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

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

APG-115 Induces SLC7A11-Mediated Ferroptosis and Upregulates PD-L1 Expression in Thyroid Cancer. (PubMed, ACS Omega) - "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."

IO biomarker • Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • MDM2 • SLC7A11

MEKMDM2: Early Phase Study Evaluating MEK and MDM2 Inhibition in Patients With NF1 and MPNST (clinicaltrials.gov) - P1/2 | N=45 | Not yet recruiting | Sponsor: AeRang Kim | Initiation date: Apr 2025 ➔ Oct 2025

Trial initiation date • Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Sarcoma • Solid Tumor

A phase 2 study of novel MDM2 inhibitor alrizomadlin (APG-115) with or without toripalimab in patients (pts) with advanced adenoid cystic carcinoma (ACC) or other solid tumors. (ASCO 2025) - P1/2 | "Alrizomadlin monotherapy showed promising antitumor activity in pts with advanced ACC or MPNST. Alrizomadlin combined with toripalimab was also well tolerated, showing antitumor activity in MPNST, BTC, and LPS and an acceptable safety profile (NCT04785196)."

Clinical • Metastases • P2 data • Adenoid Cystic Carcinoma • Anemia • Biliary Cancer • Biliary Tract Cancer • Brain Cancer • Gastroenterology • Gastrointestinal Disorder • Liposarcoma • Neurofibrosarcoma • Neutropenia • Oncology • Peptic Ulcer • Sarcoma • Solid Tumor • Thrombocytopenia

APG-115 synergizes with bortezomib to induce apoptosis in cervical cancer cells. (PubMed, Anticancer Drugs) - "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."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • CDKN1A • MCL1 • MDM2 • TP53

Live from ASCO 2025 | Ascentage Pharma Releases Promising Clinical Data on Alrizomadlin Monotherapy and Combinations in Solid Tumors (GlobeNewswire) - P1b/2 | N=95 | NCT04785196 | Sponsor: Ascentage Pharma Group Inc. | "As of the data cutoff date of February 13, 2025, 57 patients with advanced ACC, malignant peripheral nerve sheath tumor (MPNST), liposarcoma (LPS), biliary-tract cancer (BTC), and other tumors were enrolled....In the monotherapy arm, 17 patients were efficacy-evaluable. The ORR was 16.7%, and the DCR was 100% in 12 patients with ACC. The DCR was 80% in 5 patients with MPNST, 4 of whom achieved stable disease (SD)....In the combination arm, 29 patients were efficacy-evaluable. The ORR was 16.7% and the DCR was 100% in 6 patients with BTC. The ORR was also 16.7% and the DCR was 66.7% in 6 patients with LPS. Two patients with MPNST had confirmed partial response (PR) with prolonged progression free survival (PFS) of 60+ weeks and 96+ weeks, respectively."

P2 data • Adenoid Cystic Carcinoma • Biliary Tract Cancer • Liposarcoma

A Phase 2 Study of Novel MDM2 Inhibitor Alrizomadlin (APG-115) with or without Toripalimab in Patients with Advanced Adenoid Cystic Carcinoma (ACC) or Other Solid Tumors (GlobeNewswire) - P1b/2 | N=95 | NCT04785196 | Sponsor: Ascentage Pharma Group Inc. | "Ascentage Pharma...announced that new clinical data...at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting....In the monotherapy arm, 14 patients were efficacy-evaluable. The ORR was 22.2% and the disease control rate (DCR) was 100% in 9 patients with ACC. The DCR was 100% in all patients with MPNST, all 5 of whom achieved stable disease (SD)....In the combination arm, 28 patients were efficacy-evaluable. The ORR was 20% and DCR was 80% in 5 patients with BTC. The ORR was 16.7% and DCR was 66.7% in 6 patients with LPS. The ORR was 14.3% and DCR was 53.6% in patients with MPNST; furthermore, 2 patients with MPNST had confirmed partial responses (PR) with prolonged progression free survival (PFS) of 60+ weeks and 96+ weeks, respectively."

P2 data • Adenoid Cystic Carcinoma • Biliary Tract Cancer • Liposarcoma

Ascentage Pharma To Present Data from Two Clinical Studies at 2025 ASCO Annual Meeting, Including Oral Presentation on Its Key Assets Lisaftoclax and Alrizomadlin (GlobeNewswire) - "Ascentage Pharma...announced that results from two clinical studies of the Bcl-2 selective inhibitor lisaftoclax (APG-2575) and the MDM2-p53 inhibitor alrizomadlin (APG-115), two key drug candidates in the company’s apoptosis-targeted pipeline, have been selected for presentations at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. These presentations will include an oral report featuring updated results from a Phase Ib/II study of a lisaftoclax combination regimen in patients with myeloid malignancies."

Clinical data • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Myelodysplastic Syndrome

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

Combinatorial screen with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids. (PubMed, SLAS Discov) - "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."

Journal • Brain Cancer • Carcinosarcoma • Lung Cancer • Neurofibrosarcoma • Oncology • Pancreatic Cancer • Rhabdomyosarcoma • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Undifferentiated Pleomorphic Sarcoma • BCL2 • BCL2L1 • KRAS

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 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

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

Anlotinib enhances the pro-apoptotic effect of APG-115 on acute myeloid leukemia cell lines by inhibiting the P13K/AKT signaling pathway. (PubMed, Leuk Res) - "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."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5

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

New P1/2 trial • Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

Alrizomadlin (APG-115) in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma (clinicaltrials.gov) - P2 | N=15 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P2 trial • Mesothelioma • Oncology • Solid Tumor • BAP1

Novel Radiosensitizer Screen Identifies an Effective Strategy to Treat p53 Wild-Type Breast Cancer Models in a Hormone Independent Manner (ASTRO 2024) - "MDM2 inhibitors navtemadlin (AMG-232) and alrizomadlin (APG-115) were used in p53 wild-type and mutant models of estrogen receptor (p53-WT:MCF-7, p53-MT:T47D) and ER-negative BC (p53-WT: CAL-51, p53-MT: MDA-MB-231). These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-WT BC which represent the majority of BCs, regardless of hormone receptor status. Clinical trial development is currently underway to test this in women with locally advanced p53-WT BCs at high risk of locoregional recurrence."

Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • ANXA5 • ER

Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling. (PubMed, J Exp Clin Cancer Res) - "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."

Journal • Synthetic lethality • Oncology • Targeted Protein Degradation • GSDME • MDM2 • NLRP3 • ULK1

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: Jan 2025 ➔ Jun 2025 | Trial primary completion date: Jul 2024 ➔ Dec 2024

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

A Study Evaluating APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With R/R T-PLL and NHL (clinicaltrials.gov) - P2 | N=78 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | N=36 ➔ 78 | Trial completion date: May 2025 ➔ May 2027 | Trial primary completion date: May 2024 ➔ May 2026

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia

MDM2 inhibitor APG-115 synergizes with ABT-199 to induce cell apoptosis in chronic lymphocytic leukemia. (PubMed, Front Pharmacol) - "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."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CDKN1A • MDM2

APG-115 in Combination With PD-1 Inhibitor in Patients With Advanced Liposarcoma or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=95 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Jan 2025 ➔ Jan 2027 | Trial primary completion date: Apr 2024 ➔ Apr 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2 • TP53

A first-in-human phase I study of a novel MDM2/p53 inhibitor alrizomadlin in advanced solid tumors. (PubMed, ESMO Open) - "Alrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen."

Journal • Metastases • P1 data • Febrile Neutropenia • Hematological Disorders • Liposarcoma • Neutropenia • Oncology • Sarcoma • Solid Tumor • Thrombocytopenia • GDF15 • 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 | Suspended ➔ Active, not recruiting

Enrollment closed • Oncology • Salivary Gland Cancer

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

AACR 2024 | Ascentage Pharma Presents Results from Three Studies at 2024 American Association of Cancer Research Annual Meeting (PRNewswire) - "In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor