Preclinical And Clinical Studies And Modeling And Simulation To Identify Phase Ii Dose For Cerdulatinib: A Dual Syk/Jak Inhibitor For The Treatment Of B-Cell Malignancies

Background. Subsets of B cell lymphomas appear to rely on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, and thus a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways. Cerdulatinib is a dual SYK/JAK inhibitor being evaluated in patients with relapsed/refractory B cell malignancies in a dose escalation study. Patient PK and PD parameters indicated nonlinearity at doses above 30 mg QD. Exposure at the 45 mg dose was 3-fold higher than at 30 mg QD. As the dose was further increased up to 100 mg QD, the Cssmax and AUC values plateaued. PD results also appeared to plateau achieving approximately 50-90% target inhibition in peripheral blood assays at steady-state Cmin to Cmax, respectively. The target therapeutic exposure for oncology, based on pre-clinical models, is a Cssmin u003e1.5uM which would lead to u003e90% SYK/JAK inhibition at the trough concentration Objective. Pre-clinical and clinical PK/PD relationships and correlations between SYK/JAK inhibition and tumor response will be presented. A physiological-based PK (PBPK) model was developed to elucidate the relationship between dose, dosing schedule, and exposure. The goal of developing a PBPK model was to provide a strategy to increase exposure in patients to therapeutic target levels. Methods. This is a 3+3 dose escalation study with 28-day cycles and doses studied from 15 mg to 100 mg QD, and up to 45 mg BID. PK, PD, and safety were monitored. SYK and JAK inhibition was determined by multiple whole blood assays measuring signaling via the B cell antigen receptor, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Physiochemical parameters and in vitro ADME parameters were used to construct a PBPK model. Results. Exposure correlated well with PD and tumor responses in the dose escalation study. Low pH dependent solubility was identified as the rate-limiting factor in increasing plasma concentrations. The PBPK model predicted BID dosing would result in significantly higher plasma levels. The Cssmin concentration of QD doses from 40 to 100 mg QD was ∼0.70 uM while for the 45 mg BID dose for the first 3 patients the Cssmin was ∼1.5 uM. Complete target inhibition at this Cssmin was achieved with good tolerability. Conclusions. The preliminary PBPK model identified the pH dependent low solubility of cerdulabinib as the rate-limiting factor of absorption with increasing doses. Subsequent evaluation of 45 mg BID doses in patients provided higher Cmin, Cmax, and AUC values for all patients treated at this dose level and PD markers indicated complete inhibition of both pathways. We are now enrolling additional patients at this dose, in preparation for selecting our final phase II dose. Citation Format: Janet M. Leeds, Greg Coffey, Anjali Pandey, Pam B. Conley, Karen Rowland Yeo, Alice B. Ke, John T. Curnutte, Glenn Michelson. Preclinical and clinical studies and modeling and simulation to identify phase II dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT144.