Decitabine + Lisaftoclax + Olverembatinib for Leukemia

Overseen By Nicholas Short, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must be taking: BCR::ABL1 TKI

Must not be taking: CYP3A inducers

Disqualifiers: Pancreatitis, Cardiac failure, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal doses of two new drugs, lisaftoclax and olverembatinib, when combined with decitabine (a chemotherapy drug) to treat certain types of leukemia, specifically advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML). The researchers seek to understand how these drugs can work together effectively to combat these conditions. Suitable candidates for this trial include those diagnosed with CML or Ph+ AML who have not had success with at least one previous treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new drugs.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have taken strong inducers of CYP3A or p-glycoprotein within 14 days before starting the study, and certain recent treatments are restricted. It's best to discuss your current medications with the study team.

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

Research has shown that lisaftoclax has been tested for safety in patients with chronic lymphocytic leukemia. In these studies, 15% of patients experienced serious side effects like a low white blood cell count, while issues like low platelet counts and anemia were less common. Despite these side effects, many patients tolerated the treatment well over multiple cycles.

For olverembatinib, studies on patients with chronic myeloid leukemia (CML) indicate it is generally well-tolerated. Some patients reported side effects like nausea, diarrhea, and tiredness, but these were often mild and manageable.

Decitabine is an approved treatment for some blood cancers. It causes side effects such as low blood cell counts and tiredness, but its widespread use has provided a good understanding of its safety.

Overall, the safety of these drugs when used together remains under study. The current trial aims to find the best doses when combined, a common step in exploring new treatment combinations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Decitabine, Lisaftoclax, and Olverembatinib because they each offer new approaches for treating leukemia. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, Lisaftoclax is designed to specifically target and inhibit BCL-2, a protein that helps cancer cells survive. Olverembatinib, on the other hand, targets specific mutations often found in leukemia cells, potentially offering more precise and effective treatment. In combination with Decitabine, which modifies the DNA of cancer cells to slow their growth, these treatments aim to provide a more targeted and potentially less toxic alternative to current options.

What evidence suggests that this trial's treatments could be effective for advanced CML and Ph+ AML?

Research has shown that decitabine, lisaftoclax, and olverembatinib each offer potential benefits for treating leukemia. Decitabine can slow or stop the growth of cancer cells. Lisaftoclax has proven effective and well-tolerated in patients with chronic lymphocytic leukemia (CLL), even in those with extensive prior treatments. Olverembatinib targets specific proteins that aid cancer cell growth, making it effective for certain leukemia types. This trial will explore the combination of these treatments, which could be promising for individuals with advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML). ^{1 5 6 7 8}

Who Is on the Research Team?

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML). Participants should not have had previous treatments that failed. Specific health conditions and medications may exclude some individuals.

Inclusion Criteria

I am 18 or older with a specific type of leukemia.

My kidneys are working well enough (creatinine clearance ≥30 mL/min).

I have had a bad reaction or no response to a previous BCR-ABL1 TKI treatment.

Exclusion Criteria

Pregnant or breastfeeding women

Participants with psychiatric illness/social situations that would limit compliance with study requirements

I have no allergies to Decitabine, Lisaftoclax, Olverembatinib, or similar drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive varying doses of lisaftoclax in combination with decitabine and olverembatinib to establish the minimum safe and biologically-effective dose

4 cycles

Phase II Treatment

Participants receive lisaftoclax at the recommended dose found in Phase I, in combination with decitabine and olverembatinib

4 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and survival outcomes

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Lisaftoclax
• Olverembatinib

Trial Overview The study aims to determine the safe doses of lisaftoclax and olverembatinib when used together with decitabine in patients with advanced CML or Ph+ AML. It's an early-phase trial, meaning it's mostly about safety and finding the right dose.

How Is the Trial Designed?

Group I: Phase 2 Experimental Treatment 3 Interventions

Participants enrolled in Phase II, participants will receive lisaftoclax at the recommended dose that was found in Phase I

Group II: Phase 1 Experimental Treatment 3 Interventions

Participants enrolled in Phase I, the dose of lisaftoclax you receive will depend on when a participants join this study. Up to 2 dose levels of lisaftoclax will be tested. Between 3-12 participants will be enrolled at each dose level.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Ascentage Pharma Group Inc.

Industry Sponsor

Trials

54

Recruited

5,700+

Published Research Related to This Trial

In a comparison of two combination therapies for acute myeloid leukemia—glasdegib+low-dose cytarabine (LDAC) and venetoclax+LDAC—no statistically significant differences in overall survival or complete remission rates were found, suggesting similar efficacy.

When choosing between these treatments, factors like safety profiles, ease of administration, and patient preferences will be important since both therapies appear equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. Tremblay, G., Daniele, P., Bell, T., et al.[2021]

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study of 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., et al.[2022]

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

Low-dose decitabine has been shown to improve the overall response rate in elderly patients with acute myeloid leukemia (AML) compared to standard treatment options, although the median overall survival remains less than one year.

The combination of low-dose decitabine with venetoclax significantly enhances both the overall response rate and median overall survival in elderly AML patients, indicating a promising treatment strategy for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. Briski, R., Garcia-Manero, G., Kantarjian, H., et al.[2023]

Citations

1. 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 ... Lisaftoclax demonstrated significant efficacy at 400, 600, and 800 mg, and potentially 200 mg, in pts with R/R CLL who were heavily pretreated ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37074726/

Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory ... Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level.

3. ascentage.com ascentage.com/ash-2023-ascentage-pharma-to-present-results-from-three-clinical-studies-of-bcl-2-inhibitor-lisaftoclax-apg-2575-including-the-first-data-in-aml-and-mm/

ASH 2023 Conclusions: Lisaftoclax demonstrated significant efficacy and favorable tolerability in patients with CLL who were heavily pretreated and had ...

4. cllsociety.org cllsociety.org/2025/08/an-update-on-lisaftoclax-for-cll/

An Update on Lisaftoclax for CLL A total of 176 patients enrolled in the trial; 88% were relapsed / refractory and 12% were treatment-naïve. · 49 patients received lisaftoclax ...

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

Updated efficacy and safety results of BCL-2 inhibitor ... Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), ...

6. 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 ...

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

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

8. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/2326/491382/Lisaftoclax-APG-2575-Safety-and-Activity-As

Lisaftoclax (APG-2575) Safety and Activity As Monotherapy or ... Median exposure to lisaftoclax was 10.0 (0-30) cycles, including 16.5 in the lisaftoclax monotherapy group and 9.0 (1-15) in the rituximab and ...