Katrina Hui(1), YuWei-Lin(1), Anna Largajolli(1), John Maringwa(1), A. Yin Edwards(1), Antonio Goncalves(1), James Smith(1), Elly Barry(2), Eleni Venetsanakos(2), Samuel C Blackman(2), S. Y. Amy Cheung(1)
(1) Certara, Integrated Drug Development, Princeton, NJ, USA, (2) Day One Biopharmaceuticals, Inc, USA
Objectives: Growth, survival, and differentiation, are key cell functions regulated by pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway. The BRAF gene is one of the most frequently altered genes in the MAPK pathway with 90% of mutations consisting of the BRAF V600 point mutation (including amino acid substitutions V600E/K/D/R/M). Alterations in genes involved in this pathway, and dysregulation of the pathway have been described in a number of malignancies, including solid tumors. The oral, highly selective, CNS-penetrant small molecule tovorafenib (DAY101) is a Type II pan RAF kinase inhibitor that is being developed for the treatment of pediatric low-grade glioma and solid tumors harboring RAF alterations. The work presented aims to (i) quantify the relationship between tovorafenib predicted plasma concentrations and selected safety markers (creatine phosphokinase [CPK], haemoglobin and aspartate transaminase [AST]), and (ii) perform simulations to compare safety profiles across different dosing regimens to confirm recommended Phase 2 dose (RP2D) and support future study design.
Methods: A population pharmacokinetic model (1-compartment model with linear clearance and three transit compartments) was developed using data from a phase 1/1b studies (NCT01425008 and NCT02327169). Safety data were obtained from the phase 1 study (NCT01425008) and graphical evaluations identified a relationship between tovorafenib predicted concentrations and CPK, haemoglobin and AST. Direct and indirect models were explored and developed using the individual PK parameter approach for each safety marker and models were selected based on the likelihood ratio test and diagnostic plots. Simulations were then performed using the PK-safety models to compare safety profiles across dosing regimens of interest (doses: 200, 300, 400, 600 and 800 mg; frequency: every 2 to 7 days [i.e. Q2D, Q3D, Q4D, Q5D, Q6D and QW], 3 days on/4 days off or 5 days on/2 days off) for 4 cycles of 28 days. NONMEM 7.4 was used for the development of the PK-safety models and R 4.0.4 was used for exploratory data analysis, model evaluation and simulations.
Results: Overall, 149 subjects had available AST and haemoglobin data, of which, 125 had available PK data. Whereas 94 subjects had available CPK data, of which, 70 had available PK data. The final PK-safety model for AST was an indirect linear model with a tolerance compartment and IIV on kin, slope and baseline. The final PK-safety model for haemoglobin was an indirect linear model with IIV on kin and slope. Baseline was estimated using the B2 method where the observed baseline response is included as a covariate acknowledging the residual variability [1]. The final PK-safety model for CPK included an effect compartment and IIV on Emax and baseline. No covariates were included in any of the models following graphical evaluations and stepwise covariate modelling. As tovorafenib exposure increased, CPK and AST increased and haemoglobin decreased over time.
While the CPK and AST levels increase with increasing dose and dosing frequency, overall, the levels are below the CPK and AST upper limit of normal (135-397 U/L and 31-59 IU/L, respectively) for regimens with lower doses or less frequent dosing .
Conclusions: Using individual predicted tovorafenib concentrations from a developed population PK model, PK-safety models were developed and successfully qualified for CPK, haemoglobin and AST. With an increase in tovorafenib exposure, CPK and AST also increased, whilst haemoglobin decreased. The safety results from the current analysis, in conjunction with the marginal difference in efficacy between Q2D and QW dosing [2] and along with findings obtained from the exposure-safety analysis [3], provide support for clinical evaluation of 600 mg QW as the RP2D.
References:
[1] Dansirikul C, Silber HE, Karlsson MO. Approaches to handling pharmacodynamic baseline response. J Pharmacokinet Pharmacodyn. 2008. 35; 269.
[2] John Maringwa, Anna Largajolli, YuWei-Lin, et.al. Exposure-Response Analysis of Tovorafenib (DAY101) Relating Objective Response to Exposure, Patient- and Disease Characteristics. PAGE 2022 Abstract.
[3] Edwards AY, Largajolli A, Lin, YW et.al Exposure-safety analysis of Tovorafenib (DAY101), an investigational oral pan-RAF kinase inhibitor, in oncology patients with solid tumors. 2022 PAGE 2022 Abstract.
Reference: PAGE 30 (2022) Abstr 10093 [www.page-meeting.org/?abstract=10093]
Poster: Drug/Disease Modelling - Oncology