alrizomadlin (APG-115)

P1/2, N=230, Active, not recruiting, Ascentage Pharma Group Inc. | Recruiting --> Active, not recruiting | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=41, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Dec 2025

APG-115 downregulated Solute Carrier Family 7 Member 11 (SLC7A11) expression, contributing to lipid peroxidation and affecting PD-L1 expression in TC. Our study expands the clinical application value of APG-115 in cancer treatment, especially by further exploring the complex interplay between APG-115, PD-L1 immunotherapy, and ferroptosis.

The combination further amplified the effects on Ki67, BCL-2, and p21 expression, leading to enhanced tumor growth inhibition. In summary, this study demonstrates that APG-115 exerts antitumor effects in cervical cancer, and its combination with bortezomib further enhances this inhibitory effect, probably through maximal activation of p53 and inhibition of BCL-2, suggesting a potential application of APG-115 in the treatment of cervical cancer.

Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.

P1/2, N=41, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

In vivo and in vitro experimental have shown that APG-115 combined with anlotinib can promote AML cells apoptosis and inhibit the progression of disease is independent of the p53 status.

P2, N=15, Not yet recruiting, National Cancer Institute (NCI)

Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

P1/2, N=41, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jan 2025 --> Jun 2025 | Trial primary completion date: Jul 2024 --> Dec 2024

P2, N=78, Recruiting, Ascentage Pharma Group Inc. | N=36 --> 78 | Trial completion date: May 2025 --> May 2027 | Trial primary completion date: May 2024 --> May 2026

Collectively, this study demonstrates that APG-115 activates p53 and thus inhibits multiple pro-survival mechanisms, which provides a rational explanation for APG-115 efficiency in inducing cell apoptosis in CLL. The synergistic effect of APG-115 with ABT-199 suggested a potential combination application in CLL therapy.