Baneyx G. (1), Guerreiro N. (2), Meille C. (1), Fjaellskog M-L. (3) and Burks H. (3)
(1) Novartis Pharma AG, Biostatistical Sciences and Pharmacometrics, Basel, Switzerland; (2) Novartis Institutes for BioMedical Research, PK Sciences, Basel, Switzerland; (3) Novartis Institutes for BioMedical Research, Translational Clinical Oncology, Cambridge, MA, USA.
Objectives: Lacnotuzumab is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor (CSF-1) known as the primary regulator of survival, differentiation and function of M2 macrophages promoting tumor [1]. Pharmacokinetics of lacnotuzumab was characterized by a target-mediated drug disposition (TMDD) in healthy volunteers. Lacnotuzumab is currently being explored in patients with advanced malignancies and triple negative breast cancer (TNBC). An over-expression of circulating total (free + complex) CSF-1 at baseline was observed in cancer patients and this might impact the dose-exposure relationship. The objectives were i) to develop a TMDD model to characterize the dose-target engagement relationship; ii) to use model-based simulation to determine the lacnotuzumab dose leading to a substantial depletion of circulating free CSF-1 in cancer patients.
Methods: In a first step, circulating free lacnotuzumab and total CSF-1 data collected in healthy volunteers after single IV infusion of lacnotuzumab (1-20 mg/kg) was used to select the TMDD model structure. In a second step, the data collected in cancer patients after IV infusion every 3 weeks of lacnotuzumab (1-10 mg/kg) combined with spartalizumab (advanced malignancies) or carboplatin/gemcitabine (TNBC) was incorporated into the analysis dataset to refine the model structure by considering the impact of circulating total CSF-1 over-expression at baseline in cancer patients. Circulating free lacnotuzumab and total CSF-1 samples were collected on days 1, 2, 4, 8 and 15 of cycles 1 and 4 as well as on day 1 of other cycles. Then, model-based simulations were performed for pre-defined dosing regimens (1-20 mg/kg Q3W). Simulated circulating free lacnotuzumab exposure metrics and free CSF-1 depletion at end of cycle 2 were compared by dosing regimens in healthy volunteers and cancer patients. Model parameters were estimated by a nonlinear mixed effect modeling approach using Monolix2016R1 [2].
Results: Circulating free lacnotuzumab and total CSF-1 kinetics were described by a full TMDD model [3] with typical values for linear clearance (CL) of 0.20 L/h, central volume of distribution (V1) of 3.64 L, peripheral volume of distribution (V2) of 2.65 L and inter-compartmental clearance (Q) of 0.71 L/h. CL and V1 parameters were found to increase with body weight. The circulating free CSF-1 kinetics was described with an indirect response model driven by a synthesis rate (kin) and degradation rate (kout). The estimated circulating free CSF-1 degradation half-life of 26 minutes was in agreement with usual short half-life of cytokines. The complex kinetics was described with a quick association rate (kon), a slow dissociation rate (koff) and an estimated apparent degradation half-life of 44 days. The measured circulating total CSF-1 at baseline was found on average a 3-fold higher level in cancer patients (associated to large variability) compared to healthy volunteers with corresponding median values of 6200 and 2200 pg/mL. Over-expression of circulating total CSF-1 at baseline in cancer patients was modeled by a combination of higher synthesis rate (kin) and lower degradation rate (kout). At doses ≤ 5mg/kg, the model-based simulations suggested a lower circulating free lacnotuzumab through concentrations at end of cycle 2 in cancer patients than in healthy volunteers probably due to higher CSF-1 expression in cancer patients. At higher doses, the difference was limited probably due to target saturation in both populations. Based on current limitations and assumptions, model-based simulations suggested on average a circulating free CSF-1 depletion (% of baseline) of 85 and 98 % in cancer patients for 5 and 10 mg/kg Q3W dosing regimens, respectively.
Conclusions: A full TMDD model was developed to describe the dose-target engagement relationship in both healthy volunteers and patients with advanced malignancies and triple negative breast cancer. Based on current limitations and assumptions, model-based simulations suggested that on average a substantial depletion of the circulating free CSF-1 would be achievable for the administrated dosing regimens in cancer patients. In future developments, the current model will be refined by considering the positive correlation between circulating total CSF-1 at baseline and baseline tumor size. Several TMDD approximations will be tested.
References:
[1] Pixley FJ et al. TRENDS Cell Biol. 2004; 14:628-638.
[2] Kuhn et al. Computational Statistics and Data Analysis 2005; 49:1020-1038.
[3] Dua P. et al. CPT Pharmacometrics Syst. Pharmacol. 2015; 4: 324–337.
Reference: PAGE 27 (2018) Abstr 8667 [www.page-meeting.org/?abstract=8667]
Poster: Drug/Disease Modelling - Oncology