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

Trial Summary

What is the purpose of this trial?

This is a two Part study in patients with relapsed/refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), or high risk myelodysplastic syndrome (MDS) that will initially evaluate the safety and tolerability of APG-115 as a single agent in Part 1, followed by a combination of APG-115 + 5-azacitidine (5-AZA) in Part 2.

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.

What data supports the effectiveness of the drug combination APG-115 and Azacitidine for treating Acute Myeloid Leukemia?

Azacitidine has been shown to be an effective alternative for patients with acute myeloid leukemia who are not fit for intensive chemotherapy, and it has been used to prolong survival in patients with certain blood disorders. Additionally, combining azacitidine with other agents has shown some promise in improving response rates, although further optimization is needed to enhance its effectiveness and safety. ^{1 2 3 4 5}

What is the safety profile of Azacitidine in humans?

Azacitidine has been studied in many patients and is generally considered safe, though it can cause some side effects like anemia (low red blood cell count), neutropenia (low white blood cell count), and fatigue. Most side effects can be managed with additional medications, and treatment is rarely stopped because of them. ^{3 4 6 7 8}

How is the drug APG-115 + Azacitidine different from other treatments for acute myeloid leukemia?

APG-115 (Alrizomadlin) combined with Azacitidine is unique because it targets specific pathways in cancer cells, potentially offering a new approach for patients who are not suitable for intensive chemotherapy. Azacitidine is already used for patients with acute myeloid leukemia who cannot undergo aggressive treatment, and combining it with APG-115 may enhance its effectiveness. ^{3 9 10 11 12}

Research Team

Yifan Zhai, MD, PhD

Principal Investigator

Ascentage Pharma Group Inc.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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, 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Development of therapeutic agents for older patients with acute myelogenous leukemia. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. [2015]

4. England 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. [2018]

5. United States 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. [2022]

6. Switzerland 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. [2022]

7. United States 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. [2022]

8. United States 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. [2019]

9. Brazil pubmed.ncbi.nlm.nih.gov

Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Azacitidine in Elderly Patients with Acute Myeloid Leukemia with High Blast Counts. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

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