alrizomadlin (APG-115)

This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.

Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity.

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=15 --> 0 | Trial completion date: Dec 2027 --> Mar 2026 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2027 --> Mar 2026

APG-115 effectively inhibits proliferation, induces apoptosis, and enhances radiosensitivity in p53 wild-type colorectal cancer. These findings support APG-115 as a promising therapeutic candidate for colorectal cancers retaining functional p53.

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

To address these challenges, we developed a novel nanotherapeutic platform (FAB) that integrated γ-Fe2O3 nanoparticles with the MDM2-p53 inhibitor APG-115, sensitizing tumor to therapy via targeting p53/SLC7A11 axis to bidirectionally regulate ferroptosis and induce cell senescence...Notably, senescent tumor cells exhibit increased thermal susceptibility under AMF, ultimately leading to selective apoptosis. Our study not only elucidated the crosstalk between p53 activation and ferroptosis facilitation in mediating senescence but also provided a promising strategy for enhanced tumor treatment.

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