAF WT cells increases skin toxicity. Trametinib, a MEK inhibitor, targets MAPK activation in tumors harboring BRAF fusions and NF1 gene loss. This trial sought to establish the trametinib dose alone and in combination with dabrafenib in patients (pts) with relapsed solid tumors or progressive PN. Methods: Part A: safety and pharmacokinetics (PK) of trametinib (0.0125, 0.025, 0.04 mg/kg daily) were evaluated. Dose-limiting toxicity (DLT) during the first 4 wk and trough concentrations were used to determine the recommended dose (RD). Three age groups ( < 2 y, 2-12 y, > 12 y) were evaluated based on initial PK; trametinib 0.032 mg/kg was assessed in pts < 6 y. Part C: pts with BRAF V600–mutant tumors received the trametinib RD in combination with 50% or 100% of the established age-specific dabrafenib RD. Results: Part A: 40 pts (median age, 8 y [range, 0-18 y]) were enrolled. Median treatment (Tx) duration was 81 wk (range, 3-124 wk); 21 (53%) continue on Tx. DLTs (mucositis [n = 3 overall]) occurred in 5/15 pts receiving 0.04 mg/kg and 3/19 receiving 0.025 mg/kg. Frequent Tx-related adverse events (TRAEs) were paronychia (58%), diarrhea (48%), and rash (45%). Tx-related serious AEs (TRSAEs) occurring in > 1 pt included hyponatremia and pyrexia (2 each). The trametinib RD is 0.025 mg/kg daily for pts ≥6 y and 0.032 mg/kg for pts < 6 y. Part C: 12 pts (median age, 12 y [range, 2-18 y]) were enrolled. No DLTs were observed at 50% or 100% of the dabrafenib age-specific RD in combination with trametinib 0.025 mg/kg in pts ≥6 y. Median Tx duration was 41 wk (range, 11-67 wk); 8 pts continue on Tx. Frequent TRAEs were rash (67%) and pyrexia (50%). Decreased ejection fraction (n = 2) was the only TRSAE in > 1 pt. Assessment of pts < 6 y is ongoing. Conclusions: Age-specific dose, safety, and tolerability of trametinib alone and combined with dabrafenib were defined for children and adolescents; > 50% of pts continue on Tx. Clinical trial information: NCT02124772