What side effects are associated with this type of intervention?

Common side effects of BCL-2 inhibitors such as Venetoclax, when used in combination with DNA methyltransferase inhibitors like Azacitidine, include febrile neutropenia, neutropenia, thrombocytopenia, and infections. Other side effects can include gastrointestinal symptoms such as nausea, vomiting, constipation, and diarrhea, as well as hypokalemia and peripheral edema. Azacitidine alone is associated with adverse events like febrile neutropenia, thrombocytopenia, pneumonia, and anemia. These side effects are important considerations for patients undergoing treatment for AML.

What prior FDA approvals exist?

Venetoclax, a BCL-2 inhibitor, has been approved by the FDA for use in combination with Azacitidine for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in adults who are 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy. This combination has demonstrated efficacy in clinical trials, making it a relevant comparison to the APG-2575 and Azacitidine combination currently under study.

What other types of research exist?

Promising alternatives to APG-2575 in combination with Azacitidine for AML patients include: 1) Azacitidine plus Venetoclax, which has shown significant efficacy in combination with HMAs. 2) Azacitidine plus Ivosidenib, particularly for patients with IDH1 mutations. 3) Azacitidine plus Gilteritinib, especially for patients with FLT3 mutations. 4) Decitabine plus Sapacitabine, which has shown comparable outcomes to Decitabine alone. These combinations have demonstrated potential in clinical trials and may be considered as alternatives in 2024.

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Bcl-2 inhibitor

APG-2575 + Azacitidine for Acute Myeloid Leukemia

Phase 1 & 2

Recruiting

Led By Xuemi Sun, MD

Research Sponsored by Ascentage Pharma Group Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia (AML) or mixed phenotype acute leukemia (MPAL) or Chronic Myelomonocytic Leukemia (CMML) or relapsed/refractory Higher-Risk MDS by 2016 WHO classification for which no available standard therapies are indicated or anticipated to result in a durable response.

Relapsed/refractory MDS will be defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy with Overall Revised International Prognostic Scoring System (IPSS-R) score > 3 (intermediate, high or very high).

Must not have

Have acute promyelocytic leukemia (French-American-British Class M3 AML or WHO classification APL with PML-RARA) or AML/MPAL with BCR-ABL1 positive.

Unable to swallow tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 28 days

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug (APG-2575) combined with an existing drug (Azacitidine) to treat certain blood cancers that have not responded to other treatments. The goal is to see if this combination can more effectively kill cancer cells.

Who is the study for?

This trial is for adults with Acute Myeloid Leukemia (AML) or related conditions who have not responded to previous treatments. Participants must be able to swallow tablets, not have other recent cancers except certain skin cancers and in situ carcinomas, and should not have uncontrolled illnesses or infections. They must use contraception if of childbearing potential.

What is being tested?

The study tests APG-2575 combined with Azacitidine in patients with AML. It has two parts: dose escalation to find a safe dosage (Part I), followed by dose expansion to test the effectiveness at that dosage (Part II).

What are the potential side effects?

Potential side effects may include typical reactions from cancer medications such as nausea, fatigue, blood cell count changes leading to increased infection risk, liver enzyme alterations, and possible allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My leukemia has returned or didn't respond to treatment, and standard therapies are not expected to work.

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My MDS did not improve after 4 cycles of HMA therapy or it got worse after initially responding to HMA.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a specific type of leukemia (APL or AML/MPAL with BCR-ABL1 positive).

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I cannot swallow pills or have serious digestive issues.

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My cervical or breast cancer was treated while it was still in the early stage.

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I have recovered from previous cancer treatments, except for hair loss.

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I do not have any severe illnesses that would stop me from following the study's requirements.

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I agree to use birth control during the study.

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I have leukemia in my brain that is not under control.

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I have a type of skin cancer that is either basal cell or squamous cell.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 28 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~28 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 28 days for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

DLT

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: APG2575 + AzacitidineExperimental Treatment1 Intervention

200 mg APG2575 dose ramp up +AZA

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

BCL-2 inhibitors, such as APG-2575, target the BCL-2 protein to promote apoptosis in leukemia cells, while DNA methyltransferase inhibitors like Azacitidine inhibit DNA methyltransferase, leading to hypomethylation and reactivation of tumor suppressor genes. These mechanisms are important for AML patients as they directly target and kill leukemia cells, offering a potential for improved treatment outcomes.

MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models.Role of epigenetic in leukemia: From mechanism to therapy.Emerging Epigenetic Therapeutic Targets in Acute Myeloid Leukemia.