narazaciclib (HX301)

P1, N=20, Completed, Hangzhou Hanx Biopharmaceuticals, Ltd. | Active, not recruiting --> Completed

Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

P1, N=36, Recruiting, Onconova Therapeutics, Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy.

P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd. | Trial primary completion date: Apr 2023 --> Dec 2023

Previous studies have suggested that narazaciclib (ON123300), a second-generation, orally bioavailable and clinical-stage CDK4/6 inhibitor (CDKi), may trigger cell cycle arrest and significant tumor growth inhibition (TGI) in BTKi-resistant MCL models...When combined with ibrutinib, but not with the second generation therapeutic acalabrutinib, narazaciclib achieved significant synergistic antitumor activity in both BTK-sensitive and BTK-resistant cells... Narazaciclib, due to its completely distinct MoA from BTKi involving the direct modulation of the cell cycle, can achieve significant synergistic activity with ibrutinib in vitro and in vivo, especially in BTKi-resistant models of MCL. Ongoing phospho-proteomics and genetic edition assays will help deciphering the molecular bases of this unique drug cooperation at the cell cycle level. Encore Abstract - previously submitted to AACR 2023

P1/2, N=60, Recruiting, Onconova Therapeutics, Inc. | Not yet recruiting --> Recruiting

Docking data showed a higher affinity of narazaciclib with BUB1 compared to palbociclib and abemaciclib. Combination of narazaciclib with autophagy inhibitors sensitized several breast cancer cells to cell death. Narazaciclib treatment may promote antitumor immunity by influencing the expression of various immune modulators in the tumor cells which needs to be further validated in preclinical animal models; and ultimately in the clinic.

HX301 also suppressed AM7577 growth, likely due to the suppression of FLT3-ITD activity since we previously reported FLT3-ITD being the driver mutation in this model which responded to AC220, a FLT3 TKi...Further preclinical/translational studies are being conducted in order to reveal predictive biomarkers, in addition to FLT3 mutation and CSF1R expression/mutations. We believe that HX301 could be a potential candidate for treating subset of AML, warranting further clinical investigation.

P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd.

P1/2, N=60, Not yet recruiting, Onconova Therapeutics, Inc.