Abstract 4088: First-in-human dose selection for ALKS 4230, an investigational immunotherapeutic agent

Abstract ALKS 4230 is an engineered fusion protein comprised of a circularly permuted interleukin-2 (IL-2) and the IL-2 receptor (IL-2R) α chain, CD25, designed to selectively activate the intermediate-affinity IL-2R, but not the high-affinity IL-2R. Selective activation of the intermediate-affinity IL-2R by ALKS 4230 has the potential to provide enhanced tumor killing as well as improved safety and tolerability. Various in vitro and in vivo studies were conducted to characterize the primary and secondary pharmacodynamics (PD) of ALKS 4230 as well as its pharmacokinetics (PK). The results guided the selection of the starting dose for the ALKS 4230 first-in-human (FIH) clinical study based upon the Minimal Anticipated Biological Effect Level (MABEL) approach. The PK-PD relationship for ALKS 4230 was evaluated in in vitro pharmacology studies in target cells from murine, non-human primate and human donors. The mean EC10 values for activation of NK cells, memory CD8 T-cells and Tregs in target cells from human donors were 0.09, 0.18 and 0.13 nM, respectively. Using the lowest EC10 value of 0.09 nM (0.0031µg/mL) as a surrogate for the MABEL, assuming IV administration to a 70 kg human with 3 L plasma volume, a dose of 0.1 µg/kg would be expected to result in an immediate post-dose concentration of 0.0031 µg/mL. The mean EC50 values for activation of NK cells, memory CD8 T cells and Tregs in target cells from human donors were 0.46, 1.1 and 0.59 nM, respectively. Using the EC50 value as surrogate for minimal effective ALKS 4230 concentration that induces activation of human IL-2R complex, the projected minimal efficacious dose (MED) in humans to achieve a concentration of 0.46 nM (0.016 µg/mL) to 1.1 nM (0.038 µg/mL) is 0.7- 1.6 µg/kg. Based on a MABEL dose of 0.1 µg/kg and projected MED of 0.7- 1.6 µg/kg, the proposed doses to be evaluated in the FIH Phase 1 study are 0.1, 0.3, 1, 3, 10, and 30 µg/kg. In comparison, the projected Cmax at the proposed starting dose of 0.1 µg/kg is > 750-fold lower than the Cmax at the no-observed adverse effect level (NOAEL) in a repeat-dose toxicology study in monkeys. It is also about 3-fold lower than the lowest concentration of ALKS 4230 (0.01 µg/mL) tested in the cytokine release assays at which only slight elevations were observed for IL-6, IL-8, and IFN-γ in a small number of whole blood samples from healthy human donors, similar to those in the low-response control across the concentration range evaluated. Therefore, 0.1 µg/kg is considered a safe starting dose for the FIH study. The PK, PD and toxicology assessments conducted to date support the FIH investigation of ALKS 4230 at the proposed starting dose of 0.1 µg/kg. Citation Format: Lei Sun, Heather C. Losey, Juan Alvarez, Lisa von Moltke, William J. Slichenmyer. First-in-human dose selection for ALKS 4230, an investigational immunotherapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4088. doi:10.1158/1538-7445.AM2017-4088