TY - JOUR
T1 - Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory b-cell malignancies
AU - Coffey, Greg P.
AU - Feng, Jiajia
AU - Betz, Andreas
AU - Pandey, Anjali
AU - Birrell, Matt
AU - Leeds, Janet M.
AU - Der, Kenneth
AU - Kadri, Sabah
AU - Lu, Pin
AU - Segal, Jeremy
AU - Wang, Y. Lynn
AU - Michelson, Glenn
AU - Curnutte, John T.
AU - Conley, Pamela B.
N1 - Funding Information:
This study was sponsored and financially supported by Portola Pharmaceuticals, Inc. We thank the patients who participated in this study, as well as their families and the research staff at each site. Preparation of the manuscript was supported by Iwona Bucior, PhD, of Portola Pharmaceuticals, Inc. Editorial support was provided by Kimberly Brooks, PhD, CMPP, of SciFluent Communications.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2/15
Y1 - 2019/2/15
N2 - 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. Patients and Methods: 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 IC 50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 mmol/L, 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 2 patients with CLL, consistent with BCR and IL4 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
AB - 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. Patients and Methods: 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 IC 50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 mmol/L, 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 2 patients with CLL, consistent with BCR and IL4 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
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U2 - 10.1158/1078-0432.CCR-18-1047
DO - 10.1158/1078-0432.CCR-18-1047
M3 - Article
C2 - 30333224
AN - SCOPUS:85061567008
SN - 1078-0432
VL - 25
SP - 1174
EP - 1184
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -
