A Phase 1 a/b Dose Escalation Trial to Evaluate the Safety and Tolerability of CG-806 in Patients with Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas

INTRODUCTION: CG-806 is a first-in-class, oral, non-covalent, and potent inhibitor of the wild type and all known mutant forms of Bruton's tyrosine kinase (BTK, including the C481S mutation), as well as all forms of the FLT3 receptor tyrosine kinase and multiple oncogenic signaling pathways, but with a selectivity that spares normal cells by avoiding off-target inhibition of kinases known to produce toxicities. Such a kinase inhibitory profile is key to the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and certain B-cell malignancies, which are driven by dysregulated BTK, can become resistant to covalent BTK inhibitors (ibrutinib and others) by BTK C481S mutation, and may become refractory to various therapies by other compensatory kinase signaling pathways such as SYK, SRC, STATs, ERK, AKT, NFĸB and MYC. In cell lines and primary samples from CLL and B-cell ALL patients, CG-806 potently suppressed the driver and compensatory pathways (inhibited phosphorylation of BTK, FLT3, PDGFRα, SYK, SRC, ERK, STAT5 and AKT, decreased MYC levels), induced cleavage of caspase 3, potently killed cells insensitive to ibrutinib or venetoclax, and caused enhanced cell killing in combination with venetoclax. Consequently, CG-806 is currently being evaluated in a Phase I a/b trial in patients with CLL/SLL or non-Hodgkin's lymphomas (NHLs).

METHODS: A Phase 1 a/b trial of CG-806 in patients with CLL/SLL or non-Hodgkin's lymphomas (NCT03893682) is underway to evaluate the safety, tolerability and potential effectiveness of CG-806 for the treatment of patients for which either the standard treatment has failed, is no longer effective, or can no longer be administered safely. The starting dose is 150 mg PO BID and the dose will be escalated in 150 mg increments with only 1 patient at the two lowest dose levels and a minimum of 3 at the higher dose levels. Once the maximum tolerated dose or recommended dose is reached, up to 100 patients will be enrolled in the expansion cohort at the recommended dose. Primary objectives of the trial are to determine the safety and tolerability of CG-806 at the dose given orally every 12 hours that maintains a biologically active plasma concentration over a period of 28 days and to establish the recommended Phase 2 dose (RP2D) of CG-806 for future clinical trials in patients with advanced CLL/SLL or NHL. Key secondary objectives are to observe patients for any evidence antitumor activity using FDG PET-CT imaging evaluations and to measure pharmacodynamic biomarkers of drug effect including phospho-BTK levels and selected mRNA levels in peripheral white blood cells, as well as CCL3 and CCL4 circulating levels.

RESULTS: CG-806 oral capsules have been administered at a starting dose of 150 mg BID on a 28-day cycle to the first CLL patient who previously failed ibrutinib, venetoclax, rituximab, idelalisib and other medications. To date (as of July 2019), in this first patient who has received more than 40 doses of CG-806 150mg oral capsules, no dose limiting toxicities have been observed, there are no impediments to continuing dosing on study, and the tolerability is consistent with preclinical tolerability findings in rodents and dogs when CG-806 was delivered as an oral gavage. Safety and tolerance vigilance, as well as pharmacokinetic (PK) and pharmacodynamic analyses, will continue into subsequent cycles and dose levels.

CONCLUSIONS: CG-806 is an oral, non-covalent pan-BTK/pan-FLT3 inhibitor designed to suppress multiple oncogenic driver and compensatory signaling pathways in order to directly and potently kill B-cell cancer cells including those insensitive to the ibrutinib covalent BTK inhibitor and the venetoclax Bcl-2 inhibitor. Recruitment and enrollment of patients with R/R CLL/SLL and non-Hodgkin's lymphomas are continuing in a Phase 1a/b dose escalation/expansion trial, and updated safety, PK, and available biomarker data will be presented at the meeting.