APG-115 + Azacitidine for Acute Myeloid Leukemia

Recruiting at 8 trial locations

Overseen By Angela Kaiser

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ascentage Pharma Group Inc.

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

Disqualifiers: Pregnancy, Active infection, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

69 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for certain blood cancers, such as acute myeloid leukemia (AML), that have not responded to other treatments. The study first evaluates the safety of the drug APG-115 (also known as Alrizomadlin) alone, then examines its effectiveness when combined with azacitidine. It seeks patients with AML, chronic myelomonocytic leukemia (CMML), or high-risk myelodysplastic syndrome (MDS) who have not found relief with standard treatments. This trial may suit individuals with these conditions whose previous treatments have failed. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial group, offering a chance to try a potentially beneficial new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had leukemia therapy for 14 days before starting the trial. Hydroxyurea is allowed to manage white blood cell count before and during the first cycle of the study.

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

Research has shown that APG-115, whether used alone or with 5-azacitidine, is generally safe. Some side effects occur, but they are usually mild and manageable. In studies involving patients with certain types of leukemia or related conditions, APG-115, alone or with 5-azacitidine, did not cause unexpected or dangerous reactions. Most participants managed the side effects without major issues. It is important to note that this information comes from earlier studies, so experiences in new trials might differ. Overall, these findings suggest that APG-115 is relatively safe for use in these situations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about APG-115 for acute myeloid leukemia (AML) because it introduces a new approach by targeting the MDM2 protein, which is involved in regulating the tumor suppressor protein p53. Most treatments for AML, like chemotherapy, aim to destroy rapidly dividing cells, but APG-115 works by reactivating p53, potentially stopping cancer cell growth. In combination with azacitidine, a standard treatment that modifies DNA methylation, APG-115 may enhance the cancer-fighting effects, offering a fresh angle on tackling AML. This novel mechanism of action gives researchers hope for more effective treatments with potentially fewer side effects.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that APG-115, which participants in this trial may receive as monotherapy, may help treat acute myeloid leukemia (AML) by slowing tumor growth and extending survival in animal models. Another group in this trial will receive a combination of APG-115 and 5-azacitidine. Studies have found early signs of effectiveness and safety for this combination in patients whose AML has returned or is difficult to treat. These results suggest that this combination might benefit patients with challenging leukemia cases. While the initial findings are promising, further research is needed to confirm these results in a larger population. ^{1 2 3 4 6}

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 with relapsed or refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), or high-risk myelodysplastic syndrome (MDS). Participants must have a life expectancy of at least 12 weeks, adequate organ function, an ECOG performance status of ≤2, and no severe allergies to the treatments. Pregnant women and those not using contraception are excluded.

Inclusion Criteria

Ability to understand study requirements and signed informed consent

Negative serum pregnancy test required within 1 week for all women of childbearing potential

My liver, kidneys, and heart are functioning well, and I can care for myself.

Exclusion Criteria

I have previously received treatment targeting the MDM2-p53 pathway.

I still have significant side effects from my previous treatment.

Pregnant women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Dose escalation of APG-115 monotherapy using a 3+3 design, administered orally once daily on Day 1-5 every 28-day cycle

28 days per cycle

Treatment Part 2

Dose escalation of APG-115 in combination with 5-azacitidine using a 3+3 design, with 5-AZA administered subcutaneously daily on Day 1-7 every 28 days

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-azacitidine
• APG-115

Trial Overview The study examines APG-115 alone or combined with Azacitidine in patients with certain blood cancers. Initially, it will assess the safety of APG-115 as a single agent; then it will test the combination therapy's effectiveness against these diseases.

How Is the Trial Designed?

Group I: APG-115 monotherapy Experimental Treatment 1 Intervention

Monotherapy given in part 1

Group II: APG-115 + 5-azacitidine combination Experimental Treatment 2 Interventions

Combination therapy given in part 2

Who Is Running the Clinical Trial?

Ascentage Pharma Group Inc.

Lead Sponsor

Trials

54

Recruited

5,700+

Published Research Related to This Trial

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

In a study of 38 acute myeloid leukemia (AML) patients treated with azacitidine, the median overall survival was approximately 10 months for both newly diagnosed and relapsed patients, indicating its efficacy as a treatment option for those unfit for intensive chemotherapy.

The treatment showed a 29% positive effect on reducing transfusion dependency, which was linked to better survival outcomes, highlighting the potential benefits of azacitidine in managing symptoms and improving quality of life for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. Gemuenden, C., Benz, R., Senn, O., et al.[2015]

In a phase 1b/2b trial involving 113 patients with higher-risk myelodysplastic syndromes (MDS), the combination of panobinostat (PAN) and azacitidine (AZA) resulted in a higher rate of composite complete responses compared to AZA alone (27.5% vs 14.3%).

However, the combination treatment did not significantly improve overall survival or time to progression compared to AZA monotherapy, and it was associated with a higher incidence of severe adverse events and on-treatment deaths, indicating a need for further optimization of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Garcia-Manero, G., Sekeres, MA., Egyed, M., et al.[2018]

Azacitidine has been shown to significantly prolong the time to progression to acute myeloid leukemia or death in myelodysplastic syndromes (MDS) patients, with a median time of 21 months compared to 13 months for supportive care in a study of 191 patients.

In a larger trial with 358 patients, azacitidine also significantly improved overall survival, extending it to 24.5 months compared to 15.0 months with conventional care, establishing it as a key first-line treatment for higher-risk MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Fenaux, P., Ades, L.[2022]

Azacitidine (AZA) significantly prolonged overall survival by 3.9 months compared to conventional care regimens in older patients (≥65 years) with acute myeloid leukemia (AML).

Patients treated with AZA experienced lower rates of treatment-emergent adverse events (TEAEs) and related hospitalizations compared to those receiving best supportive care, suggesting that AZA is a safer option for older patients who cannot tolerate intensive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence rates of treatment-emergent adverse events and related hospitalization are reduced with azacitidine compared with conventional care regimens in older patients with acute myeloid leukemia. Seymour, JF., Döhner, H., Minden, MD., et al.[2019]

Azacitidine, a treatment for acute myeloid leukaemia (AML), shows improved survival in patients with low bone marrow blast counts (<30%), but its benefits are significantly reduced in those with higher blast counts (>30%).

A cost-utility analysis revealed that azacitidine has an incremental cost-effectiveness ratio (ICER) of $Can160,438 per quality-adjusted life-year, indicating it is unlikely to be cost-effective compared to conventional care in the Canadian healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Azacitidine in Elderly Patients with Acute Myeloid Leukemia with High Blast Counts. Coyle, D., Villeneuve, PJA.[2020]

Azacitidine is effective for treating adult patients with acute myeloid leukemia (AML) who have 20%-30% blasts and multilineage dysplasia, significantly prolonging median overall survival compared to conventional care, as shown in the AZA-001 phase III trial.

The review also highlights the potential benefits of combining azacitidine with other treatments for AML, suggesting it may enhance patient outcomes further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. Font, P.[2017]

A 52-year-old woman with refractory acute myeloid leukemia (AML) and high-risk genetic abnormalities achieved morphological remission after three cycles of treatment with azacitidine and lenalidomide.

The combination therapy not only led to remission but also resulted in the disappearance of certain chromosomal abnormalities, suggesting that azacitidine plus lenalidomide could be an effective salvage therapy for difficult-to-treat AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report. Todaro, J., Bollmann, PW., Rother, ET., et al.[2018]

In a phase 3 trial involving 488 patients aged 65 and older with newly diagnosed acute myeloid leukemia (AML), azacitidine significantly improved median overall survival to 10.4 months compared to 6.5 months with conventional care regimens (CCRs).

The one-year survival rate was also higher for azacitidine at 46.5% versus 34.2% for CCR, indicating that azacitidine is a promising treatment option for older patients with AML, while maintaining a safety profile consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Dombret, H., Seymour, JF., Butrym, A., et al.[2022]

In a study involving 283 elderly patients with acute myeloid leukemia, the FLUGA regimen showed a higher complete remission rate after 3 cycles compared to azacitidine (18% vs 9%), indicating its potential for initial treatment effectiveness.

Despite the initial remission advantage, azacitidine demonstrated superior overall survival rates at 1 year (47% vs 27%) and longer median overall survival (9.8 months vs 4.1 months), suggesting it may be a better long-term treatment option for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia. Vives, S., Martínez-Cuadrón, D., Bergua Burgues, J., et al.[2022]

Acute myeloid leukemia (AML) treatment has seen little change in 40 years, but new agents like IDH inhibitors and antibody-drug conjugates show promise in improving outcomes, either alone or with traditional chemotherapy.

A variety of novel therapies, including cytotoxic agents, epigenetic modifiers, and targeted inhibitors, are currently being tested in clinical trials, indicating a potential shift in AML management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. Saygin, C., Carraway, HE.[2023]

Acute myelogenous leukemia (AML) is more prevalent in older adults, and traditional chemotherapy may not be suitable for them due to various biological factors, highlighting the need for tailored treatments.

Promising new treatment options for older AML patients include CPX-351, a liposomal formulation of cytarabine and daunorubicin, and other therapies like alvocidib, clofarabine, tipifarnib, decitabine, and azacitidine, which are being evaluated for their efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of therapeutic agents for older patients with acute myelogenous leukemia. Hourigan, CS., Karp, JE.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04358393

NCT04358393 | A Study of APG-115 Alone or Combined ... This is a two Part study in patients with relapsed/refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5954/504636/Alrizomadlin-APG-115-Alone-or-Combined-with

Alrizomadlin (APG-115) Alone or Combined with Azacitidine ... Here, we present safety and efficacy results of this therapy in these pts. Methods. This open-label dose escalation and expansion trial included ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123125535

Alrizomadlin (APG-115) Alone or Combined with ... Alrizomadlin alone or combined with AZA demonstrated a manageable safety profile and preliminary efficacy in pts with R/R AML and HMA-refractory MDS.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8093284/

MDM2 inhibitor APG-115 exerts potent antitumor activity ... APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate ...

5. withpower.com withpower.com/trial/phase-2-leukemia-11-2020-dc602

APG-115 + Azacitidine for Acute Myeloid Leukemia In a study of 38 acute myeloid leukemia (AML) patients treated with azacitidine, the median overall survival was approximately 10 months for both newly ...

6. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/11659/487639/Trial-in-Progress-Phase-1b-2-Study-of-Alrizomadlin

Trial in Progress: Phase 1b/2 Study of Alrizomadlin (APG-115 ... This multicenter trial is evaluating alrizomadlin alone or in combination with AZA in patients with AML, CMML, or MDS in order to determine dose-limiting ...