What is the mechanism of action of this treatment?

The most common treatments for Prolymphocytic Leukemia (PLL) include targeted therapies such as MDM2 inhibitors and Bcl-2 inhibitors. APG-115, an MDM2 inhibitor, works by blocking the MDM2 protein, thereby enhancing the activity of the tumor suppressor p53, which leads to increased cancer cell death. APG-2575, a Bcl-2 inhibitor, targets the Bcl-2 protein that prevents apoptosis, promoting programmed cell death in cancer cells. These mechanisms are significant for PLL patients as they offer a targeted approach to treatment, potentially improving efficacy and reducing side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

MDM2 inhibitors, such as APG-115, commonly cause side effects including nausea, fatigue, thrombocytopenia (low platelet count), and neutropenia (low white blood cell count). Bcl-2 inhibitors, like APG-2575, are known to cause side effects such as neutropenia, thrombocytopenia, anemia, and gastrointestinal issues like diarrhea and nausea. Both types of inhibitors can also lead to an increased risk of infections due to their impact on blood cell counts.

What prior FDA approvals exist?

Prolymphocytic Leukemia (PLL) has limited FDA-approved treatments. Historically, treatments have included purine analogs like cladribine and pentostatin, and monoclonal antibodies such as alemtuzumab. More recently, targeted therapies have gained attention. Venetoclax, a Bcl-2 inhibitor, has shown promise in treating various leukemias, including PLL, due to its mechanism of inducing apoptosis in cancer cells. While there are no specific FDA approvals for MDM2 inhibitors in PLL, the ongoing study of APG-115 (MDM2 inhibitor) and APG-2575 (Bcl-2 inhibitor) reflects a growing interest in these targeted therapies for managing PLL.

What other types of research exist?

Promising novel alternatives for T-PLL patients in 2024 may include: 1) Venetoclax (Bcl-2 inhibitor) which has shown efficacy in various hematologic malignancies, 2) CAR T-cell therapies targeting specific antigens on T-PLL cells, and 3) novel MDM2 inhibitors currently in clinical trials. These alternatives should be discussed with a healthcare provider to determine the best personalized treatment plan.

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MDM2-p53 Inhibitor

APG-115 + APG-2575 for Leukemia

Phase 2

Recruiting

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

Require laboratory TLS parameters to be within acceptable range and clinical TLS parameters no higher than grade 2 at study baseline, with or without TLS treatment, before initiation of study treatment.

Adequate kidney function, defined as a calculated creatinine clearance ≥ 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula

Must not have

Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies)

Patients with COVID-19 who are tested with positive swab.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 21 days

Awards & highlights

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects of APG-115 and APG-2575 may include reactions related to the immune system, liver issues reflected by blood tests changes, fatigue, digestive disturbances such as nausea or diarrhea, skin reactions and increased risk of infection.

Eligibility Criteria

Inclusion Criteria

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

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

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My kidneys work well, with a creatinine clearance rate of at least 50 mL/min.

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My liver enzymes are within acceptable limits.

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I am 18 years old or older.

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I can take care of myself and am up and about more than half of my waking hours.

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I have T-PLL that has come back or didn't respond to treatment and I've had at least one prior therapy.

Exclusion Criteria

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

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I have been diagnosed with HIV.

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I have tested positive for COVID-19.

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I need treatment for graft versus host disease or must continue taking drugs that suppress my immune system.

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I do not have any severe illnesses that could interfere with the study.

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I have been treated with an MDM2 inhibitor before.

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I have an active brain tumor that is not under control.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 21 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~21 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 21 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

Maximum tolerated dose of APG-115

Maximum tolerated dose of APG-115+APG-2575

Awards & Highlights

No Placebo-Only Group

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

Trial Design

3Treatment groups

Experimental Treatment

Group I: APG-115 monotherapy partExperimental Treatment1 Intervention

APG-115 will be given alone

Group II: APG-115 + APG-2575 combination dose expansion partExperimental Treatment2 Interventions

APG-115 is given in combination with APG-2575

Group III: APG-115 + APG-2575 combination dose escalation partExperimental Treatment2 Interventions

APG-115 is given in combination with APG-2575

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

APG-115

2016

Completed Phase 1

~50

0 / 12Eligibility 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

The most common treatments for Prolymphocytic Leukemia (PLL) include targeted therapies such as MDM2 inhibitors and Bcl-2 inhibitors. APG-115, an MDM2 inhibitor, works by blocking the MDM2 protein, thereby enhancing the activity of the tumor suppressor p53, which leads to increased cancer cell death. APG-2575, a Bcl-2 inhibitor, targets the Bcl-2 protein that prevents apoptosis, promoting programmed cell death in cancer cells. These mechanisms are significant for PLL patients as they offer a targeted approach to treatment, potentially improving efficacy and reducing side effects compared to traditional chemotherapy.

Immunotherapy based approaches in myelofibrosis.Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 clinical study with biomarkers of angiogenesis.Thalidomide as a novel therapeutic agent: new uses for an old product.