APG-2575 for Blood Cancers

Recruiting at 5 trial locations

Overseen By Laura Glass

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Ascentage Pharma Group Inc.

Must not be taking: Antibiotics, Antifungals, Antivirals, others

Disqualifiers: Transplant history, CNS involvement, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called APG-2575 (also known as Lisaftoclax) for individuals with certain blood cancers, such as multiple myeloma and non-Hodgkin's lymphoma. The main goal is to determine the right dose and assess its effectiveness for those who cannot tolerate or have not benefited from current treatments. For those dealing with blood cancer who have tried other treatments without success, this trial might be a suitable option. As an Early Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Do I need to stop my current medications to join the trial?

The protocol does not specify if you need to stop your current medications. However, you cannot have received chemotherapy, biologic, small molecule targeted therapies, or other anti-cancer therapy within a certain period before the study. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that APG-2575 is likely to be safe for humans?

Research has shown that APG-2575, also known as lisaftoclax, has undergone safety testing in people with blood cancers. In earlier studies, patients with chronic lymphocytic leukemia (CLL) and similar conditions used APG-2575. Many tolerated it well, though some experienced side effects, which were usually manageable. These studies did not reveal any unexpected or serious safety issues. However, APG-2575 remains in the early stages of testing. While initial safety results appear promising, further research is necessary to confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for blood cancers, which often include chemotherapy and targeted therapies like tyrosine kinase inhibitors, APG-2575 works differently by targeting a protein called BCL-2. This protein helps cancer cells survive, and by inhibiting it, APG-2575 aims to trigger cancer cell death more effectively. Researchers are excited about APG-2575 because it offers a novel mechanism of action that could potentially overcome resistance seen with current therapies and provide a new option for patients who have limited responses to existing treatments.

What evidence suggests that APG-2575 might be an effective treatment for blood cancers?

Research has shown that APG-2575, also known as lisaftoclax, holds promise for treating blood cancers. APG-2575 blocks certain proteins that help cancer cells survive, potentially stopping these cells from growing. Early studies have demonstrated its effectiveness both alone and in combination with other treatments for various blood cancers. In this trial, participants will receive APG-2575 as a single-agent treatment. One study found that patients with hard-to-treat blood cancers responded well to APG-2575. These results suggest that APG-2575 might be effective for blood cancers, but further research is needed to fully understand its benefits and risks. ^{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?

This trial is for adults over 18 with certain blood cancers like multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma who haven't responded to or can't have standard treatments. They should expect to live at least 3 more months, be relatively active (able to care for themselves), and have a minimum level of white blood cells, hemoglobin, and platelets.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I have been diagnosed with a specific type of blood cancer.

My condition hasn't improved with standard treatments, or I can't tolerate them.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

APG-2575 is administered orally, once daily for 4 weeks per cycle. Dose escalation follows a single patient cohort model, increasing from 20mg to 800mg, with conversion to a 3+3 design if certain toxicities are observed.

28 days per cycle

Dose Expansion

After determining the Maximum Tolerated Dose (MTD), up to 20 patients will be treated at that dose level to further assess safety and efficacy.

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment, with anti-tumor effects evaluated every 8 weeks.

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• APG-2575

Trial Overview The study is testing APG-2575's safety and how well it works in two stages: first finding the right dose and then seeing its effects on a larger group. It's an open-label trial which means everyone knows they're getting APG-2575; there’s no placebo.

How Is the Trial Designed?

Group I: single-agent, open-label, Phase I study of APG-2575 Experimental Treatment 1 Intervention

The study consists of the dose escalation stage and the dose expansion stage

APG-2575 is already approved in China, United States for the following indications:

Approved in China as Lisaftoclax for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

Approved in United States as Lisaftoclax for:

• None approved yet; under investigation for CLL/SLL, Waldenström macroglobulinemia, multiple myeloma, and acute myeloid leukemia

Who Is Running the Clinical Trial?

Ascentage Pharma Group Inc.

Lead Sponsor

Trials

54

Recruited

5,700+

Published Research Related to This Trial

Venetoclax is a highly effective small-molecule inhibitor targeting BCL2, showing a remarkable 79% response rate and 20% complete remission in patients with chronic lymphocytic leukemia (CLL) during a phase II trial.

The drug induces rapid apoptosis and significantly reduces tumor size within hours of administration, demonstrating both high efficacy and safety, and has been approved by the FDA and EMA for specific patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Targeting BCL2 in Hematological Cancers. Scheffold, A., Jebaraj, BMC., Stilgenbauer, S.[2019]

In advanced breast cancer, the risk of bone metastasis is high, with 65-75% of patients affected, highlighting the importance of understanding bone metabolism parameters like RANK, RANKL, and OPG in developing new treatments.

Denosumab, a human monoclonal antibody targeting RANKL, shows promise as a therapeutic option for preventing bone loss and treating bone metastases in breast cancer patients, due to its protective effects on bone health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RANK, RANKL and OPG Expression in Breast Cancer - Influence on Osseous Metastasis. Ney, JT., Fehm, T., Juhasz-Boess, I., et al.[2021]

Venetoclax, a proapoptotic drug, has shown significant clinical activity in pediatric patients with relapsed or refractory leukemias, with 5 out of 10 patients achieving hematologic complete remission (CR) in a study conducted across 11 Polish pediatric hemato-oncology centers.

The drug appears particularly effective in certain leukemia subtypes, such as poor-prognosis acute lymphoblastic leukemia (ALL) with TCF::HLF fusion, suggesting that BH3-mimetics like venetoclax could be beneficial in targeted treatments for children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey. Bobeff, K., Pastorczak, A., Urbanska, Z., et al.[2023]

A conditionally replicating adenovirus (CRAd) called Ad5-Δ24-sOPG-Fc-RGD has been engineered to selectively target and destroy prostate cancer cells while also reducing osteoclast activity, which is crucial for the growth of bone metastases.

In murine models, treatment with Ad5-Δ24-sOPG-Fc-RGD significantly inhibited the progression of advanced prostate cancer bone metastases compared to an unarmed control, suggesting its potential as a new therapeutic option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of osteoprotegerin from a replicating adenovirus inhibits the progression of prostate cancer bone metastases in a murine model. Cody, JJ., Rivera, AA., Lyons, GR., et al.[2023]

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]

Venetoclax treatment in patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) showed minimal impact on circulating T cells and natural killer (NK) cells, suggesting that these immune cells remain largely unaffected by the drug.

Significant depletion of B-cell populations was observed in patients with breast cancer receiving long-term venetoclax, indicating that while venetoclax can affect certain immune cells, it may be a suitable candidate for combination with immunotherapies to enhance antitumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax treatment in patients with cancer has limited impact on circulating T and NK cells. Teh, CE., Peng, H., Luo, MX., 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 phase I study of the gamma secretase inhibitor RO4929097 in combination with neoadjuvant chemotherapy for triple-negative breast cancer showed that the maximum tolerated dose was likely 10 mg, as higher doses led to significant toxicities like thrombocytopenia and hypertension.

Despite the challenges with toxicity, 36% of patients achieved a pathologic complete response (pCR), indicating that RO4929097 may have potential efficacy when combined with chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer. Sardesai, S., Badawi, M., Mrozek, E., et al.[2021]

Lenalidomide, in combination with dexamethasone, was administered to 1438 patients with relapsed or refractory multiple myeloma, showing a median treatment duration of 15.4 weeks and confirming its efficacy in this patient population.

The most common adverse events included hematological issues (49%), gastrointestinal problems (59%), and fatigue (55%), with serious adverse events like pneumonia occurring in 8% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Chen, C., Reece, DE., Siegel, D., et al.[2021]

PF-06650808, an anti-Notch3 antibody-drug conjugate, was generally well tolerated in a phase I study with 40 patients, showing no dose-limiting toxicities at doses up to 2.0 mg/kg, and an estimated maximum tolerated dose of 2.4 mg/kg.

The treatment showed early signs of antitumor activity, with 5 patients achieving partial responses and 51.6% of patients experiencing stable disease, particularly in those with estrogen receptor-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Rosen, LS., Wesolowski, R., Baffa, R., et al.[2022]

The novel conditionally replicating adenovirus Ad5/3Delta24hCG effectively targets and kills hormone refractory prostate cancer cells, demonstrating significant tumor growth inhibition in preclinical models.

Ad5/3Delta24hCG shows promise for cancer-specific replication, as indicated by high levels of hCGbeta production in cancerous tissue while remaining low in normal tissue, suggesting its potential for targeted therapy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of prostate cancer with Ad5/3Delta24hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo. Rajecki, M., Kanerva, A., Stenman, UH., et al.[2020]

The oncolytic viruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF were found to be safe for cancer treatment in clinical trials, with common side effects being mild fatigue, fever, and injection site pain, indicating a good safety profile for further development.

In patients treated with Ad5-RGD-D24-GMCSF, 50% showed stabilization of their disease after one treatment, and there was evidence of induced immune responses against tumors, suggesting potential for enhanced antitumor efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors. Pesonen, S., Diaconu, I., Cerullo, V., et al.[2020]

The redesigned adenovirus, Ad5NULL-A20, shows enhanced tumor selectivity by targeting the αvβ6 integrin, which is present in aggressive epithelial cancers but absent in healthy tissues, making it a promising option for targeted cancer therapy.

In preclinical models, Ad5NULL-A20 demonstrated significantly reduced off-target effects, with a 107-fold decrease in liver accumulation compared to the original Ad5, while also improving survival rates in cancer models, indicating its potential for effective and safer cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ad5NULL-A20: A Tropism-Modified, &#945;v&#946;6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies. Uusi-Kerttula, H., Davies, JA., Thompson, JM., et al.[2019]

In a phase I trial involving 24 patients with newly diagnosed aggressive non-Hodgkin's lymphoma, lenalidomide was safely combined with R-CHOP chemotherapy, with 25 mg being established as the maximum tolerated dose.

The treatment resulted in a remarkable overall response rate of 100% and a complete response rate of 77%, indicating high efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Nowakowski, GS., LaPlant, B., Habermann, TM., et al.[2020]

In a Phase I trial involving 42 patients with advanced malignancies, tarextumab was found to be generally well-tolerated at doses below 2.5 mg/kg weekly and 7.5 mg/kg every other or every three weeks, with gastrointestinal toxicity being the most common side effect.

The maximum tolerated dose (MTD) was established at 2.5 mg/kg weekly, and the study confirmed that tarextumab effectively inhibits Notch pathway signaling, which is important for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors. Smith, DC., Chugh, R., Patnaik, A., et al.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6505

Phase 1b/2 study of lisaftoclax (APG-2575) combined with ... We evaluated the safety and efficacy of LISA plus AZA in pts with myeloid malignancies. Methods: This open-label, multicenter study enrolled pts ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10330157/

Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory ... This global phase 1 trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3202/529924/Lisaftoclax-APG-2575-a-Novel-BCL-2-Inhibitor-in

Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor, in ... We present follow-up safety and efficacy data from a phase 1b/2 clinical trial evaluating lisaftoclax combined with azacitidine in adults (≥ 18 years) with MDS.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03537482

APG-2575 Study of Safety, Tolerability ,PK/PD in Patients ... Age ≥18 years old. Histologically confirmed diagnosis of either one of the B-cell hematologic malignancies including multiple myeloma, chronic lymphocytic ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7078

Updated efficacy and safety results of BCL-2 inhibitor ... Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1900/500060/Updated-Efficacy-and-Safety-Results-of-Lisaftoclax

Updated Efficacy and Safety Results of Lisaftoclax (APG-2575 ... We report updated efficacy and safety data of pts with CLL treated with lisaftoclax in phase 1b/2 studies APG-2575-CN001 (NCT03913949) and APG- ...

7. 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 ... Lisaftoclax is a novel investigational oral selective Bcl-2 inhibitor that has shown enhanced treatment response when combined with azacitidine in prior ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666634025003125

Safety, tolerability, and pharmacokinetics of lisaftoclax ... Lisaftoclax (APG-2575) is a potent BCL-2 inhibitor (BCL-2i) under clinical development for relapsed and refractory CLL/SLL and other hematologic ...