Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory B-cell malignancies
Mené sur 43 patients atteints d'une hémopathie maligne à cellules B récidivante ou réfractaire (8 cas de leucémie lymphocytaire, 13 cas de lymphome folliculaire, 16 cas de lymphome diffus à grandes cellules B, 6 cas de lymphome à cellules du manteau), cet essai de phase I évalue les caractéristiques pharmacodynamiques, l'efficacité, du point de vue de la réponse tumorale, et la dose maximale tolérée du cerdulatinib, un inhibiteur de SYK et de JAK
Purpose: Preclinical studies suggest SYK and JAK contribute to tumor intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated. Experimental Design: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses. Results: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration and IC50s against B-cell antigen receptor (BCR), IL-2, IL-4, and IL-6 signaling pathways were 0.27-1.11 μM, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in two patients with CLL, consistent with BCR and IL-4 suppression and loss of proliferative capacity. Conclusions: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382)