APG-115 + APG-2575 for Leukemia

Recruiting at 2 trial locations

Overseen By Jocelyn Budzynski

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Ascentage Pharma Group Inc.

Must not be taking: CYP2C8 inhibitors, CYP3A4 inhibitors

Disqualifiers: CNS malignancy, Graft versus host, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests two experimental drugs, APG-115 and APG-2575, in patients with a rare type of leukemia called T-PLL. APG-115 aims to stop cancer cells from growing, while APG-2575 targets and kills cancer cells. The study will help determine if these drugs are safe and effective.

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.

What data supports the effectiveness of the drug APG-115 + APG-2575 for treating leukemia?

While there is no direct data on APG-115 and APG-2575 for leukemia, similar drugs like venetoclax have shown effectiveness in treating acute myeloid leukemia (AML), especially in combination with other agents. Venetoclax, a BCL-2 inhibitor like APG-2575, has been effective in achieving remission in AML patients, suggesting potential for similar drugs. ^{1 2 3 4 5}

What makes the drug combination APG-115 and APG-2575 unique for treating leukemia?

The combination of APG-115 and APG-2575 is unique because it targets specific proteins involved in cancer cell survival, potentially offering a novel approach compared to traditional chemotherapy. APG-115 is known to inhibit MDM2, a protein that regulates the tumor suppressor p53, while APG-2575 targets BCL-2, a protein that helps cancer cells avoid death, making this combination potentially more effective in inducing cancer cell death. ^{6 7 8 9 10}

Research Team

Yifan Zhai, MD, PhD

Principal Investigator

Ascentage Pharma Group Inc.

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• APG-115 (MDM2-p53 Inhibitor)
• APG-2575 (Other)

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

References

1. China 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]. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia. [2022]

4. England 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? [2022]

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

6. China 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism. [2018]

8. India pubmed.ncbi.nlm.nih.gov

Anti-lymphocyte globulin therapy in acquired aplastic anaemia. [2004]

9. United States pubmed.ncbi.nlm.nih.gov

Biological and immunological characterization of ATG and ALG. [2021]

10. England 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) [2019]