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Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-Cell Malignancies

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Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-Cell Malignancies Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory B-cell malignancies Running title: Pharmacodynamic correlates with cerdulatinib tumor response Greg P. Coffey,1 Jiajia Feng,2 Andreas Betz,2 Anjali Pandey,3 Matt Birrell,4 Janet M. Leeds,5 Kenneth Der,6 Sabah Kadri,7 Pin Lu,7 Jeremy Segal,7 Y. Lynn Wang,7 Glenn Michelson,7 John T. Curnutte,2 Pamela B. Conley9 1Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, CA; 2Research and Development, Portola Pharmaceuticals, Inc., South San Francisco, CA; 3Medicinal Chemistry and Chemical Development, Portola Pharmaceuticals, Inc., South San Francisco, CA; 4Corporate Development, Portola Pharmaceuticals, Inc., South San Francisco, CA; 5Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CA; 6Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CA; 7Department of Pathology, University of Chicago, Chicago, IL; 8Clinical Development, Portola Pharmaceuticals, Inc., South San Francisco, CA; 9Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA. Keywords: B-cell chronic lymphocytic leukemia, B-cell lymphoma, non-Hodgkin lymphoma, JAK kinase, SYK kinase 1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abbreviations: ALC, absolute lymphocyte counts; AUC, area under the curve; BCR, B-cell antigen receptor; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; Cmax, maximal plasma concentration; CRP, C-reactive protein; DLBCL, diffuse large B-cell lymphoma; FACS, fluorescence-activated cell sorting; FL, follicular lymphoma; GM-CSF, granulocyte-macrophage colony-stimulating factor; IC50, half-maximal inhibitory concentration; IL, interleukin; JAK, Janus kinase; LC-MS/MS, liquid chromatography tandem-mass spectrometry; MCL, mantle cell lymphoma; NK, natural killer; SLL, small lymphocytic lymphoma; SSCtrough, steady-state minimal plasma concentration; SYK, spleen tyrosine kinase; vWF, von Willebrand factor. Financial support: This study was sponsored by Portola Pharmaceuticals, Inc. Conflict of interest disclosure statement: GPC, JF, AB, AP, MB, JML, KD, JTC, and PBC are employees and stockholders of Portola Pharmaceuticals, Inc. The other authors declare no potential conflicts of interest. Corresponding author: Greg P. Coffey, PhD Portola Pharmaceuticals, Inc. 270 East Grand Avenue South San Francisco, CA 94080 Email: [email protected] Phone: (650) 246-7565 2 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of Translational Relevance (limit = 150 words): 103 words Abstract (limit = 250 words): 250 words Word count for manuscript text (limit = 5,000 words): 4,856 words Total number of figures and tables (limit = 6): 6 figures Total number of references (limit = 50): 48 references This manuscript contains a supplementary appendix. 3 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of Translational Relevance The spleen tyrosine kinase (SYK) and Janus kinase (JAK) family members can contribute to both tumor intrinsic and microenvironment-derived survival signals, promoting cancer cell growth in certain B-cell malignancies. The dual inhibitor of SYK and JAK, cerdulatinib, was therefore developed and investigated in a phase I dose-escalation study. To further explore the mechanism of action of cerdulatinib antitumor activity in patients with relapsed/refractory B-cell malignancies, multiple pharmacodynamic measures of SYK/JAK inhibition were correlated with tumor response. These data are presented herein. A phase IIa study is ongoing to confirm safety and antitumor activity of cerdulatinib in additional patients with B- or T-cell malignancies. 4 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT 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. 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 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 5 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382) 6 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 17, 2018; DOI: 10.1158/1078-0432.CCR-18-1047 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Normal B-cell development depends on signals originating from the B-cell antigen receptor (BCR) and various costimulatory cytokines; importantly, these cell signaling networks may also cooperate to support the growth and survival of subsets of B-cell malignancies. This was originally observed with diffuse large B-cell lymphoma (DLBCL) cell lines, which demonstrate a reliance on spleen tyrosine kinase (SYK) (1,2) and Janus kinase (JAK) (3) signaling for survival. Selective inhibition of SYK additionally antagonizes BCR survival signals in primary chronic lymphocytic leukemia (CLL) and blocks tumor cell secretion of chemokine ligands 3 and 4, which facilitate recruitment of accessory cells to the tumor microenvironment (4,5). Proinflammatory cytokines are elevated in patients with CLL (6) and are of predictive value for disease outcome (7-9). Interleukin (IL)-2, IL-4, and interferon alpha enhance CLL survival in vitro by upregulation of BCL-2 family members (10-13). By this mechanism, IL-4 protects cultured CLL cells from death induced by fludarabine and chlorambucil (14). Moreover, IL-4 promotes surface IgM expression and restores BCR signaling capacity in CLL cells, which is associated with resistance to idelalisib and ibrutinib in vitro (15-17). Study of the tumor microenvironment of follicular lymphoma (FL) also suggests an important IL-4 signaling axis that is critical for survival. In contrast to unaffected nodes, lymph nodes from patients with FL have greater numbers of follicular helper T cells that express high levels of IL-4 (18). A subpopulation of patients with FL present with activating mutations to STAT6; these mutations prolong the transcription factor’s engagement with its promoter and overall retention in the nucleus, again suggesting FL tumors rely on IL-4 signaling (19). Finally, subsets of DLBCL cell lines, particularly of the activated B-cell–like subtype, appear to generate an 7 Downloaded from clincancerres.aacrjournals.org
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