Early Results from the Phase Ia/b Dose Escalation Trial of CG-806 in CLL/SLL and NHL

Early results from a phase Ia/b dose escalation trial evaluating the safety and tolerability of CG-806 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small cell lymphoma (SLL) or non-Hodgkin’s lymphomas (NHL) were presented at the American Association for Cancer Research (AACR) Annual Virtual Meeting 2020, held from April 27-28, 2020.¹

“CG-806 is an orally bioavailable non-covalent kinase inhibitor that potently inhibits key clusters of related kinases involved in oncogenic signaling,” Rafael Bejar, MD, PhD, chief medical officer for Aptose, said during a poster presentation of the data at AACR.² “These include the tight cluster of kinases that include BTK, ITK, and related kinases.”

The ongoing trial is treating patients with relapsed or refractory CLL/SLL or NHL who failed or were intolerant to 2 or more lines of established therapy, or for whom no other treatment options are available.³ Patients are dosed twice daily with CG-806 in 28-day cycles, with the researchers expecting to perform 6 dose levels.

“The study design includes an accelerated titration, followed by a 3 plus 3 dose escalation to establish the recommended phase II dose for planned expansion cohorts in future studies,” said Bejar.

The primary objectives for the trial are to assess the safety and tolerability of CG-806, and to determine the recommended phase II dose for future clinical trials in this patient population. Key secondary objectives are to evaluate the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity of CG-806. As of January 2020, a total of 5 patients had 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 (Imbruvica), venetoclax (Venclexta), rituximab (Rituxan), and idelalisib (Zydelig), is still being treated following 8 cycles at 150 mg BID. The second patient, who has unmutated-IgHV CLL and marrow involvement, enrolled with severe neutropenia and thrombocytopenia and was treated at 300 mg BID for 4 cycles without further decline of platelet level. Moreover, 3 patients are currently being treated at the 450 mg BID level. 

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. Further, the level of phospho-BTK Tyr223, 1 of the CG-806 PD biomarkers, was significantly reduced in the whole blood of patient 2 collected at 4 hours post dose, but not of patient 1. 

Thus far, there have been no treatment emergent adverse events. As of the last data collection, CG-806 has maintained a favorable safety profile and there has been no suggestion of myelosuppression at any dose level. 

“CG-806 is a novel and unique cluster-specific kinase inhibitor with activity against clinically validated targets in both lymphoid and myeloid malignancies,” Bejar said. “The ongoing phase 1 study of relapsed/refractory B-cell malignancies has demonstrated the safety of CG-806 to date, pharmacologic activity, and predictable pharmacokinetic behavior.” 

Moving forward, the investigators have also planned a phase I clinical trial of CG-806 in patients with relapsed or refractory acute myeloid leukemia.

References:

1. AACR. 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. AACR website. Published April 27, 2020. abstractsonline.com/pp8/#!/9045/presentation/10667. Accessed April 27, 2020. 

2. AACR. 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. AACR website. Published April 27, 2020. aacr20.onlineeventpro.freeman.com/posters/24211230/Early-clinical-findings-from-a-phase-1ab-dose-escalation-trial-to-evaluate-the-safety-and-tolerability-of-CG-806-in-patients-with-relapsed-or-refractory-CLLSLL-or-non-Hodgkins-lymphomas. Accessed April 27, 2020. 

3. Zhang H, Rastgoo N, Benbatoul K, Sheng S, Thayer M, Howell S, Rice W. 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. Presented at the AACR Annual Virtual Meeting 2020. Published April 27, 2020. d1io3yog0oux5.cloudfront.net/_96dc3a3a3ca91517818da2ef7f053378/aptose/db/841/7258/file/AACR+2020+Slides+-+no+audio.pdf. Accessed April 27, 2020.