Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone.

Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured.

Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (>80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state C_min and C_max concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more.

Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab.