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Authors Hongying Zhang , Nasrin Rastgoo , Khalid Benbatoul , Susan Sheng , Matthew Thayer , Stephen Howell , William Rice , Rafael Bejar
Abstract Text Background: CG-806 potently and reversibly inhibits wild type and ibrutinib-resistant C481S-mutant forms of the Bruton’s tyrosine kinase (BTK). In cell lines and primary samples from CLL patients, CG-806 suppressed the oncogenic BCR signaling and compensatory pathways (including SYK, ERK, AKT, MAPK, PDGFRα and FLT3), killed cells insensitive to ibrutinib or venetoclax at low nM concentrations, 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 (NCT03893682). Aims: The primary objectives of the clinical study are to assess the safety and tolerability of CG-806, and to determine the recommended Phase 2 dose (RP2D) for future clinical trials in patients with advanced CLL/SLL or NHL. Key secondary objectives are to assess the PK profile, PD activity, preliminary evidence of antitumor activity of CG-806, and to select 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 February 2020, a total of 6 patients have been treated with CG-806 at doses of 150 mg (n=1), 300 mg (n=1) and 450 mg (n=4). The first patient at 150 mg BID, who has CLL with TP53 mutation and had previously failed chemotherapy, ibrutinib, venetoclax, rituximab, and idelalisib, remains on treatment after 8 cycles. The second patient, who has unmutated-IGHV CLL and marrow involvement, entered the study with severe neutropenia and thrombocytopenia and was treated at 300 mg BID for 4 cycles without further decline of platelet level. The second patient experienced lymphocytosis upon initiation of CG-806 therapy, and the level of phospho-BTK Y223, one of CG-806 PD biomarkers detected by ELISA assay, was significantly reduced in the whole blood of patient 2 (dose level 2) collected at 4 hours post dose. Plasma levels of CG-806 over multiple cycles attained in patient 2 were sufficient to significantly reduce phosphorylated BTK-Y551, BTK-Y223, SYK-Y525/526 and ERK-T202/Y204 in EOL-1 reporter cells, as determined by plasma inhibitory activity assay, documenting target engagement at the 300 mg BID dose level. The maximum (Cmax) and steady-state (Cmin) plasma levels and area under the curve (AUClast) of CG-806 on cycle 2 day 1 in patient 2 were 1.20 µM, 0.81 µM, and 8.06 µM*hr, respectively, and remained at similar levels over multiple cycles. Three patients (2 follicular lymphoma and 1 CLL/SLL) are currently being treated at the 450 mg BID level. There have been no drug related TEAEs and no evidence of myelosuppression at these dose levels. Conclusion: CG-806 has been well-tolerated in the patients treated at 150, 300, 450 mg BID over multiple cycles. There have been no drug related TEAEs. Oral absorption was sufficient to produce plasma concentrations in humans known to be effective in murine leukemia models. Pharmacodynamic studies using patient whole blood and plasma documented engagement of the BTK target. Enrollment of patients with R/R CLL/SLL and NHL is continuing and updated safety, PK, and available biomarker data will be presented at the meeting.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 mutant chronic lymphocytic leukemia predicted - sensitive CG-806 Case Reports/Case Series Actionable In a Phase I trial, CG-806 treatment was well-tolerated, and a patient with chronic lymphocytic leukemia harboring a TP53 mutation stayed on treatment for more than 8 cycles (25th Annual Congress of EHA (Jun 2020), Abstract EP711; NCT03893682). detail...