Abstract CT239: Early clinical findings from a phase 1a/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
Authors: Zhang Hongying , Rastgoo Nasrin , Benbatoul Khalid , Sheng Susan , Thayer Matthew , Bejar Rafael , Howell Stephen , Rice William 
Published: September 2020

Abstract
Introduction: 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 potently suppressed the oncogenic BCR signaling and compensatory pathways, 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 (NCT03893682). Methods: 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 pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity of CG-806. Eligible patients are those 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 January 2020, a total of 5 patients have been treated with CG-806 at doses of 150 mg (n=1), 300 mg (n=1) and 450 mg (n=3). The first patient, who has CLL with TP53 mutation and had previously failed chemotherapy, ibrutinib, venetoclax, rituximab, and idelalisib, remains on treatment after 8 cycles at 150 mg BID. 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. Three patients are currently being treated at the 450 mg BID level. There have been no TEAEs. Steady-state (Cmin) plasma levels of CG-806 over multiple cycles in patients 1 and 2 were 0.06-0.1 and 0.6-1 µM, respectively. The level of phospho-BTK Tyr223, 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 but not of patient 1 (dose level 1). To date, CG-806 has maintained a favorable safety profile and there has been no suggestion of myelosuppression at any dose level. Conclusions: CG-806 was well-tolerated in the patients treated at 150 and 300 mg BID over multiple cycles. There have been no TEAE. Oral absorption was sufficient to produce plasma concentrations in humans approaching exposures known to be effective in murine leukemia models. Pharmacodynamic studies using patient plasma documented engagement of the BTK target. Enrollment of patients with R/R CLL/SLL and NHL is continuing in this Phase 1a/b dose escalation/expansion trial, and updated safety, PK, and available biomarker data will be presented at the meeting.
Citation Format: Hongying Zhang, Nasrin Rastgoo, Khalid Benbatoul, Susan Sheng, Matthew Thayer, Rafael Bejar, Stephen Howell, William Rice. Early clinical findings from a phase 1a/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 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT239.