A Phase 1 a/b Dose Escalation Study of the Mutation Agnostic BTK/FLT3 Inhibitor CG-806 in Patients with Relapsed or Refractory CLL/SLL or Non-Hodgkin’s Lymphomas

INTRODUCTION: CG-806 is a potent, non-covalent oral inhibitor of Bruton’s tyrosine kinase (BTK), FMS-like tyrosine kinase 3 (FLT3) and certain other validated driver kinases of malignancies, while sparing kinases typically associated with clinical toxicity. In cell lines and primary samples from chronic lymphocytic leukemia (CLL) patients, CG-806 suppressed BCR signaling (LYN, SYK, BTK, AKT, ERK) and pathways operative in AML (FLT3, AKT, CSF1R, MAPK, PDGFRα, others), killed malignant B-cell cells insensitive to ibrutinib or venetoclax at low nM concentrations, and showed enhanced activity in combination with venetoclax. CG-806 is currently being evaluated in a Phase 1 a/b trial in patients with CLL and select relapsed or refractory B-cell malignancies (NCT03893682). A parallel Phase 1 a/b clinical study of CG-806 in patients with relapsed or refractory (R/R) FLT3-mutant or FLT3-wildtype AML is in progress (NCT04477291).

AIMS: The primary objectives of the clinical study NCT03893682 are to assess the safety and tolerability of CG-806 and to determine the recommended Phase 2 dose for future clinical trials in patients with advanced CLL/small lymphocytic lymphoma (SLL) or non-Hodgkin lymphoma (NHL). Key secondary objectives include elucidation of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, preliminary evidence of antitumor activity, and selection of a starting dose for a trial in patients with R/R AML.

METHODS: Eligible patients are those with CLL/SLL or NHL for which either the standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated per disease specific guidelines. CG-806 is administered as capsules PO BID in 28-day cycles.

RESULTS: As of July 24, 2020, a total of 11 patients (age 66.2 ± 7.4 years, male 54.5%, female 45.5%, 5 CLL/SLL, 3 follicular lymphoma, 1 Richter transformation lymphoma, 1 Waldenstrom’s macroglobulinemia, 1 mantle cell lymphoma) with a median of 7 prior systemic regimens have been treated with CG-806 at doses of 150 mg (n=1), 300 mg (n=1), 450 mg (n=5), and 600 mg (n=4). No dose limiting toxicities or related serious adverse event have been reported. The most common drug related or possible related TEAEs included diarrhea, nausea, neutropenia in 3 (27.3%) each; fatigue, lymphocytosis and vomiting in 2 (18.2%) patients each. Drug related or possible related grade 3 or greater TEAEs included diarrhea (n=1, 9.1%) and neutropenia (n=2, 18.2%), but no fevers were reported – those two neutropenia events occurred in a patient with Richter transformation from CLL who had failed 12 prior regimens including ibrutinib, venetoclax, binutuzumab, CAR-NK and CAR-T and was found to have a prior therapy-related myeloid neoplasm after enrollment. Among three classic CLL patients placed on study, all experienced on-target lymphocytosis upon initiation of CG-806 therapy, as well as inhibition of phospho-BTK measured in the whole blood by ELISA and measured by a plasma inhibitor activity (PIA) assay with reporter cells. Steady state plasma levels of CG-806 in patients treated with CG-806 at 300 mg or higher doses dramatically reduced phosphorylated BTK-Y551, BTK-Y223, SYK-Y525/526, ERK-T202/Y204 and FLT3-Y591 in EOL-1 reporter cells, as determined by PIA assay, documenting multi-target engagement. Preliminary PK analyses showed the steady-state (Cmin) plasma levels of CG-806 on cycle 2 day 1 in patients treated with ≥300 mg BID were generally in the 1µM range and were sustained over multiple cycles.

CONCLUSIONS: CG-806 demonstrated a favorable safety profile in patients treated to date with 150, 300, 450 or 600 mg BID over multiple cycles. Oral absorption in patients produced plasma concentrations known to be effective in murine leukemia models. Pharmacodynamic studies using patient whole blood and plasma documented inhibition of SYK, BTK and ERK in the BCR signaling pathway. Further, the trial allowed selection of a potentially therapeutically active starting dose for AML patients (450mg). Enrollment of patients with R/R CLL/SLL and NHL at dose level 5 (750mg) is ongoing and updated clinical data will be presented at the meeting.