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DRUG:

pelcitoclax (APG-1252)

i
Other names: APG-1252, APG 1252 12A
Company:
Ascentage Pharma
Drug class:
Bcl2 inhibitor, Bcl-xL inhibitor
Related drugs:
4ms
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.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
Cabometyx (cabozantinib tablet) • pelcitoclax (APG-1252)
12ms
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Recruiting, National Cancer Institute (NCI) | Initiation date: Feb 2024 --> Sep 2023
Trial initiation date
|
BRAF (B-raf proto-oncogene) • BCL2L1 (BCL2-like 1)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
1year
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.
P1 data • Preclinical • Journal • Metastases
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
pelcitoclax (APG-1252)
1year
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Recruiting, National Cancer Institute (NCI) | Initiation date: Nov 2023 --> Feb 2024
Trial initiation date
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
over1year
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Recruiting, National Cancer Institute (NCI) | Initiation date: Aug 2023 --> Nov 2023
Trial initiation date
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
over1year
Updated study results of pelcitoclax (APG-1252) combined with osimertinib in patients (pts) with EGFR-mutant non-small cell lung cancer (NSCLC) (ESMO 2023)
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
|
EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
TP53 mutation • EGFR mutation • EGFR positive
|
Tagrisso (osimertinib) • pelcitoclax (APG-1252)
over1year
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Recruiting, National Cancer Institute (NCI) | Initiation date: May 2023 --> Aug 2023
Trial initiation date
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
over1year
Emerging BCL 2 Inhibitors (SOHO 2023)
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 demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.
IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 overexpression • BCL2 expression
|
Venclexta (venetoclax) • Rituxan (rituximab) • azacitidine • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • navitoclax (ABT 263) • pelcitoclax (APG-1252) • lisaftoclax (APG-2575) • sonrotoclax (BGB-11417) • S55746 • AZD0466 • FCN-338
over1year
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting
Enrollment open
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
over1year
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers (clinicaltrials.gov)
P1, N=42, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Jun 2026 | Trial primary completion date: Oct 2024 --> Jun 2026
Trial completion date • Trial primary completion date
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
over1year
Caspase-3 mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer (AACR 2023)
Taken together, our data indicated that anti-HER2 agents could upregulate the expression of GSDME, and the combination of lapatinib and APG-1252 showed a synergistic antitumor effect against HER2-positive gastric cancer through inducing caspase-3/GSDME mediated apoptosis and pyroptosis.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3) • GSDMB (Gasdermin B) • GSDME (Gasdermin E)
|
HER-2 positive • HER-2 negative • HER-2 expression • GSDMB expression
|
lapatinib • pelcitoclax (APG-1252)
over1year
A Study of Pelcitoclax (APG-1252) in Patients With Neuroendocrine Tumors (clinicaltrials.gov)
P1, N=60, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Oct 2023 --> Jun 2024
Trial completion date • Trial primary completion date
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
almost2years
New P1 trial
|
BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • pelcitoclax (APG-1252)
2years
Therapeutic potential of the novel Bcl-2/Bcl-X dual inhibitor, APG1252, alone or in combination against non-small cell lung cancer. (PubMed, Mol Carcinog)
This study focused on evaluating the therapeutic efficacy of the novel Bcl-2/Bcl-X dual inhibitor, APG1252-M1 (also named APG-1244; an in vivo active metabolite of APG1252 or pelcitoclax), as a single agent or in combination, against non-small cell lung cancer (NSCLC) cells. Importantly, the combination was effective in inhibiting the growth of osimertinib-resistant tumors in vivo. Collectively, these results demonstrate the efficacy of APG1252 alone or in combination against human NSCLC cells.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
EGFR mutation • MCL1 expression
|
Tagrisso (osimertinib) • pelcitoclax (APG-1252) • APG1244
over2years
Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X dual inhibitor that induces Bax-dependent apoptosis. (PubMed, Neoplasia)
Deficiency of Bax in CRC cells abolished APG-1252-M1's ability to induce apoptosis, indicating that APG-1252-M1 induces Bax-dependent apoptosis. The current study thus demonstrates the potential of APG-1252-M1 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with an Mcl-1 inhibitor, warranting further evaluation in vivo and in the clinic.
Journal • PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
|
MCL1 expression
|
pelcitoclax (APG-1252) • APG1244
over2years
Updated study results of pelcitoclax (APG-1252) in combination with osimertinib in patients (pts) with EGFR-mutant non–small cell lung cancer (NSCLC). (ASCO 2022)
Osimertinib in combination with targeted therapies has been of clinical interest to improve the outcomes of patients with EGFR-mutant NSCLC. Pelcitoclax plus osimertinib was well tolerated and showed comparable efficacy in TKI-naïve pts. Further randomized control trials are warranted to elucidate the role of pelcitoclax when combined with osimertinib.
Clinical • Combination therapy • IO biomarker
|
EGFR (Epidermal growth factor receptor) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
EGFR mutation • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
|
Tagrisso (osimertinib) • pelcitoclax (APG-1252)
3years
A Study of Pelcitoclax (APG-1252) in Patients With Neuroendocrine Tumors (clinicaltrials.gov)
P1, N=60, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting
Enrollment open
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
3years
Dual BCL-2/BCL-XL Inhibitor Pelcitoclax (APG-1252) Overcomes Intrinsic and Acquired Resistance to Venetoclax in Multiple Myeloma Cells (ASH 2021)
Simultaneous inhibition of MCL-1 (via S63845) or BCL-xL (via A155463) and BCL-2 (via venetoclax) increased BIM release and enhanced cell death in resistant clones (vs single agents), with combination index values < 0.3 in all doses. In vivo study using pelcitoclax is ongoing and will be presented at the meeting. In conclusion, we report that venetoclax resistance in MM evolves from outgrowth of persister clones displaying activation of the ERK pathway and a shift in mitochondrial dependency towards BCL-xL, which can potentially be effectively targeted via the novel BCL-2/BCL-xL inhibitor pelcitoclax (APG-1252), which is currently in clinical investigation for solid tumors (NCT03080311).
Preclinical • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
Chr t(11;14) • MCL1 expression
|
Venclexta (venetoclax) • S63845 • pelcitoclax (APG-1252)
3years
A Study of Pelcitoclax (APG-1252) in Patients With Neuroendocrine Tumors (clinicaltrials.gov)
P1, N=60, Not yet recruiting, Ascentage Pharma Group Inc. | Initiation date: Jun 2021 --> Oct 2021
Clinical • Trial initiation date
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
3years
APG-1252 in Patients With SCLC or Advanced Solid Tumors (clinicaltrials.gov)
P1, N=24, Terminated, Ascentage Pharma Group Inc. | N=50 --> 24 | Trial completion date: Oct 2021 --> Apr 2021 | Recruiting --> Terminated | Trial primary completion date: Oct 2021 --> Nov 2020; The company adjusts strategy.
Clinical • Enrollment change • Trial completion date • Trial termination • Trial primary completion date
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
over3years
[VIRTUAL] Phase 1b Study of Pelcitoclax (APG - 1252) in Combination With Osimertinib in Patients With EGFR TKI - Resistant NSCLC (IASLC-WCLC 2021)
Ongoing studies are investigating the efficacy of this combination in treatment-naive and second-line patients with the EGFR T790M mutation. Internal study identifier APG1252NC101; Clinical trial registration: NCT04001777.
Clinical • P1 data • Combination therapy • IO biomarker
|
EGFR (Epidermal growth factor receptor) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
EGFR mutation • EGFR T790M
|
Tagrisso (osimertinib) • pelcitoclax (APG-1252)
over3years
Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway. (PubMed, Cell Death Dis)
Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
gemcitabine • pelcitoclax (APG-1252)
over3years
Clinical • New P1 trial
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
over3years
[VIRTUAL] Targeting BCL-xL addiction with APG-1252 (pelcitoclax) to overcome apoptotic blockade in neuroendocrine neoplasm (NEN) (AACR 2021)
Current targeted therapies such as VEGFR inhibitor sunitinib and mTOR inhibitor everolimus extend progression-free survival (PFS) in patients with Grade 1 (G1) and G2 neuroendocrine tumors (NET), but the objective response rate remains low. Concurrent expression of BCL-xL and MCL-1 proteins suggests that a combination treatment targeting both proteins might be more effective in NEN. Our findings inform development of a BCL-2/BCL-xL inhibitor for NEN therapy.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression
|
sunitinib • everolimus • pelcitoclax (APG-1252)
over3years
[VIRTUAL] Mcl-1 levels critically determines the sensitivities of human colon cancer cells to APG1244, a novel Bcl-2 and Bcl-XLinhibitor, that induces Bax- and caspase-8- dependent apoptosis (AACR 2021)
The novel BH3 mimetic, APG1244 (a prodrug for APG1252), is a highly potent Bcl-2 and Bcl-XL dual inhibitor and being tested in clinical trials as a potential cancer therapeutic agent. Furthermore, blockage of caspase-8 with a caspase-8 specific inhibitor abolished cleavage of caspase-3 and PARP including attenuation of cytochrome C and Smac release induced by APG1244, suggesting a caspase-8-dependent mechanism. The current study thus demonstrates the potential of APG1244 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with a Mcl-1 inhibitor for CRC treatment, warranting further evaluation in vivo and in the clinic.
PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • FADD (Fas associated via death domain) • CASP3 (Caspase 3) • CASP8 (Caspase 8)
|
MCL1 expression
|
pelcitoclax (APG-1252) • APG1244
4years
[VIRTUAL] Trial in Progress: Phase Ib/II Study of Bcl-2/Bcl-Xl Inhibitor Pelcitoclax (APG-1252) in Patients with Myelofibrosis (MF) That Progressed after Initial Therapy (ASH 2020)
Study Objectives: The primary objective of this open-label trial is to evaluate the safety and efficacy of APG-1252, as monotherapy and when combined with ruxolitinib, in adults with histologically or cytologically confirmed MF who require therapy and are ineligible for JAK2 inhibitors (and can receive single-agent APG-1252) or have had inadequate responses to ruxolitinib-based therapy (and can receive this treatment plus APG-1252). For further information, contact: yzhai@ascentage.com. Registration: ClinicalTrials.gov Identifier NCT04354727.
Clinical • P1/2 data • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
JAK2 mutation
|
Jakafi (ruxolitinib) • pelcitoclax (APG-1252)
4years
A Study of APG-1252 in Patients With SCLC or Other Solid Tumors (clinicaltrials.gov)
P1, N=50, Completed, Ascentage Pharma Group Inc. | Active, not recruiting --> Completed
Clinical • Trial completion
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
over4years
APG-1252 in Patients With SCLC or Advanced Solid Tumors (clinicaltrials.gov)
P1, N=50, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2019 --> Oct 2021 | Trial primary completion date: Dec 2019 --> Oct 2021
Clinical • Trial completion date • Trial primary completion date
|
BCL2L2 (BCL2 Like 2)
|
pelcitoclax (APG-1252)
over4years
[VIRTUAL] Co-targeting BCL-xL and HER2 high expression to overcome apoptosis blockade in gastric cancer (AACR-II 2020)
Our results demonstrate the on-target antitumor activity of APG-1252, the potential of BCL-xLhigh as a predictive biomarker, and the resistance mechanism conferred by MCL-1. Furthermore, the data provide a scientific rationale for the combined therapy with BCL-xL and HER2 inhibitors to achieve better clinical outcomes in a subset of HER2+ gastric cancers.
IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
HER-2 overexpression • HER-2 expression
|
lapatinib • pelcitoclax (APG-1252)
over4years
[VIRTUAL] Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models (AACR-II 2020)
NCI-H1975-C797S derived-xenografts were treated with APG-1252, cisplatin/docetaxel or their combinations.Combination therapy with APG-1252 and cisplatin or docetaxel exhibited synergistic antitumor activity. Similar results were demonstrated in a patient-derived xenograft (PDX) tumor model derived from an osimertinib-resistant NSCLC patient harboring 19del-T790M-C797S mutations. Furthermore, the combinations also exhibited enhanced antitumor activity in an osimertinib-resistant PDX model that the resistant mechanism remained unknown.In summary, our results suggest that the combination treatment with APG-1252 and chemotherapeutics can overcome acquired resistance to osimertinib and the combination deserves further clinical evaluations.
Preclinical • IO biomarker
|
EGFR (Epidermal growth factor receptor) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
EGFR mutation • MET amplification • EGFR exon 20 insertion • EGFR C797S • EGFR exon 20 mutation • EGFR H1975 • EGFR T790M + exon 19 deletion
|
cisplatin • Tagrisso (osimertinib) • docetaxel • pelcitoclax (APG-1252)
over4years
Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma. (PubMed, Cancer Med)
Moreover, Ki-67 was remarkably decreased in the combination group compared to other groups. In conclusion, APG-1252-M1 had a strong antitumor effect by inducing apoptosis and was synergistic with chemotherapy.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
pelcitoclax (APG-1252)
over4years
[VIRTUAL] First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors. (ASCO 2020)
Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Research Funding: Ascentage Pharma Group Inc., Rockville, MD
Clinical • P1 data
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
pelcitoclax (APG-1252)