Background
SAR’245 is a clinical-stage site-specific PEGylated human interleukin-2 (IL-2) that selectively engages IL-2 alpha receptor binding but retains near-native-binding affinity for beta/gamma complex. This results in a unique ‘T-cell remodeling’ mechanism of action (MoA) characterized by robust increase in CD8+ T cells coupled with potent natural killer (NK) cell activation/expansion without inducing regulatory T-cell expansion. Herein, we integrate clinical PK/PD biomarkers and safety to identify RP2D for SAR’245.
Methods
Intravenous SAR’245 monotherapy was administered every 3 weeks (Q3W) [Cohort B], every 2 weeks (Q2W) [Cohort A], or every week (QW) [Cohort G]. Peripheral blood and serum were collected for PD biomarker assessment including circulating immune cells, cytokines, and efficacy surrogate biomarker circulating DNA (ctDNA). A semi-mechanistic population PK/PD model was developed to depict IL-2-induced cell trafficking away from blood to expansion sites immediately after administration and subsequent reappearance of expanded cells in blood. Joint modeling was carried out to explore dose-biomarker and dose-safety relationships. RP2D was selected based on PK, PD, safety, and efficacy surrogate biomarker data.
Results
Samples from 32 (Cohort A), 35 (Cohort B), and 15 (Cohort G) subjects were available. Simulations with Pop-PK-PD model suggested: 1) more frequent dosing triggers additional expansion and continuous accumulation of CD8+ T cells (4.94 [1.77–14.39], 2.14 [1.04–8.01], 1.38 [1.00–5.06]-fold increase) and NK cells (16.04 [4.50–45.20], 5.53 [1.27–23.03] and 2.65 [1.02–13.76]-fold increase) when administering 16µg/kg at QW, Q2W, and Q3W, respectively; 2) the expansion capacity flattens out at higher dose levels for CD8+ T cells (7.12 [2.41–18.95], 2.77 [1.08–10.95] and 1.62 [1.00–6.84]-fold increase) and NK cells (22.02 [6.58–55.87], 7.56 [1.44–29.57] and 3.34 [1.03–17.65]-fold increase) when administering 24µg/kg at QW, Q2W, and Q3W, respectively; data presented as median [90% confidence interval]. The joint modeling integrating CD8+ T cells and NK cells, dose-limiting toxicity (DLT), and ctDNA-derived molecular responses suggested QW dosing at 16 or 24 µg/kg could serve as an adequate dosing schedule to expand MoA biomarkers.
Conclusions
The analysis lays the groundwork in establishing the novel joint modeling platform which integrates the biological responses of biomarkers, the PK/PD model and the DLT safety parameters. Such a quantitative approach can be useful to support dosing selection when there are challenges of limited patient number and tumor type heterogeneity in early clinical studies.
Acknowledgements
We acknowledge Tjokosela Tikiso for contributions to PK/PD modeling. This study was sponsored by Sanofi. Medical writing support was provided by Aruna Meka and Deepa Warrier from Sanofi.
Trial Registration
NCT04009681.
Ethics Approval
The study was conducted in compliance with the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice guidelines, and 250 other applicable laws, rules, and regulations. The IRB approved the protocol. All participants provided informed consent prior to the initiation of the study.