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

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.

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 IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/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 ID:NCT01994382).

• Authors: Greg P Coffey, Jiajia Feng, Andreas Betz, Anjali Pandey, Matt Birrell, Janet M Leeds, Kenneth Der, Sabah Kadri, Pin Lu, Jeremy Segal, Y Lynn Wang, Glenn Michelson, John T Curnutte, Pamela B Conley
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 4 Pg. 1174-1184 (02 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30333224 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide
• Protein Kinase Inhibitors
• Pyrimidines
• Receptors, Antigen, B-Cell
• Sulfones
• Janus Kinases
• SYK protein, human
• Syk Kinase

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• B-Lymphocytes (drug effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Janus Kinases (antagonists & inhibitors, genetics)
• Lymphoma, B-Cell (drug therapy, genetics, pathology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, pathology)
• Lymphoma, Non-Hodgkin (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Pyrimidines (administration & dosage, pharmacokinetics)
• Receptors, Antigen, B-Cell
• Signal Transduction (drug effects)
• Sulfones (administration & dosage, pharmacokinetics)
• Syk Kinase (antagonists & inhibitors, genetics)
• Tumor Microenvironment (drug effects)