pelcitoclax (APG-1252) / Ascentage Pharma - LARVOL DELTA

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

ADAPT/A2: ALLG AMLM28/A2 (ADAPT): Achieving Durable remissions via Adaptive Pro-survival Targeting in acute myeloid leukaemia (AML)) – VEN/AZA/Pelcitoclax. A therapeutic arm of the ALLG AMLM28 ADAPT Study-Master Protocol. (ANZCTR) - P1/2 | N=50 | Not yet recruiting | Sponsor: Australasian Leukaemia and Lymphoma Group

New P1/2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

SYNERGISTIC EFFECTS OF OLVEREMBATINIB (HQP1351) COMBINED WITH BCL-2 INHIBITOR LISAFTOCLAX (APG-2575) AND BCL-2/BCL-XL INHIBITOR PELCITOCLAX (APG-1252) IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL) (EHA 2025) - "Molecular mechanisms of action were assessed by western blotting.In both T-ALL cell lines, olverembatinib in combination with lisaftoclax or APG-1244 exhibited synergistic antiproliferative effects compared with single agents. Olverembatinib in combination with lisaftoclax and/or pelcitoclax demonstrated synergistic antitumor effects in T-ALL, providing a scientific rationale for further clinical evaluation of this novel combination therapy in patients with this condition."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ANXA5 • BCL2L1 • CASP3 • MCL1 • MYC

Structural, Functional and Inhibitory Annotations of Lumpy Skin Disease Virus Hypothetical Protein LSDV004: An In-Silico Study. (PubMed, Vet Med Sci) - "Molecular docking studies with HDOCK reveal pelcitoclax as exhibiting better docking characteristics compared to other Bcl-2 inhibitors. However, it's important to note that these predictions require validation through wet laboratory experiments to confirm the LSV004 protein's structural, functional and inhibitory properties. These findings suggest LSDV004's role in LSD pathogenesis and its potential as a drug target and also highlight areas for further experimental studies to confirm its function, supporting efforts toward effective treatments and control."

IO biomarker • Journal • Dermatology • BAK1

A Study of APG-1252 Plus Osimertinib(AZD9291) in EGFR TKI Resistant NSCLC Patients (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

Albumin nanocomplex of BCL-2/xL inhibitor reduced platelet toxicity and improved anticancer efficacy in myeloproliferative neoplasm and lymphoma. (PubMed, Biomaterials) - "Furthermore, Nano-1252 exhibited preferential accumulation in lymphoid organs, leading to enhanced anticancer efficacy in Mantle Cell Lymphoma (MCL) and Myeloproliferative Neoplasms (MPNs) mouse models. Our study not only develops a potential formulation to overcome the current translational barrier of APG-1252 but also reveals novel properties of the well-established albumin nanoformulation, thereby expanding its clinical applications."

Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • BCL2

A Study of Pelcitoclax (APG-1252) in Patients With Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=2 | Terminated | Sponsor: Ascentage Pharma Group Inc. | N=60 ➔ 2 | Recruiting ➔ Terminated; Company Strategy

Enrollment change • Trial termination • Endocrine Cancer • Neuroendocrine Tumor • Solid Tumor • BCL2L2

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

A clinical study of olverembatinib in combination with APG-1252 for the treatment of relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia or T-cell acute lymphoblastic lymphoma (ChiCTR) - P1 | N=12 | Sponsor: Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University; Shanghai Children's Medical Center, School of Medicine, Shangha

New P1 trial • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T-cell Acute Lymphoblastic Lymphoma

Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Feb 2027 | Trial primary completion date: Jun 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Endometrial Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • Uterine Cancer • BCL2L1 • BRAF

The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer. (PubMed, Acta Pharmacol Sin) - "Mechanistically, APG-1252 combined with lapatinib synergistically induced GSDME-mediated pyroptosis in HER2-positive gastric cancer by activating caspase-dependent pathways and blocking the phospho-AKT/GSK-3β/MCL-1 signaling pathway. Our data indicated that the combination of lapatinib and APG-1252 had a synergistic antitumor effect on HER2-positive gastric cancer through the induction of caspase-3/GSDME-mediated apoptosis and pyroptosis."

IO biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • CASP3 • GSDME

Recent clinical data of Pelcitoclax (APG-1252) in combination with osimertinib in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). (CSCO 2024) - "Study Group: [Organizing Committee]"

Clinical data • Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma by suppressing MEK/ERK and CREB/Bcl-xl pathways. (PubMed, Int Immunopharmacol) - "Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1

In-silico characterization of LSDV132 protein divulged its BCL-2-like nature. (PubMed, Heliyon) - "The docking results revealed that pelcitoclax exhibited best docking scores i.e., -9.1841 kcal/mol, among all of the other docked complexes. This fact signified that this compound might serve as an inhibitor of LSDV132 protein."

Journal • Dermatology • BCL2

Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Feb 2024 ➔ Sep 2023

Trial initiation date • Endometrial Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • Uterine Cancer • BCL2L1 • BRAF

First-in-Human Study with preclinical data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors. (PubMed, Clin Cancer Res) - "Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1."

Journal • Metastases • P1 data • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • BCL2 • BCL2L1 • MCL1

First-in-Human Study with preclinical data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors (Clin Cancer Res) - P1 | N=50 | NCT03080311 | Sponsor: Ascentage Pharma Group Inc. | "Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell- based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models....Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein MCL-1. Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule."

P1 data • Preclinical • Gastric Cancer • Small Cell Lung Cancer

Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Nov 2023 ➔ Feb 2024

Trial initiation date • Endometrial Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • Uterine Cancer • BRAF

Updated study results of pelcitoclax (APG-1252) combined with osimertinib in patients (pts) with EGFR-mutant non-small cell lung cancer (NSCLC) (ESMO 2023) - P1 | "Further studies are needed to elucidate the role of pelcitoclax when combined with osimertinib in treating this pt population. Internal study: APG1252NC101; CT.gov: NCT04001777."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • EGFR • TP53

Emerging BCL 2 Inhibitors (SOHO 2023) - P1, P1/2, P1a/1b, P1b/2, P2 | "Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia • Waldenstrom Macroglobulinemia • BCL2L1

Live from ESMO 2023 | Oral Report Featuring Latest Data of Pelcitoclax (APG-1252) Combined with Osimertinib Demonstrates Potential as a New Treatment Option for TP53-and EGFR-Mutant NSCLC (PRNewswire) - P1 | N=80 | NCT04001777 | Sponsor: Ascentage Pharma Group Inc. | "Ascentage Pharma...announced today that it has released the latest clinical data of its dual Bcl-2/Bcl-xL inhibitor, APG-1252 (pelcitoclax), combined with osimertinib for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) in a Mini Oral at the 2023 European Society of Medical Oncology (ESMO) Congress....In the 26 efficacy-evaluable EGFR-TKI-naïve patients, 21 partial responses (PRs) were observed, resulting in an ORR of 80.8%. In the 16 EGFR-TKI- naïve patients with TP53 and EGFR mutations, 14 PRs were observed, resulting in an ORR of 87.5% and a median progress-free survival (mPFS) of 16.39 months (95%Cl, 8.11-NR). Furthermore, preliminary biomarker data from patients resistant to third-generation EGFR-TKIs suggest that the combination regimen can potentially prolong the PFS of patients with high Bcl-xL expressions."

Biomarker • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

APG-1252 Monotherapy or in Combination With Other Therapeutic Agent in Subjects With Relapsed or Refractory Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=51 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 ➔ Mar 2026 | Trial primary completion date: Sep 2023 ➔ Sep 2025

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Aug 2023 ➔ Nov 2023

Trial initiation date • Endometrial Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • Uterine Cancer • BRAF

ESMO 2023 | Ascentage Pharma to Present Results from Two Clinical Studies, including One Oral Presentation, at 2023 ESMO Congress (PRNewswire-Asia) - "Ascentage Pharma...announced today that it is going to release results from two clinical studies at the 2023 European Society of Medical Oncology (ESMO) Congress. These presentations include a Mini Oral featuring the latest data from a study of pelcitoclax (APG-1252), a Bcl-2/BcL-xL dual-targeted inhibitor, combined with osimertinib in patients with EGFR-mutant non-small cell lung cancer (NSCLC); and a Poster on a study evaluating olverembatinib (HQP1351), the first and only China-approved third-generation BCR-ABL inhibitor, in patients with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST)."

P1 data • Gastrointestinal Stromal Tumor • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Thoracic Cancer