Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B Cell Malignancies: Results from a Phase I Dose Escalation Study

Abstract

Preclinical studies suggest that the spleen tyrosine kinase (SYK) and Janus kinase (JAK) family members can contribute to both tumor intrinsic and microenvironment-derived survival signals. A dual inhibitor of these kinases (cerdulatinib) was therefore developed, and a phase I dose-escalation study was completed to understand tolerability and efficacy, and their relationship to pharmacokinetics (PK) and pharmacodynamics (PD). Here, we report on PK/PD relationships and associations with tumor response in patients from the phase I dose-escalation portion of the clinical trial (NCT01994382).Repeat CT scans were obtained from 6 patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), 12 patients with follicular lymphoma (FL), 12 patients with diffuse large B cell lymphoma, and 6 patients with mantle cell lymphoma. Meaningful clinical responses were observed in patients with CLL/SLL and FL, as previously reported (Hamlin et al, 2016); hence, the correlation between tumor response and PD markers was examined in these patient populations.Complete inhibition of SYK and JAK signaling pathways was achieved in whole blood of dosed patients at tolerated exposures. The level of target inhibition in blood correlated with serum cerdulatinib concentration, and the concentrations at which 50% inhibition was acheived (IC50) against B cell antigen receptor (BCR), interleukin (IL)-2, IL-4, and IL-6 signaling pathways ranged from 0.22-1.08 μM, depending on the phosphorylation event measured. Significant correlations were observed between inhibition of both SYK and JAK signaling pathways and tumor response, most notably the BCR and IL-4 signaling pathways. Serum markers of inflammation were also reduced following cerdulatinib administration, several of which significantly correlated with tumor response, including β-2 microglobulin, C-reactive protein, interferon γ-induced protein 10 (IP10), and macrophage inflammatory protein 3β (MIP3β). Of note, lymphocytosis was observed in CLL, SLL, and FL patients. Evidence of diminished tumor cell surface expression of CD69 and CD86, diminished CD5 expression (a negative regulator of BCR signaling), and enhanced C-X-C chemokine receptor type 4 (CXCR4) expression were observed in 2 patients with CLL, consistent with suppression of BCR and IL-4 signaling.Fresh tumor samples were obtained from the peripheral blood of 6 CLL patients treated with cerdulatinib, as well as archival tumor biopsies obtained from 4 FL patients and 1 MCL patient, which were submitted for next-generation sequencing. Clinical activity was observed in CLL patients bearing mutations to NOTCH1, ATM, p53, and KRAS, which are among the most frequently observed mutations in this disease. One of the responding patients bore a 17p deletion. Importantly, 2 patients with ibrutinib-relapsed CLL who progressed within the first cycle of therapy with cerdulatinib had 3 mutations in common: p53, EP300, and BTK (C481S). Genetic correlates in FL were more limited, with data on 4 patients, 3 of whom had evidence of tumor reduction and 1 which progressed. The 2 best responding patients with whom we have genetic information bore mutations to ZMYM3, KMT2D, FAT4, BCL2, BCL6, CD79B, and STAT6 . Lastly, strong clinical activity was observed in a transformed FL patient who presented with increased MYC, BCL2, and BCL6 expression by immunohistochemistry (“triple-hit” lymphoma).These data demonstrate the ability of cerdulatinib to potently and selectively inhibit SYK and JAK signaling at tolerated exposures in patients with relapsed/refractory B cell malignancies. Moreover, the extent of target inhibition, as well as suppression of inflammation, correlated with tumor response. Cerdulatinib is currently under investigation as part of a phase IIa study to further evaluate efficacy and tolerability in this population. DisclosuresCoffey:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Feng:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Betz:Portola Pharmaceuticals, Inc: Employment, Equity Ownership. Pandey:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Birrell:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Der:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Kadri:Portola Pharmacueticals, Inc.: Research Funding. Lu:Portola Pharmacueticals, Inc.: Research Funding. Segal:Portola Pharmacueticals, Inc.: Research Funding. Wang:Karyopharm: Research Funding; Portola: Research Funding. Michelson:Portola Pharmacueticals, Inc.: Employment. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Conley:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties.