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Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with

Greg P Coffey1, Jiajia Feng2, Andreas Betz2

  • 1Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, California. gcoffey@portola.com.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 19, 2018
PubMed
Abstract

Insights

Cerdulatinib effectively inhibited SYK and JAK pathways in patients with B-cell malignancies. This target inhibition correlated with reduced inflammation and improved tumor response, showing promise for treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Immunology

Background:

  • Spleen tyrosine kinase (SYK) and Janus kinase (JAK) pathways are implicated in tumor cell survival and the tumor microenvironment.
  • Understanding the pharmacodynamics of dual SYK/JAK inhibitors is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor.
  • To assess the association between cerdulatinib's target inhibition and tumor response in patients with B-cell malignancies.

Main Methods:

  • A Phase I dose-escalation study of oral cerdulatinib in adult patients with relapsed/refractory B-cell malignancies.
  • Enrollment included patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma.
  • Correlation of tumor response with pharmacodynamic markers was analyzed in patients with notable clinical responses.

Main Results:

  • Cerdulatinib achieved complete SYK and JAK pathway inhibition at tolerated doses.
  • Target inhibition correlated with serum drug concentration and suppressed B-cell antigen receptor (BCR) and cytokine signaling.
  • Reduced inflammation markers and modulation of B-cell activation markers (CD69, CD86) and CXCR4 expression were observed, correlating with tumor response.

Conclusions:

  • Cerdulatinib demonstrates potent and selective inhibition of SYK/JAK signaling in B-cell malignancies.
  • The degree of target inhibition and inflammation suppression correlates with tumor response.
  • These findings support the therapeutic potential of cerdulatinib in relapsed/refractory B-cell malignancies.

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