Dabrafenib and Trametinib dose optimization in 6-17 year old tumor agnostic patients based on established efficacy surrogate targets in adults
Maja Skataric, Yu-Yun Ho, Mark Russo, Eugene Tan, and Bart Hendriks
Novartis
Objectives: To support pediatric dose selection of solid formulations of dabrafenib and trametinib in 6 to 17 year old patients with BRAF V600E–mutated solid tumors.
Methods: Data from two pediatric PhI/IIa and one Ph II study in solid tumors were used to update the existing adult popPK models for dabrafenib and trametinib using a Bayesian approach, and additional covariates were tested. The updated models were utilized to run simulations at different doses of trametinib and dabrafenib that match adult PK and other clinical criteria to support the dose selection for dabrafenib and trametinib solid formulations in combination in 6 to 17 year old pediatric patients. From the established exposure efficacy relationship in adults, an increased response rate (76%) was noted with higher trametinib average concentration (Cavg ≥ 10 ng/mL), hence achieving the steady state Cavg of 10 ng/mL of higher was set as the efficacy target of trametinib in this analysis. For dabrafenib, a response rate of ~75% was observed at dabrafenib Cavg of around 250 ng/mL in the adult melanoma patients. In addition, a flat exposure-response relationship was observed around Cavg of 250 ng/mL to 600 ng/mL. Thus, a Cavg target range of 200 to 300 ng/mL was used to guide the dose recommendation of dabrafenib in this analysis. The proposed doses were constrained to not exceed the highest clinically tested dose of 0.04 mg/kg for trametinib and the upper recommended dose of 5.9 mg/kg/day for dabrafenib to ensure patient safety, and were limited by the available dose strengths (0.5 mg and 2 mg tablets for trametinib, and 50 mg and 75 mg capsules for dabrafenib).
Results: Doses explored in the three studies were mg/kg –based and adjusted by age, moreover different age cut-off was used for dabrafenib and trametinib (<6 and year of age for trametinib and <12 and and year of age for dabrafenib).
Our Pop PK pediatric model indicated that body weight (not age) was an important covariate for both dabrafenib and trametinib, and was identified as the main patient-related factor affecting exposure. Therefore, body weight was used to guide pediatric dosing using available capsule and tablet strengths for dabrafenib and trametinib, respectively, both because of large weight variability for each age and to avoid the requirement for a dose change when reaching an age threshold) in pediatric 6 to 17 year old patients.
Due to combination of dabrafenib and trametinib, an effort was made to align as much as possible dabrafenib and trametinib posology’s body-weight groups.
Conclusions: Final posology of dabrafenib and trametinib in combination in 6-17 tumor agnostic patients was based on popPK modeling and simulations.
The following BID dosing scheme is recommended for dabrafenib in 6-17 year old tumor agnostic subjects based on the simulations from the estimated pop PK model in the 6 to 17 year old tumor agnostic patients: flat dose of 150 mg BID (corresponding to ≤5.9 mg/kg/day doses) for subjects weighing ≥51 kg, dose of 100 mg BID (corresponding to doses between 4.0-5.26 mg/kg/day) for those with body weight in the range 38-50 kg, and 75 mg BID (corresponding to 4.1-5.8 mg/kg/day) for 26-37 kg. No dose recommendation is made for patients below 26 kg. For trametinib, the following dosing scheme was recommended: flat dose of 2 mg QD for subjects weighing 51 kg or more, dose of 1.5 mg QD for those with body weight in the range 38-50 kg, 1 mg QD for 26-37 kg. No dose recommendation is made for patients below 26 kg.
Dabrafenib and trametinib are approved by the FDA in June 2022 as the first tumor-agnostic therapy for BRAF V600E–mutated solid tumors in both adults and 6 to 17 years old pediatric patients.
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