APG-115 + APG-2575 for Leukemia

Recruiting at 2 trial locations

Overseen By Jocelyn Budzynski

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ascentage Pharma Group Inc.

Must not be taking: CYP2C8 inhibitors, CYP3A4 inhibitors

Disqualifiers: CNS malignancy, Graft versus host, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment involving two medications, APG-115 (Alrizomadlin) and APG-2575 (Lisaftoclax), for certain types of leukemia and lymphoma. Researchers aim to evaluate how these drugs work alone and together in treating T-cell prolymphocytic leukemia (T-PLL) and non-Hodgkin lymphoma (NHL). This trial suits those who have tried other treatments without success or cannot undergo standard treatment options. Participants should not have received chemotherapy or certain other medications immediately before starting the trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking chemotherapy or antibody therapy 7 days before starting the study drugs. If you are taking strong CYP2C8 inhibitors or moderate/strong CYP3A4 inhibitors or inducers, you must stop them at least 14 days or 7 half-lives before starting the study drugs, whichever is longer.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies found APG-115 to be generally safe when used alone. About 68% of patients experienced nausea, indicating that most tolerated it well, though some might feel mild stomach discomfort.

Research indicates that the combination of APG-115 and APG-2575 works effectively in fighting cancer. Although less safety information exists for this combination, APG-2575 alone was tested in patients with leukemia and showed promise without major safety concerns.

Both treatments remain under study, so more safety information will become available in the future. Current evidence suggests they are generally safe for most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about APG-115 and APG-2575 because they target leukemia in a new way. Unlike traditional chemotherapy and targeted therapies that primarily focus on killing rapidly dividing cells or blocking specific proteins, APG-115 is a small molecule that inhibits MDM2, a protein that regulates the tumor suppressor p53. This can potentially reactivate p53, leading to cancer cell death. APG-2575 targets BCL-2, a protein that helps cancer cells avoid death, allowing for a more direct induction of apoptosis in cancer cells. Together, these treatments offer a novel approach by simultaneously disrupting the pathways cancer cells use to survive, potentially leading to more effective outcomes for patients.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research has shown that APG-115 may be helpful in treating leukemia. In this trial, some participants will receive APG-115 alone, which studies have found can reduce leukemia in the body and help patients live longer. Other participants will receive a combination of APG-115 and APG-2575. This combination has shown promise, especially for patients whose leukemia did not respond to previous treatments. In one study, 22.2% of patients responded positively, and all patients in a specific group had their disease controlled. These results suggest that APG-115, both alone and with APG-2575, could be effective in fighting leukemia. ^{2 3 6 7 8}

Who Is on the Research Team?

Yifan Zhai, MD, PhD

Principal Investigator

Ascentage Pharma Group Inc.

Are You a Good Fit for This Trial?

Adults with T-PLL leukemia who've had at least one prior therapy can join. They must be in good enough health, not have received certain treatments recently, and agree to use contraception. People with severe allergies to the drugs, active infections like HIV or COVID-19, heart problems, other untreated cancers or those needing strong immune system drugs can't participate.

Inclusion Criteria

My lab tests for tumor lysis syndrome are within safe limits and any symptoms are mild.

Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless related to leukemic involvement

I am not pregnant and agree to use contraception during the study.

Exclusion Criteria

I have been diagnosed with HIV.

I haven't taken strong medication that affects liver enzymes in the last 14 days or 7 half-lives.

I have tested positive for COVID-19.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive APG-115 as a single agent or in combination with APG-2575 to evaluate pharmacokinetics, safety, and efficacy

21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• APG-115
• APG-2575

Trial Overview The trial is testing APG-115 alone or combined with APG-2575 on patients with T-PLL leukemia. It's an open-label phase IIa study looking at how the body processes these drugs and their safety and effectiveness across multiple centers involving 24-36 participants.

How Is the Trial Designed?

Group I: APG-115 monotherapy part Experimental Treatment 1 Intervention

APG-115 will be given alone

Group II: APG-115 + APG-2575 combination dose expansion part Experimental Treatment 2 Interventions

APG-115 is given in combination with APG-2575

Group III: APG-115 + APG-2575 combination dose escalation part Experimental Treatment 2 Interventions

APG-115 is given in combination with APG-2575

Who Is Running the Clinical Trial?

Ascentage Pharma Group Inc.

Lead Sponsor

Trials

54

Recruited

5,700+

Published Research Related to This Trial

Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG) are both effective treatments for aplastic anemia, but they exhibit significant differences in their immunological properties and lot-to-lot variation, with ALG generally showing more variability.

The study found that while both ATG and ALG can induce T-cell activation and lysis, certain lots of ALG, including one previously deemed inactive, demonstrated lower toxicity and variable efficacy, suggesting that not all preparations are equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological and immunological characterization of ATG and ALG. Raefsky, EL., Gascon, P., Gratwohl, A., et al.[2021]

In a study of 35 patients with acquired aplastic anaemia treated with anti-lymphocyte globulin (ALG), the overall response rate was 54.3%, with a notably higher response of 73.3% in those with non-severe aplastic anaemia (NSAA).

While ALG treatment showed effectiveness, particularly in NSAA patients, there were significant safety concerns, as all non-responders died, and some responders experienced serious complications, including hepatitis and myelodysplasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-lymphocyte globulin therapy in acquired aplastic anaemia. Agarwal, MB., Agarwal, UM., Bhave, AB., et al.[2004]

In a multicenter study of 30 patients with severe aplastic anemia (SAA) who did not respond to initial immunosuppressive therapy, 77% achieved transfusion independence after a second treatment with rabbit ATG (r-ATG), indicating its efficacy as a second-line therapy.

The treatment was found to be safe, with no significant side effects reported, although one patient died from sepsis; overall survival was high at 93% over a median follow-up of 914 days, suggesting r-ATG is a viable alternative to horse ALG for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO) Di Bona, E., Rodeghiero, F., Bruno, B., et al.[2019]

Venetoclax, an oral BCL-2 inhibitor, has shown promising efficacy in treating acute myeloid leukemia (AML) in elderly patients who cannot undergo intensive chemotherapy, with complete remission rates of 66.4% and 48% in phase III trials.

The introduction of venetoclax-based therapies has significantly improved treatment options for these patients, but further studies are needed to evaluate the long-term durability of responses and to explore its effectiveness compared to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer? Agarwal, S., Kowalski, A., Schiffer, M., et al.[2022]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

The combination of venetoclax and hymeglusin significantly enhances apoptosis in acute myeloid leukemia (AML) cells, showing greater effectiveness than either drug alone, based on experiments with HL-60 and KG-1 cell lines.

This combination treatment does not significantly increase toxicity in normal mononuclear cells, suggesting it could be a safer alternative for elderly patients with AML who may resist or be intolerant to venetoclax alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia. Zhou, C., Wang, Z., Yang, S., et al.[2022]

In a study of 65 patients with severe aplastic anemia (SAA), combined therapy using Chinese drugs and immunosuppressors like anti-lymphocyte globulin (ALG) resulted in an 85.9% total effective rate, with 45.6% of patients achieving a basic cure.

The treatment's effectiveness was influenced by factors such as age, duration of illness, and neutrophil count, while adverse reactions were relatively mild, suggesting that the combination therapy may enhance efficacy while reducing toxicity compared to Western medicine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe aplastic anemia by immunosuppressor anti-lymphocyte globulin/anti-thymus globulin as the chief medicine in combination with Chinese drugs. Zheng, BR., Shen, JP., Zhuang, HF., et al.[2021]

This study is the first to use pharmacokinetic-pharmacodynamic (PK-PD) modeling to analyze the effects of polyclonal antilymphocyte globulins (ALGs) on lymphocyte counts in kidney transplant patients, revealing significant interindividual variability in response.

The research found that genetic polymorphism in the FcgammaRIIIa receptor influences the effectiveness of ALG, with FCGR3A-V carriers requiring lower concentrations of ALG to achieve a 50% inhibition of lymphocyte input compared to FCGR3A-F/F patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism. Ternant, D., Büchler, M., Bénéton, M., et al.[2018]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

Citations

1. ascentage.com ascentage.com/live-from-asco-2025-ascentage-pharma-releases-promising-clinical-data-on-alrizomadlin-monotherapy-and-combinations-in-solid-tumors/

Live from ASCO 2025 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36240005/

Lisaftoclax in Combination with Alrizomadlin Overcomes ... Our study aimed to determine if treatment with novel anticancer agents targeting BCL-2 and mouse double minute 2 (MDM2) could overcome ...

3. ascentage.com ascentage.com/ascentage-pharma-announces-clinical-data-of-lisaftoclax-which-shows-therapeutic-potential-in-venetoclax-refractory-patients-selected-for-oral-report-at-asco-2025/

Ascentage Pharma Announces Clinical Data of Lisaftoclax ... 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 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04496349

NCT04496349 | A Study Evaluating APG-115 as a Single ... The goal of this study is to evaluate the pharmacokinetics (PK), safety, and efficacy of APG-115 as a single agent or in combination with APG-2575 in patients ...

5. sec.gov sec.gov/Archives/edgar/data/2023311/000121390025050238/ea024434401ex99-2_ascentage.htm

Ascentage Pharma Presents Clinical Data on Bcl-2 ... In 22 efficacy-evaluable patients with R/R MDS/CMML, the ORR was 50%, with CR, mCR, and PR achieved by 27.3%, 18.2%, and 4.5% of patients, ...

6. aacrjournals.org aacrjournals.org/mct/article/20/12_Supplement/P208/676129/Abstract-P208-Synergistic-antitumor-activity-of

Abstract P208: Synergistic antitumor activity of lisaftoclax (APG-2575 ... Lisaftoclax (APG-2575) and alrizomadlin (APG-115) are novel BCL-2 and MDM2 inhibitors, respectively. They show unique pharmacological properties as well as ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41109219/

Safety, tolerability, and pharmacokinetics of lisaftoclax ... Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 ...

8. researchgate.net researchgate.net/publication/356771735_Abstract_P208_Synergistic_antitumor_activity_of_lisaftoclax_APG-2575_and_alrizomadlin_APG-115_through_dual_targeting_of_BCL-2MDM2-P53_apoptotic_pathways_in_preclinical_models_of_acute_myeloid_leukemia

Abstract P208: Synergistic antitumor activity of lisaftoclax (APG ... These data support investigation into the clinical outcomes of the combination treatment in patients with TP53 wild-type AML. Citation Format: Douglas D. Fang, ...