alrizomadlin (APG-115) / Ascentage Pharma - LARVOL DELTA

APG115XC103: APG-115 Alone or in Combination With APG-2575 in Recurrent or Refractory Neuroblastoma or Solid Tumors (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Phase classification: P1 ➔ P1/2 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Phase classification • Trial primary completion date • Neuroblastoma • Oncology • Solid Tumor

MEKMDM2: Early Phase Study Evaluating MEK and MDM2 Inhibition in Patients With NF1 and MPNST (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: AeRang Kim | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • NF1

CAPS: APG-115 in Salivary Gland Cancer Trial (clinicaltrials.gov) - P1/2 | N=41 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial primary completion date: Jul 2026 ➔ Jan 2026

P53WT • Trial primary completion date • Oncology • Salivary Gland Cancer

Keynote MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Ascentage Pharma Group Inc.; Trial completion date: Jan 2023 ➔ Aug 2023

Clinical • Combination therapy • Trial completion date • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Liposarcoma • Lung Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Urothelial Cancer • Uveal Melanoma • ATM • PD-L1

Keyonte MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Ascentage Pharma Group Inc.; N=143 ➔ 203

Clinical • Combination therapy • Enrollment change • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Liposarcoma • Lung Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Urothelial Cancer • Uveal Melanoma • ATM • PD-L1

Keynote MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=224 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Oct 2023 ➔ Mar 2024 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • Uveal Melanoma • PD-L1

TRIM22-mediated ubiquitin-dependent degradation of FLT3-ITD overcomes TKI resistance in acute myeloid leukemia. (PubMed, Life Med) - "Unlike inhibitors such as AC220, which suppress FLT3 signaling but downregulate p53, APG-115 restores p53 function and induces TRIM22, enabling potent synergy with FLT3 inhibitors. It shows robust efficacy in preclinical xenograft models, reducing tumor burden and extending survival. This work establishes targeting the p53/TRIM22 axis, reliant on TRIM22's unique activity against FLT3-ITD, as a highly promising therapeutic approach for FLT3-ITD AML, including resistant disease."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • FLT3 • TRIM22

Keyonte MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=143; Recruiting; Sponsor: Ascentage Pharma Group Inc.; Trial completion date: Feb 2022 ➔ Dec 2022; Trial primary completion date: Dec 2021 ➔ Sep 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Liposarcoma • Lung Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Urothelial Cancer • Uveal Melanoma • ATM • MDM2 • PD-L1

Keyonte MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=143; Recruiting; Sponsor: Ascentage Pharma Group Inc.; N=67 ➔ 143; Trial completion date: May 2021 ➔ Feb 2022; Trial primary completion date: Sep 2020 ➔ Dec 2021

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Eye Cancer • Liposarcoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Urothelial Cancer • Uveal Melanoma • ALB • ATM • MDM2 • PD-L1

Keynote MK-3475-B66: A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=224 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • Uveal Melanoma • PD-L1

Alrizomadlin (APG-115) alone or in combination with lisaftoclax (APG-2575) for the treatment of pediatric patients with relapsed/metastatic rhabdomyosarcoma (RMS) or other soft-tissue sarcomas (STSs). (ASCO 2026) - P1 | "Alrizomadlin alone or in combination with lisaftoclax showed a manageable safety profile, with preliminary antitumor activity in heavily pretreated R/R RMS, EWS, and NB. The potential mechanisms, safety, and efficacy of alrizomadlin combined with lisaftoclax for pediatric RMS and other STSs warrant further investigation."

Clinical • Combination therapy • IO biomarker • Metastases • Ewing Sarcoma • Febrile Neutropenia • Hematological Disorders • Leukopenia • Neuroblastoma • Neutropenia • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Thrombocytopenia • BCL2L1 • MCL1 • TP53

Ascentage Pharma Presents Its First Dataset on MDM2-p53 Inhibitor Alrizomadlin (APG-115) in Pediatric Solid Tumors at ASCO 2026 (GlobeNewswire) - "In the monotherapy arm, 1 patient with refractory RMS achieved CR. In the combination arm, among 17 response-evaluable pediatric patients with relapsed/refractory solid tumors, the ORR was 23.5%, including 1 CR in a patient with EWS, as well as PRs in 2 patients with RMS and 1 patient with NB. The disease control rate (DCR) was 70.6%....No dose-limiting toxicities (DLTs) were observed in either the monotherapy or combination arm."

P1 data • Ewing Sarcoma • Neuroblastoma • Rhabdomyosarcoma • Soft Tissue Sarcoma

Alrizomadlin (APG-115) alone or in combination with lisaftoclax (APG-2575) for the treatment of pediatric patients with relapsed/metastatic rhabdomyosarcoma (RMS) or other soft-tissue sarcomas (STSs) (GlobeNewswire) - "Ascentage Pharma releases latest clinical data...at ASCO 2026....This is a multicenter clinical trial conducted in China, evaluating the safety and preliminary efficacy of alrizomadlin (APG-115) as monotherapy or in combination with lisaftoclax (APG-2575) in heavily pretreated pediatric patients with neuroblastoma (NB), as well as relapsed/metastatic rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), and other soft-tissue sarcomas (STSs). Results showed that no dose-limiting toxicities (DLT) were observed in either monotherapy or combination groups. Adverse events were mainly gastrointestinal and hematologic, with few serious adverse events, and no treatment-related deaths or discontinuations. In terms of clinical benefit, one patient with refractory RMS in the monotherapy group achieved CR; in the combination group, the objective response rate (ORR) was 30% and the disease control rate (DCR) was 80%."

P1 data • Ewing Sarcoma • Neuroblastoma • Rhabdomyosarcoma • Soft Tissue Sarcoma

MDM2 Inhibition with Alrizomadlin (APG-115) in TP53 wild-type salivary gland cancers: a phase I clinical trial. (PubMed, Nat Commun) - P1/2 | "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."

Clinical • Journal • P1 data • Adenoid Cystic Carcinoma • Oncology • Salivary Gland Cancer • TP53

Ascentage Pharma to Present Data from Multiple Trials, Including Three Rapid Oral Presentations, at ASCO 2026 (GlobeNewswire) - "...These data highlight the global innovation and clinical value of Ascentage Pharma’s portfolio, inclusive of Olverembatinib (HQP1351), the first third-generation BCR-ABL inhibitor approved in China; Lisaftoclax (APG-2575), the first approved China-developed Bcl-2 selective inhibitor; and Alrizomadlin (APG-115), an MDM2-p53 inhibitor."

Clinical data • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Rhabdomyosarcoma • Small Lymphocytic Lymphoma • Soft Tissue Sarcoma

Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) (AACR 2024) - "Mechanistically, this combination likely modulated pathways related to DNA methylation, cell cycle, and apoptosis. The findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin for PCa patients."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDK6 • CDKN1A • DNMT1 • MCL1 • UHRF1

MDM2 inhibitor alrizomadlin induces ferroptosis through p53 dependent and independent pathways in TP53 wildtype NSCLC (AACR 2025) - "The sustained expression of PTGS2 enhances ferroptosis, ultimately contributing to the cytotoxic effects of APG-115 in tumor cells. Collectively, our study reveals that APG-115 induces ferroptosis in TP53-wildtype NSCLC by stabilizing the expression of PTGS2 protein, providing a new direction for further clinical investigation of APG-115 as a monotherapy or combination therapy.Keywords:Alrizomadlin; Ferroptosis; PTGS2; USP22; Ubiquitin-proteasome system"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PACERR • PTGS2 • USP22

The MDM2-p53 Axis in Osteosarcoma: Current Understanding of Regulatory Mechanisms and Targeted Therapeutic Strategies. (PubMed, Pharmaceuticals (Basel)) - "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."

Journal • Review • Gene Therapies • Hematological Disorders • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • MDM2

Alrizomadlin (APG-115) in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: 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

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Mesothelioma • Oncology • Solid Tumor • BAP1

Novel antagonist APG-115 targets MDM2-p53 to induce p53-mediated apoptosis and radiosensitization in colorectal cancer. (PubMed, Clin Exp Med) - "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."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • CDKN1A • MDM2

CAPS: APG-115 in Salivary Gland Cancer Trial (clinicaltrials.gov) - P1/2 | N=41 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Jun 2026 ➔ Nov 2026 | Trial primary completion date: Dec 2025 ➔ May 2026

P53WT • Trial completion date • Trial primary completion date • Oncology • Salivary Gland Cancer

Magnet-Responsive Nanomaterials Trigger Ferroptosis and Cellular Senescence Modulation via p53/SLC7A11 Axis for Tumor Therapy. (PubMed, Adv Healthc Mater) - "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."

Journal • Oncology • GPX4 • SLC7A11

Alrizomadlin (APG-115) Alone or Combined with Azacitidine (AZA) in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) or Relapsed or Progressive Higher-Risk Myelodysplastic Syndrome (HR-MDS): Phase 1b Trial Results (ASH 2023) - P1 | "One of 10 pts with R/R AML treated with venetoclax + HMA experienced a CRi. Internal study (CT. gov) identifiers: APG-115-AC101 (NCT04275518)."

Clinical • P1 data • Acute Myelogenous Leukemia • Cardiovascular • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Novel Coronavirus Disease • Oncology • Pulmonary Embolism • Respiratory Diseases

Keynote MK-3475-B66: A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=230 | Active, not recruiting | Sponsor: Ascentage Pharma Group Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Cutaneous Melanoma • Eye Cancer • Melanoma • Mucosal Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • Uveal Melanoma • PD-L1

CAPS: APG-115 in Salivary Gland Cancer Trial (clinicaltrials.gov) - P1/2 | N=41 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Dec 2025

P53WT • Trial completion date • Trial primary completion date • Oncology • Salivary Gland Cancer